Metabolic, Traumatic, and Miscellaneous Diseases

C H A P T E R

16 Metabolic, Traumatic, and Miscellaneous Diseases William W. King1, Michael T. Drake2,3 1

Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI, United States; 2Research Resources Facilities, University of Louisville, Louisville, KY, United States; 3Division of Comparative Medicine, Washington University School of Medicine, St. Louis, MO, United States

I. INTRODUCTION Success in producing and managing specificpathogen-free status has greatly reduced the potential for inadvertent introduction of infectious agents into contemporary rodent colonies. Enhanced understanding of the nutritional requirements for these species has produced improved growth and reproduction rates. While challenges in addressing management-related, neoplastic, and microbial-based diseases undoubtedly remain, perhaps opportunities for more significant advances exist in further defining noninfectious diseases of laboratory rats. To further remove these sources of pain, distress, and model system variability, recognition of congenital, degenerative, traumatic, and other spontaneous diseases is paramount. This chapter reviews noninduced diseases not associated with infectious agents or neoplasia. While a work of this scope could diverge into a general description of all lesions described in laboratory rats, the authors have attempted to focus primarily on those conditions that either result in recognized clinical signs or are likely to be identified in postmortem examinations by the laboratory animal clinician. The term “recognized,” however, is an admitted shortcomingdattempts to distinguish incidental findings from clinically relevant conditions may simply represent an inability to appreciate subtle clinical signs in laboratory rodents. Nonetheless, for a more encyclopedic description of lesions that have been discovered in rats and their significance, the reader is referred to one of the many texts and online resources devoted to the pathology of this species. In companion animal practice, some of the more commonly identified nonneoplastic, noninfectious

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diseases include ulcerative dermatitis (UD), “ringtail,” pododermatitis, malocclusion, chronic renal disease, or radiculoneuropathy (Brown and Donnelly, 2012; Fallon, 1996); environmental and standard husbandry practices in modern vivaria often control for some of these disorders. At least historically, the incidence of noninfectious, nonneoplastic causes of spontaneous death has been estimated at 29.0% in males and 12.0% of females (Ettlin et al., 1994), mostly associated with age-related diseases. In specific-pathogen-free rats, the most significant sources of morbidity are neoplasia, chronic progressive nephropathy (CPN), myocardial degeneration, and polyarteritis nodosa (PAN) (Berg and Simms, 1960; Coleman et al., 1977; Ettlin et al., 1994; Keenan et al., 1995b; Maeda et al., 1985). Other frequently cited lesions include radiculoneuropathy, skeletal muscle degeneration, and bile duct hyperplasia (Anver et al., 1982; Coleman et al., 1977). Interestingly, many of these diseases may be coincidental, e.g., hypertension, CPN, PAN, and myocardial degeneration (Barthold et al., 2016; Bishop, 1989; Rapp, 1973; Saito and Kawamura, 1999; Weber et al., 1990, 1993; Wexler et al., 1981; Wilens and Sproul, 1938b). As additional information elucidates the aging process and associated cellular degeneration, these and other relationships may be clarified. A concerted effort to summarize documented incidence rates of various disorders has been made in this chapter. A vital component of appreciating a condition’s significance is an understanding of its possible genetic predisposition. Highlighting stock and strain differences may also yield important clues to pathogenesis and prevention. Strict interpretation of incidence rate has risks, however, depending on the intent of the referenced

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16. METABOLIC, TRAUMATIC, AND MISCELLANEOUS DISEASES

report and attention to what might be considered “incidental” by the author, e.g., a summary of all lesions regardless of severity versus those thought related to morbidity/mortality. In an attempt to control some of this variability, the incidence rates in the tables cite, when available, only those animal groups with disease of moderate or greater severity, and therefore more likely to be of clinical significance. Other causes of variability include genetic drift, the use of different diets, the criteria and statistical methods used by the pathologist to identify lesions (Roe, 1994), environmental conditions, husbandry practices, specific health status, and even individual animal differences. Differences accorded to sex, which may be illustrated when strain, diet, health status, and age are controlled for, may be attributable to the hormonal milieu, but might also be indirectly related to differences in body weight and/or conformation (Berg and Simms, 1960). Thus, while the specific incidence rate values themselves should be interpreted cautiously, general trends should provide useful tools to the clinical diagnostician. A note should be made regarding the impact of ad libitum feeding on degenerative diseases. The beneficial effects of dietary restriction have been touted since the 1930s (Cornwell et al., 1991). Commercial rodent diet formulations optimize early development, growth, and the increased metabolic demands of reproduction and lactation (Goldstein et al., 1988). Therefore, older and more sedentary rats may suffer the consequences of overfeeding afforded by the common practice of ad libitum feeding (Keenan et al., 1995a). In fact, enhanced growth rates and increased body weight have been cited as culpable for dramatic reductions in the survivability of many rat stocks and strains (Keenan et al., 1995b; Rao et al., 1990). Although feed restriction involves an initial stress response as evidenced by behavioral assays (Heiderstadt et al., 2000), even moderate dietary restriction in rats has a significantly positive effect on life span, primarily through the impact on spontaneous diseases such as CPN and cardiomyopathy (Keenan et al., 1994, 1995b; Masoro, 1991; Masoro et al., 1991; Roe et al., 1991). Levels as low as 10% restriction result in significant improvements in a “doseeresponse” manner (Duffy et al., 2004a, 2004b). The contribution of protein and calories to overfeeding continues to be debated, and may be organ or disease specific (Keenan et al., 1995a; Maeda et al., 1985; Masoro et al., 1989; Rao et al., 1996). Calorie restriction may circumvent the course of aging (Stern et al., 2001) by optimizing energy utilization through cellular mechanisms such as glucocorticoid or glucose metabolism, or free oxygen radical production (Masoro et al., 1991).

Various methods of limiting caloric intake have been explored. Formulations of diets with lower protein and higher fiber content effect reductions in body weight and subsequently striking declines in both the incidence and the severity of chronic renal and cardiac disease (Haseman et al., 2003; Rao et al., 2001). Otherwise, restricting food amounts to laboratory rodents presents considerable challenges. A precise, automated method of dispensing limited feed amounts based on weight rather than volume has been described (Petruska et al., 2001). Supplying measured quantities also generally depends upon individual housing, which eliminates opportunities for social engagement. Automated access via individual microchipping in group-housed rats has been explored, but is likely cost prohibitive for widespread use (Kasanen et al., 2009). Kasanen et al. described the use of a “diet board,” in which feed pellets are fixed into small hardwood planks requiring gnawing for feed access and resulting in a 15% reduction in body weight with no apparent ill effects in group-housed rats (Kasanen et al., 2009a, 2009b). Unconditional concerns that dietary restriction in a group-housing setting risks increased cage-mate aggression and inadequate feed intake in animals with lower social standing may be unfounded. Studies by Moneo et al. (2017) identified little aggression among cage-mates despite a 70% reduction in diet, suggesting the feasibility of simply restricting feed access in group-housed rats. It is conceivable that further advancements will result in dietary restriction as the standard for rats, thus avoiding the health- and research-related complications associated with ad libitum feeding. Should this prove successful, the incident rates of many of the disorders described in this chapter will probably be dramatically affected. Note, however, that given its current widespread use, the incident tables included in this chapter reflect only animals fed ad libitum. Similarly, microbiota status profoundly affects the onset and severity of spontaneous diseases. Germ-free rats are resistant to CPN (Barthold et al., 2016), myocardial degeneration, and PAN (Pollard and Kajima, 1970), but are more susceptible to urolithiasis (Gustafsson and Norman, 1962). Effects of microbiota on numerous animal models of disease, ranging from obesity and metabolic diseases to inflammation-related disorders, and behavior, are profound (Hansen et al., 2014; Hakkak et al., 2017). Reduced incidence of degenerative disease may be related to the relative caloric restriction in germ-free environments (Cornwell et al., 1991). Heightened awareness and interest in studying both axenic and gnotobiotic animals could reveal additional insight into the relationship between dietary restriction, microbiota, and age-related illnesses.

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II. CARDIOVASCULAR SYSTEM

II. CARDIOVASCULAR SYSTEM A. Congenital Heart Defects A survey of SpragueeDawley (Hsd:Spraguee Dawley SD) fetuses revealed cardiac defects in approximately 2.3% of the fetal hearts, including dextrocardia, atrial and ventricular septal defects, endocardial cushion defecteventricular attachments, and aortic valve defects (Johnson et al., 1993). The OlsoneGoss subline of the LongeEvans rat has been reported to have a 30% incidence of congenital membranous interventricular septal defects, compared with 4% in the California subline (Fox, 1969; Jimenez-Marin, 1971). In addition, a high rate of ventricular septal defect with biventricular hypertrophy and associated pulmonary regurgitation has been reported in normotensive WistareKyoto rats. Other abnormalities observed included valvular defects and patent ductus arteriosus (Slama et al., 2002). An increased frequency of persistent ductus arteriosus has been described in a strain of epilepsy-prone rats (GEPR) originally derived from a SpragueeDawley stock (Spier et al., 2005) and also in the Brown Norway (BN) strain (Bokenkamp et al., 2006; Hsieh et al., 2014; Kota et al., 2007). The BN strain is also noted to have an increased number of ruptures in the internal elastic lamina in the abdominal aorta, iliac, and renal arteries (Behmoaras et al., 2005; Capdeville et al., 1989; Kota et al., 2007).

B. Myocardial Degeneration and Fibrosis Myocardial degeneration and fibrosis relate to atrophy and scarring of the heart muscle. This can include cardiomyocytes with varying degrees of vacuolation, necrosis, infiltration of affected areas with inflammatory infiltrates, and resultant fibrosis (Jokinen et al., 2005, 2011). Some of the earliest literature describing lesions in older rats involves the cardiovascular system. In a pair of surveys of spontaneous cardiovascular diseases, Wilens and Sproul (1938a, 1938b) discussed intracardiac thrombosis, chronic auriculitis, endocarditis, coronary artery sclerosis, cardiac hypertrophy, pericarditis, and calcification of various arteries. Noting the relative paucity of literature on cardiovascular lesions in laboratory rats, these authors also recognized that the significance of myocardial degeneration and fibrosis was far greater than other spontaneous diseases of this system. Others have noted that this disorder ranks third behind neoplasia and chronic renal disease for causes of mortality in SpragueeDawley rats (Keenan et al., 1995b). The onset of myocardial degeneration varies with age, sex, and strain. Lesions are commonly found in laboratory rats beginning at 12 months, with the incidence and severity increasing with age (Anver and Cohen,

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1979; Lewis, 1992). Myocardial degeneration occurs more commonly and at an earlier age in males (Barthold et al., 2016; Keenan et al., 1995b), which also develop more severe, multifocal lesions, contrasting with the focal lesions seen in females (Dixon et al., 1995). The incidence has been estimated at 80.7% in Fischer 344 (F344) males (Maeda et al., 1985), and 73.2%e85.9% in SpragueeDawley stocks (Anver et al., 1982; Cohen et al., 1978). Conversely, germ-free rats may be resistant to myocardial degeneration (Pollard and Kajima, 1970). Cardiomyopathy is another term that has been applied to degenerative myocardial lesions that result in fibrosis (Jokinen et al., 2005). In particular, a retrospective evaluation of studies in F344 rats by the National Toxicology Program identified varying degrees of spontaneous cardiomyopathy, i.e., not related to treatment, with greater extent of involvement in the left ventricular wall, interventricular septum, and right ventricle. Consistent with other cardiac abnormalities, the review found these spontaneous degenerative lesions to be more common with age and at an increased frequency in males (Jokinen et al., 2005, 2011). However, associated necrosis and inflammatory cell infiltrate can be observed as early as 3e4 months of age (Berridge et al., 2016; Jokinen et al., 2011). Table 16.1 summarizes various reported age, sex, and stock/strain incidences of myocardial degeneration and fibrosis. In most cases, lesions are discovered during routine or scheduled necropsy with no appreciable clinical signs (Anver et al., 1982; Keenan et al., 1995b). Although slight variations in electrocardiogram findings have been noted (Berg, 1955), microscopic evidence of congestive heart failure is usually absent (Cornwell et al., 1991). Differences in most physiological indices of cardiac function in Wistar rats between 6 and 12 months of age are insignificant (Lee et al., 1972); however, the rate of myocardial degeneration is typically low in this strain. A correlation between the onset and progression of myocardial fibrosis in F344 rats between 20 and 29 months of age and increased end-diastolic pressure suggests that subtle cardiac functional changes may be present although clinically unapparent (Anversa and Capasso, 1991). Lesions may be difficult to discern grossly, although foci of pale to grayish tissue may be present in severe cases (Anver and Cohen, 1979; Barthold et al., 2016). Foci are often distributed randomly (Dixon et al., 1995), but with a predilection for the left ventricular papillary muscles, their sites of attachment, and the interventricular septum (Anver and Cohen, 1979; Barthold et al., 2016; Simms and Berg, 1957). Histological evidence follows a progression of myocardial atrophy, necrosis, and focal interstitial myocarditis composed primarily of mononuclear cells, followed by interstitial fibrosis and accumulation of fibrous connective tissue

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654 TABLE 16.1

16. METABOLIC, TRAUMATIC, AND MISCELLANEOUS DISEASES

Stock/Strain, Age, and Gender Distribution of Myocardial Degeneration and Fibrosis in Laboratory Rats. Incidence (%)* of Myocardial Degeneration and Fibrosis 0e52 Weeks of Age

53e104 Weeks of Age

>104 Weeks of Age

Stock/Strain

Male

Female

Male

Female

Male

Female

Reference

Fischer 344

79.1

22.8

d

d

d

d

Dixon et al., 1995

0.0e46.1

d

35.0e75.0

d

76.6e86.7

d

Coleman et al., 1977

d

d

d

d

33.1

17.6

Goodman et al., 1979

10.9

0.0

19.0e34.7

5.2e12.5

31.1

15.0

Biology Databook Editorial Board, 1985

18.0e33.3

d

51.7e74.6

d

75.0e100.0

d

Maeda et al., 1985

32.1 (between 0 and 9 months)

11.1 (between 0 and 9 months)

d

d

d

d

Hall et al., 1992

67.9 (by 6e9 months)

22.2 (by 6e9 months)

d

d

d

d

Hall et al., 1992

d

d

d

d

40.2

18.9

Goodman et al., 1980

d

d

65.6

d

d

55.3

Wilens and Sproul, 1938a

0.0

0.0

9.4e19.2

0.0e4.5

16.9

7.7

Biology Databook Editorial Board, 1985

2.4

0.0

2.1e3.8

0.0e1.9

21.8

8.3

Biology Databook Editorial Board, 1985

90.0

14.0

16.0

5.6

d

d

Lewis, 1992

0.4

d

1.2

d

2.2e3.4

d

Cornwell et al., 1991

OsborneeMendel

SpragueeDawley

LobundeWistar

* Age distributions were not consistent in all references cited. Some references may have stated average age rather than age ranges; such values were approximated in the divisions employed this table. It should also be noted that some references may have used smaller age ranges, or even more divisions among age ranges; these were included with similar age groups for ease of comparison.

(Anver et al., 1982; Coleman et al., 1977; Dixon et al., 1995; Jokinen et al., 2011; Keenan et al., 1995b, Fig. 16.1). As severity increases, lesions coalesce to form large areas of fibrous tissue with mineralization (Masoro et al., 1989). Mineralization, which may be associated with concurrent with renal or parathyroid disease, may be observed more frequently in aged, male rats (Ruben et al., 2000). Numerous predisposing factors have been proposed in the pathogenesis of myocardial degeneration and fibrosis in rats. The lesions have been suggested to be primarily of inflammatory origin as a sequela of chronic myocarditis or myocardial ischemia (Coleman et al., 1977; Fairweather, 1967). A strong correlation exists between the onset and severity of cardiomyopathy and CPN suggesting a developmental relationship between these two significant age-related diseases (Maeda et al., 1985). Dietary restriction, or diets with lower protein and/or calorie and higher fiber content, reduces both the incidence and the severity of cardiomyopathy in

FIGURE 16.1 Myocardial degeneration and fibrosis. Affected animal (left) shows atrophy and loss of ventricular myofibers with vacuolar degeneration and interstitial fibrosis compared with normal animal (right). H&E stain; bar, 50 mm. Image courtesy of the Unit for Laboratory Animal Medicine, University of Michigan.

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II. CARDIOVASCULAR SYSTEM

several rat stocks and strains (Duffy et al., 2004a; Keenan et al., 1994; Maeda et al., 1985; Masoro et al., 1989; Rao et al., 2001), with differences evident by 30 weeks of age (Cornwell et al., 1991). This may be related to the reduction of CPN with dietary restriction, although some diets affecting CPN do not prevent myocardial fibrosis (Iwasaki et al., 1988). Certain forms of renovascular hypertension lead to cardiac myocyte necrosis and fibrosis, although the mechanisms are not clear (Weber et al., 1990). The relationships between hypertension, CPN, and myocardial fibrosis warrant further investigation (Weber et al., 1993).

C. Intracardiac Thrombi Intracardiac thrombi in one or more heart chambers are not uncommon. The incidence of this ageassociated condition varies between stocks and strains, ranging from 0.5% in SpragueeDawley to 2.1% in F344 (Biology Databook Editorial Board, 1985), 0%e6.4% in OsborneeMendel (Biology Databook Editorial Board, 1985; Wilens and Sproul, 1938a), and 3% of female, 12% of male BN/Bi rats (Burek, 1978; Carlton and Engelhardt, 1991a). Although thrombi may be encountered in any chamber, the left atrium is most frequently affected (Carlton and Engelhardt, 1991a; Lewis, 1992; Yoshizawa et al., 2005). Grossly, thrombi are characterized as firm, laminated, gray-red masses that progress to wellorganized accumulations of fibrous connective tissue seen in histological sections (Ayers and Jones, 1978). Older thrombi may involve the endo- and myocardium (Anver and Cohen, 1979). Large thrombi may induce pulmonary congestion and ventricular hypertrophy (Lewis, 1992).

D. Valvular Endocardiosis Heart valve thickening with myxomatous connective tissue in aging rats has been referred to as valvular endocardiosis, spontaneous valvulopathy, chronic valvular fibrosis, chronic valvular disease, valvular myxoma, myxomatous degeneration, mucinous degeneration, and valvular endocarditis (Ayers and Jones, 1978). This lesion affects up to 10% of rats in some SpragueeDawley colonies, usually involving the atrioventricular valves (Anver et al., 1982; Johnson and Nyska, 2017a). Although there are no known clinical effects, these masses microscopically resemble those associated with systolic murmurs and congestive heart failure in dogs (Anver and Cohen, 1979; Ayers and Jones, 1978).

E. Endocardial Proliferative Lesions Endocardial and subendothelial proliferative lesions have been noted in many stocks and strains of rats.

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The condition, also described as (sub)endocardial fibrosis, fibroelastosis, endocardiosis, or endocardial fibromatous proliferation, is without sex predilection, but is generally seen in animals older than 71 weeks of age (Boorman et al., 1973; Novilla et al., 1991), although it is reported younger rats (Frith et al., 1977). Microscopically, the lesions are composed of endocardial accumulations of fibroblast-like cells, with occasional lymphocytic infiltration, expanding into grossly evident tumors penetrating the myocardium (Boorman et al., 1973; Zaidi et al., 1982). They have also been described as a thin layer of mesenchymal cells with little myocardial infiltration (Berridge et al., 2016). The nature of these lesions is controversial (Boorman et al., 1973; Frith et al., 1977), with some authors suggesting these masses are intermediate forms of developing Schwann cell malignancies (Alison et al., 1987), and others making distinctions between neoplasia and fibroproliferative masses based on the discrete morphological features (Novilla et al., 1991). The stock/strain-related differences in the occurrence of these lesions range from 1% in the Wistar-derived CIVO rats to 4% in the Wistar-derived SAG/Rij and 7% in the BN (BN/Rij) rat (Boorman et al., 1973). An overall incidence of 0.2% has been described in F344, Wistar, SpragueeDawley, and LongeEvans rats (Novilla et al., 1991); one report documented a 1.25% incidence in a SpragueeDawley colony (Zaidi et al., 1982).

F. Polyarteritis Nodosa Although described in dogs, cats, and various other mammals, PAN, often observed grossly in the mesentery as thickened, tortuous vessels, has been principally characterized in laboratory rats (Bishop, 1989). The first survey of inflammatory vascular wall lesions in rats provided by Wilens and Sproul (1938b) described a 9.7% incidence of periarteritis in an OsborneMendel colony. Polyarteritis was attributed as the cause of death (or euthanasia in extremis) in 19.2% and 7.5% male and female OFAeSandoz (SpragueeDawley-derived) rats, respectively (Ettlin et al., 1994). Polyarteritis is considered a degenerative disease of aging rats and often identified as an incidental finding except in more severe cases (Carlton and Engelhardt, 1991b; Skold, 1961). Early reports discussed a preponderance in females (Cutts, 1966; Wilens and Sproul, 1938b), although more recent references describe a predisposition in males (Barthold et al., 2016; Bishop, 1989; Yang, 1965). Incidence rates in various arteries differ greatly (Table 16.2). Polyarteritis occurs with increased frequency in SpragueeDawley (Simms and Berg, 1957; Yang, 1965), spontaneously hypertensive rat (SHR; Race and Peschel, 1954; Saito and Kawamura,

CLINICAL CARE AND DISEASE

TABLE 16.2

Stock/Strain and Age Distribution of Laboratory Rats With Lesions Associated With Polyarteritis Nodosa.

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Incidence (%)e of Polyarteritis Nodosa Stock/Strain

0e52 weeks of Age

52e110 weeks of Age

110e128 weeks of Age

>128 weeks of Age

Reference

F344

0.0

0.0

0.2

0.0

Biology Databook Editorial Board (1985)

e

Coleman et al. (1977)

1.6 p

e

2.4 s OsborneeMendel

August

CLINICAL CARE AND DISEASE

SpragueeDawley

b

SpragueeDawley

c

SpragueeDawley

d

1.0

0.0

0.0

Biology Databook Editorial Board (1985)

0.0

3.0

13.1

15.7

Wilens and Sproul (1938b)

0.0

36.4

75.0

85.7

Opie et al. (1970)

0.0

0.0

25.9 t

48.8 t

Anver et al. (1982)

15.4 s

28.6 s

17.6 m

22.2 m

9.4 p

16.3 p

9.1 t

35.3 t

e

Anver et al. (1982)

9.1 s

15.2 s

18.2 m

14.7 m

18.2 p

2.9 p e

Cohen et al. (1978)

0.0

9.2 p

e

13.1 s 0.6

3.1

1.8

6.5

Biology Databook Editorial Board (1985)

e

14.6

e

e

Yang (1965)

e

e

60.0

e

Berg (1967)

LongeEvans

0.0

0.0

0.0

1.6

Opie et al. (1970)

Stroke-prone SHR

57.1 t

100.0 t

e

e

Saito and Kawamura (1999)

28.6 m

60.0 m

e

42.9 t

e

e

Saito and Kawamura (1999)

Stroke-resistant SHR

28.6 m Wistar

0.0

7.1

0.0

4.3

Opie et al. (1970)

WistareKyoto

0.0

0.0

e

e

Saito and Kawamura (1999)

m, mesenteric artery; p, pancreatic artery; s, splenic artery; SHR, spontaneously hypertensive rat; t, testicular artery. a Crl:COBS[R]CD[R](SD). b Hap:(SD). c Crl:CD(SD)BR. d Designation not specified. e Age distributions were not consistent in all references cited. Some references may have stated average age rather than age ranges; such values were approximated in the divisions employed this table. Some references may have used smaller and/or more divisions or slightly different age ranges or divisions; these were included with similar age groups for ease of comparison.

16. METABOLIC, TRAUMATIC, AND MISCELLANEOUS DISEASES

SpragueeDawley

a

0.0

II. CARDIOVASCULAR SYSTEM

1999; Suzuki et al., 1979), and MendeleShermann rats (Johnson and Nyska, 2017b). A majority of male SHR rats develop PAN by 15 months of age (Bishop, 1989; Suzuki et al., 1979), although there are differences in the histological appearance within this strain (Wexler et al., 1981). Other stocks or strains of rats that have been reported to be affected by PAN include Wistar, LongeEvans (Johnson and Nysak, 2017b), Holtzman, August (Opie et al., 1970), August Copenhagen Irish (ACI/SegHsd) (Cohen et al., 2007), red-hooded (Carlton and Engelhardt, 1991b), and H/C rats (Cutts, 1966). The stock or strain of rat has an impact on the site affected, with medium-sized muscular arteries such as the mesenteric, splenic, testicular, and pancreatic arteries being commonly involved (Anver et al., 1982; Bishop, 1989; Saito and Kawamura, 1999; Skold, 1961).

FIGURE 16.2 Polyarteritis nodosa, mesenteric vasculature, gross appearance. Mesenteric arteries are tortuous and nodular (arrows). Image courtesy of the Unit for Laboratory Animal Medicine, University of Michigan.

(A)

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Other organs with PAN-associated lesions include the kidney, tongue, urinary bladder, brain, salivary glands, liver, thymus, seminal vesicles, lymph nodes, cecum, skeletal muscle, adrenal glands, stomach, intestine, heart, ovary, and uterus (Anver and Cohen, 1979; Anver et al., 1982; Wilens and Sproul, 1938b; Yang, 1965). Lung tissue and the aorta are not affected and arterioles are also sometimes spared (Bishop, 1989; Carlton and Engelhardt, 1991b). Polyarteritis may be grossly visible in medium- to large-sized arteries that appear firm with discolored segmental thickening, tortuous, and nodular with aneurismal dilations and thrombi due to congestion and potential subsequent hemorrhage (Barthold et al., 2016; Bishop, 1989; Carlton and Engelhardt, 1991b; Kohn and Barthold, 1984; Opie et al., 1970, Fig. 16.2). Early changes include fibrinoid necrosis of the intima and media leading to a mixed inflammatory cell population with infiltration and disruption of the media and adventitia (Bishop, 1989; Carlton and Engelhardt, 1991b; Simms and Berg, 1957). Chronic lesions are characterized by intimal proliferation and a marked fibrotic reaction within the adventitia and media; both acute and chronic changes may be appreciated during microscopic evaluation (Anver and Cohen, 1979; Skold, 1961, Fig. 16.3). Subsequent features include stenosis (with or without recanalization), thromboses, and aneurysm formation (Anver and Cohen, 1979; Barthold et al., 2016; Bishop, 1989). Aneurysm formation occurring subsequent to elastic laminar disruption without further evidence of PAN has also been reported in the anterior cerebral artery of a 35-week-old SpragueeDawley rat (Kim and Cervo´s-Navarro, 1991). The differences in onset and severity related to age, strain, and sex indicate multifactorial influences on the development of PAN. An immune-mediated pathogenesis has been proffered (Yang, 1965). In humans, PAN lesions respond to immunosuppressive therapy (Bishop, 1989), and may be seen concurrent with other

(B)

FIGURE 16.3

Polyarteritis nodosa, mesenteric vasculature, histologic appearance. Overview appearance (A) and higher magnification (B) of an affected vessel with fibrinoid necrosis of the vascular wall (arrows), medial and adventitial hypertrophy, and robust periarterial inflammation (asterisk), ranging from neutrophilic to mononuclear. H&E stain; bars, 100 mm (A) and 20 mm (B). Image courtesy of the Unit for Laboratory Animal Medicine, University of Michigan.

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16. METABOLIC, TRAUMATIC, AND MISCELLANEOUS DISEASES

collagen-associated vascular diseases such as rheumatoid arthritis, polymyositis, myocarditis, and dermatitis (Yamazaki et al., 1997). PAN-like lesions may be experimentally induced in rats by administering chemical agents such as 40 -fluoro-10-methyl-1,2-benzanthracene (Hartmann et al., 1959) and dopaminergic agonists (Kerns et al., 1989). Similarly, rats treated with indole 3-carbinol and fitted with telemetric devices were reported to develop PAN, which was prevented by angiotensin-converting enzyme inhibition, suggesting a role of the renineangiotensin system (Peters et al., 2010). A relationship between hypertension and PAN was previously noted. PAN lesions in SHR rats affect testicular arterioles at an earlier age and become more severe in mesenteric arteries, especially in stroke-prone versus stroke-resistant strains, but are absent in the normotensive WistareKyoto rat (Saito and Kawamura, 1999). Various surgical and mechanical renal insults producing renal secondary hypertension can induce PAN (Cutts, 1966; Yang, 1965). Several other factors influence the progression of PAN, including nonspecific stress and reproduction history (Bishop, 1989). A positive correlation between the incidence and the number of pregnancies has been demonstrated in a colony of SpragueeDawley rats (Wexler, 1970), although supplemental estrogen may decrease the age of onset in female hooded (H/C strain) rats (Cutts, 1966). Lesion development adjacent to a pancreatic endocrine tumor in a male Holtzmann rat led to the speculation of a role for pancreatic hormones in the pathogenesis of PAN (Baczako and Dolderer, 1997). Like myocardial and skeletal muscle degeneration, germ-free Wistar rats are reportedly resistant to PAN development (Pollard and Kajima, 1970).

G. Arteriosclerosis and Atherosclerosis Arteriosclerosis is a proliferative and/or degenerative process involving arterial tunica media and intima that results in decreased elasticity and luminal constriction; atherosclerosis, a form of arteriosclerosis, is distinguished by the accumulation of lipid- and inflammatory celleladen plaque (Johnson and Nyska, 2017c). Descriptions of age-associated changes in the arteries of rats have included arteriosclerosis and atherosclerosis of the aorta, carotid, coronary, cerebral, iliac, and renal arteries; aortic and carotid lesions resembling Mo¨nckeberg’s medial sclerosis; and other changes seen in the arterial wall (Anver and Cohen, 1979; Lewis, 1992; Malinow et al., 1956; Wexler and True, 1963). Rats are generally regarded as resistant to atherosclerosis except

following relatively invasive experimental treatments and in those strains specifically bred for studying related cardiovascular diseases, such as the SHR, obese SHR, La/N-cp rat, stroke-prone rat, arteriolipidosis-prone rat, normotensive atherogenic rat, and myocardial infarction rat (Ritskes-Hoitinga and Beynen, 1988). Nonetheless, spontaneous lesions have been described in common stocks and strains. In F344, arteriosclerosis was reported in 0.06% of males over 104 weeks of age (Biology Databook Editorial Board, 1985). Sex-related differences have been shown in OsborneeMendel rats, affecting 10.9% of males and 2.7% of females between 109 and 126 weeks of age (Goodman et al., 1980). Others estimate the incidence in this strain to be approximately 3.3% in animals over 52 weeks of age (Biology Databook Editorial Board, 1985). A difference in the incidence of arteriosclerosis between retired male breeders of one line of SpragueeDawley-derived stocks (Crl: COBS[R]CD[R](SD)) and virgins of another (Hap:(SD)) may be related to either subtle genetic differences or variations induced by reproductive status (Anver et al., 1982). Similar to PAN, repeated breeding appears to increase the likelihood of arteriosclerosis (Wexler, 1964, 1970). Medial calcification tends to occur primarily in the pulmonary artery (Cohen et al., 1978; Coleman et al., 1977; Goodman et al., 1979).

H. Hypertension Hypertension, which can be identified via intraarterial catheter, tail-cuff plethysmography, or telemetry (Plehm et al., 2006), is usually associated with strains bred specifically to develop this condition, such as the SHR and substrains that are susceptible or resistant to the effects of salt, such as Dahl and Sabra (Yagil and Yagil, 1998). Nonetheless, spontaneous hypertension can develop in aged rats of various traditional stocks and strains (Anver and Cohen, 1979). A 46% incidence was reported in male SpragueeDawley rats over 120 weeks of age, which, as with other spontaneous cardiovascular diseases, are more prone to hypertension than females (Berg and Harmison, 1955). Of particular interest is the relationship between hypertension and other age-related, degenerative diseases, including CPN (Alden and Frith, 1991; Magro and Rudofsky, 1982; Rapp, 1973; Rudofsky and Magro, 1982; Wexler et al., 1981), myocardial degeneration (Weber et al., 1990, 1993) and PAN (Bishop, 1989; Rapp, 1973; Saito and Kawamura, 1999; Wexler et al., 1981). Decreased nociception in hypertensive rats, like humans, may have clinical relevance in their care and use (Dworkin et al., 1979; Ghione, 1996; Sacco` et al., 2013).

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III. HEMOLYMPHATIC SYSTEM Extramedullary hematopoiesis (EMH) is characterized by foci of myeloid, lymphoid, and erythroid precursors outside of the bone medulla (Eustis et al., 1990; van Zwieten and Hollander, 1997a). There are conflicting opinions relating to the significance of spontaneous EMH and hemosiderosis in rats; the finding has been considered normal in young animals but with increased frequency in diseased adults. Reports range from over 50% in some SpragueeDawley-derived colonies less than 1 year of age (Anver et al., 1982) to 100% in 19- to 21-week-old F344 rats (Dixon et al., 1995), suggestive of an incidental, regular physiologic occurrence. Conversely, increased EMH can be associated with an underlying pathologic condition (Barthold et al., 2016; Eustis et al., 1990; Suttie, 2006) or occur subsequent to hemorrhage or phlebotomy (Scipioni et al., 1997). Nonetheless, EMH must be distinguished from other conditions such as inflammation or neoplastic activity (van Zwieten and Hollander, 1997a). In some rat strains the incidence of EMH appears to be greater in females (Barthold et al., 2016; Dixon et al., 1995; Suttie, 2006). When present, EMH is found primarily in the spleen, but other sites such as the liver, lymph nodes, adrenal glands, and perirenal adipose tissue can also contain hematopoietic cells (Eustis et al., 1990; van Zwieten and Hollander, 1997a). Spontaneous hemorrhage may occur secondary to hypovitaminosis K in germ-free rats. The absence of gut flora synthesizing vitamin K can lead to increased prothrombin times and result in hemorrhage (Gustafsson, 1948, 1959). In addition, autoclaving of feeds that results in excessive destruction of dietary vitamin K could predispose rats to bleeding (Gustafsson, 1959; Kohn and Barthold, 1984). It has also been reported that certain anesthetic agents administered to rats, notably urethane and ketamineexylazine combinations, can alter coagulation assays (Stringer and Seligmann, 1996). Immunosenescence, especially in the thymus, has been the focus of multiple investigations. This process is characterized morphologically by an age-associated proliferation of thymic epithelial components, including epithelial cords, tubules, and cysts (Cherry et al., 1967; Meihuizen and Burek, 1978). However, it has been reported that there is preservation of the proportion of thymocytes that exhibit a mature phenotype (Quaglino et al., 1998). Sex hormones appear to play a role in thymic involution (Elmore, 2006; Hobbie et al., 2017), advancing more rapidly in males (Kuper et al., 1986). Although some cellular responses from the aging thymus tissue are generally uncompromised (Cherry et al., 1967), thymic involution has been associated with reduced T-cell-dependent function and diminished

immune competence (Aspinall and Andrew, 2000; Gruver et al., 2007; Kuper et al., 1986; Mazzeo, 1994; Shinkai et al., 1997).

IV. RESPIRATORY SYSTEM A. Aspiration Pneumonia One of the more common means of introducing foreign material into the lungs is through the deviation of inoculum from oral gavage. Gavage-associated complications such as aspiration or airway injury are more frequent with gavage volumes at or exceeding 10 mL/ kg of body weight (Brown et al., 2000; Damsch et al., 2011; Eichenbaum et al., 2011). Unintended refluxrelated and adverse respiratory effects may be decreased by reducing the gavage volume and fasting for a period prior to dosing (Damsch et al., 2011; Eichenbaum et al., 2011). Spontaneous aspiration pneumonia is also an occasional finding in older rats (Maeda et al., 1985), or may occur during recovery from general anesthesia in animals recumbent in bedded cages. Inhaled foreign bodies, including dusty bedding and food, result in an inflammatory response (Barthold et al., 2016); microscopic evaluation may reveal traces of plant material and mineral deposits (Kohn and Barthold, 1984) (Fig. 16.4). Although such findings are not uncommon, most are focal and rarely associated with significant disease (Hollander, 1976). Residual endotoxin and other microbial cell wall elements in bedding, even if autoclaved, may induce airway responses in rats, including

FIGURE 16.4

Inhalation (foreign body) pneumonia. Aspirated plant material (arrow) within the bronchiolar lumen surrounded by neutrophilic exudate and peribronchiolar inflammation. H&E stain; bar, 50 mm. Image courtesy of the Unit for Laboratory Animal Medicine, University of Michigan.

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moderate, multifocal, perivascular, and interstitial inflammatory infiltration (Ewaldsson et al., 2002). The morphology of the rat stomach (Luciano and Reale, 1992), the gastroesophageal junction (Montedonico et al., 1999), and the absence of neural circuitry (Horn et al., 2013) have been suggested as reasons that rats cannot vomit (Lennox and Bauck, 2012). As such, aspiration pneumonia following inhalation of vomitus (e.g., during general anesthesia) is improbable. If esophageal disorders are present, however, susceptibility to a secondary inhalation pneumonia may exist (see Gastrointestinal System). Pulmonary emphysema with an age-related tracheal cartilage degeneration and seromucinous adenitis has been described in F344 rats; the use of a rigid, metal gavage cannula or the irritant properties of the inoculated material may have been contributing factors, although spontaneous lesions occurred in untreated rats and may be seen as early as 6 weeks of age (Germann et al., 1995; Germann and Ockert, 1994). These inflammatory lesions were thought to lead to impaired salivation; food and bedding may have become lodged in the oropharyngeal cavity, resulting in asphyxia (Germann and Ockert, 1994). Microscopically, lesions begin as diffuse lymphohistiocytic inflammation of the tracheal seromucinous glands and nodular granuloma formation. This can become extensive at the epiglottise arytenoid junction and lead to osseous metaplasia of the tracheal chondrocytes (Germann et al., 1995).

B. Agent-Induced Pulmonary Edema Pulmonary edema has been noted to occur more frequently in rats dying spontaneously versus those undergoing euthanasia (Maeda et al., 1985). Euthanasia technique, however, has also been shown to have an impact on pulmonary lesions. Danneman et al. (1997) described mild perivascular edema and intraalveolar hemorrhage following euthanasia with pentobarbital, and mild to marked perivascular edema, perivascular hemorrhage, and intraalveolar hemorrhage following euthanasia with concentrations of carbon dioxide ranging from 60% to 100%. Feldman and Gupta (1976) noted that most common methods of euthanasia, including inhalant gas anesthetic and sodium pentobarbital overdose, may all result in some level of pulmonary vascular change, ranging from mild capillary congestion to significant pulmonary edema. Carbon dioxide asphyxiation and physical methods such as decapitation and cervical dislocation may result in frank blood within alveolar spaces (Feldman and Gupta, 1976). In addition to its clinically useful effects of sedation, muscle relaxation, and analgesia, and its negative impact on glucose metabolism (Koppel et al., 1982), the

a2-adrenergic agonist xylazine induces pulmonary edema in rats Miller et al. (2015). When administered intramuscularly at doses of greater than 20 mg/kg, xylazine results in pleural effusion and alveolar edema (Amouzadeh et al., 1991). The optimal “edemagenic” dose is approximately 42 mg/kg, which has been used to study the progression of increased pulmonary vascular permeability (Amouzadeh et al., 1993).

C. Respiratory Effects of Environmental Conditions The impact of environmental contaminants present in housing has been the subject of many investigations. For example, softwood organic compounds are known to influence hepatic enzyme function (Vesell, 1967; Weichbrod et al., 1988) and mortalities have occurred with SpragueeDawley rats housed on cedar wood used as a bedding (Barthold et al., 2016). The sanitation level of primary enclosures has also been cited as a major contributor to hepatic microsome dysfunction (Vesell et al., 1973). Although such changes might result from metabolic toxins other than ammonia (Schaerdel et al., 1983), many have discussed the potential for ammonia-induced toxicity and its effects on pulmonary function. The concentration of ammonia, which is a by-product of bacterial urease breakdown of urine-soiled bedding material, can be quite varied within the environment of rodent primary enclosures. Multiple factors such as caging system and bedding substrate contribute to ammonia levels within the cage (Burn et al., 2006; Ferrecchia et al., 2014; Gamble and Clough, 1976; Koontz et al., 2016; Perkins and Lipman, 1995). Using filtered microisolator cage covers facilitates ammonia accumulation if soiled bedding is not removed within 5 or 6 days (Serrano, 1971). Ammonia levels are lowered considerably in individually ventilated cage systems compared with static caging (Ferrachia et al., 2014; Teixeira et al., 2006). Controversy remains, however, over the minimal concentration of ammonia that is deleterious to laboratory rats and its mechanism of toxicity. Some studies have demonstrated ammonia-induced lesions in nasal passages at low levels (Broderson et al., 1976), whereas others have shown no apparent pulmonary effect (Horn et al., 2012). Exposure of rats to ammonia levels of approximately 200 ppm has resulted in histological changes in the tracheal epithelium in 4 days and epithelial hyperplasia with loss of cilia within 8 days (Gamble and Clough, 1976). Exposure to 500 ppm for 3 weeks induced evidence of nasal and upper respiratory epithelial inflammation; these changes were absent after 8 weeks, suggesting the existence of a compensatory mechanism (Richard et al.,

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1978). However, Schaerdel et al. (1983) found that following a peak in blood ammonia concentration at 8 h, exposure to concentrations over 700 ppm for 7 days failed to incite changes in blood pH or pCO2 and caused minimal lesions within the lung or trachea. These findings also indicated the presence of compensatory metabolic mechanisms (Manninen et al., 1988) and suggested that ammonia concentrations in contemporary rat facilities may have little direct toxicity (Schaerdel et al., 1983). What is evident is the potentiation of environmental ammonia on murine respiratory mycoplasmosis (MRM), a multifactorial condition with decreasing prevalence in contemporary facilities. Ammonia levels as low as 25 ppm increase the severity of MRM-induced lesions (Broderson et al., 1976). Exposure to 50e100 ppm augments the growth of Mycoplasma pulmonis in the respiratory tract of rats and mice (Saito et al., 1982). The enhancement of MRM in the lower respiratory tract is probably a secondary consequence, as most gaseous ammonia is absorbed in the nasal passages (Schoeb et al., 1982). In addition, other bedding-related components may also affect the respiratory pathway, but consideration should be given to underlying pathogen status and potential interactions (Burn et al., 2006).

Fig. 16.5), which were first thought to result from cirrhogenic and protein- or pantothenic acidedeficient diets (Beaver et al., 1963), are considered spontaneous, incidental findings in laboratory rats (Yang et al., 1966). The incidence has been estimated as high as 55.3% and 52.8% in male and female 19- to 21-week-old F344 rats (Dixon et al., 1995). The origin of PFCs remains an enigma. Studies of rats with dietary- and carbon tetrachlorideeinduced hyper b-lipoproteinemia suggest PFCs are lipid-laden monocytes that migrate into pulmonary alveoli (Shibuya et al., 1991, 1995, 1997). Increased concentration of PFCs in conjunction with eosinophilic infiltration has been associated with biotin-deficient diets (Tanaka et al., 1995). Their numbers are greater in lobes with other lesions, such as pneumonia and neoplasia, suggesting a relationship with the liberation of adjacent cellular lipids (Shibuya et al., 1986). Their distribution has led to speculation that their accumulation occurs from the lymphatic system following chronic hypoxic conditions (Wolman et al., 1993). PFCs have also been observed with cryptococcal and Pneumocystis sp. infection (el-Nassery et al., 1994; Goldman et al., 1994). Although a specific etiology has not been identified, it is not thought to be infectious as of this writing.

D. Alveolar Histiocytosis

E. Eosinophilic Granulomatous Pneumonia

An age-related change of questionable clinical significance is the subpleural accumulation of pulmonary foam cells (PFCs), also known as alveolar histiocytes, foamy macrophages, and xanthoma cells, which may be appreciated grossly as pale stippling (Anver and Cohen, 1979; Beaver et al., 1963; Cesta et al., 2015; Herbert et al., 2018). These lipid-laden phagocytes (see

BN rats are known to have hyperresponsive airways under experimental conditions and therefore are commonly used as animal models for associated pulmonary research (Abadie and Prouvost-Danon, 1980; Pauluhn, 2005; Schneider et al., 1997; Takahashi et al., 1990; Tarayre et al., 1992). Eosinophilic granulomatous pneumonia is a condition that can occur in BN rats

(A)

(B)

FIGURE 16.5

Alveolar histiocytosis, gross (A) and histological (B) appearance. (A) Raised yellow-to-white plaques (arrow) are apparent on the pleural surface. (B) Histologically these foci correspond to clusters of infiltrating foamy macrophages (arrows) within alveoli. H&E stain; bar, 20 mm. Image courtesy of the Unit for Laboratory Animal Medicine, University of Michigan.

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that have not been exposed to experimental manipulation (Germann, 1998; Kohn and Barthold, 1984). Young rats of both sexes have been observed with the condition, although various ages can also been affected. Histologically the condition appears as multifocal granulomatous lesions within the lung parenchyma that consist of macrophages, eosinophils, and lymphocytes, with varied amounts of multinucleated giant cells. In addition, accumulation of these inflammatory cell infiltrates can also be observed adjacent to airway and vascular structures (Barthold et al., 2016; Noritake et al., 2007). There are thoughts that the condition may arise from inadvertent exposure to allergens or other ambient particles in the environment (Noritake et al., 2007; Ohtsuka and Doi, 2003). A direct association with an infectious etiology has not been demonstrated (Barthold et al., 2016; Germann, 1998; Noritake et al., 2007).

V. GASTROINTESTINAL SYSTEM A. Malocclusion and Periodontitis A characteristic of the family Muridae is continually erupting (elodontic) incisors that will elongate and overgrow if malocclusion is present (Capello and Lennox, 2012; Emily, 1991; Lennox and Bauck, 2012). Occlusal stress is a primary influence that regulates the rate of incisor eruption, although other components may contribute as well (Kuijpers et al., 1996). Fracture of one incisor is often associated with overgrowth of the opposing one (Barthold et al., 2016; Sharp and LaRegina, 1998), but any genotypic, dietary, infectious, or traumatic condition interrupting the normal apposition and natural attrition of the occlusal surfaces can lead to overgrowth (Bilhun, 1997; Harkness et al., 2010). As rats age it is prudent to monitor and maintain awareness of the condition, especially if rapid weight loss and loss of body condition are observed (Dontas et al., 2010). Malocclusion may lead to a mechanical obstruction of the ability to masticate and dysphagia, ptyalism, anorexia, dehydration, weight loss, and potentially death (Anver and Cohen, 1979; Harkness et al., 2010). Incisor overgrowth may continue until the soft tissues of the palatum or mandible are penetrated (Fig. 16.6) and lead to ulcerative inflammatory lesions, secondary bacterial infections, abscess formation, and cellulitis (Barthold et al., 2016; Brown and Donnelly, 2012; Kuijpers et al., 1996). Ptyalism that is associated with overgrown incisors may also cause moist dermatitis (Harkness et al., 2010). Further, chronic inflammation induced by overgrown incisors has been implicated in the development of a rhabdomyosarcoma (Brockus et al., 1999).

FIGURE 16.6 Malocclusion. Image courtesy of the Research Resources Facilities, University of Louisville.

Overgrown incisors are treated by physically reducing the length of the tooth or teeth involved. Clippers or rongeurs may be used to quickly treat conscious rats, but must be used with caution as the teeth tend to split longitudinally, producing jagged edges and predisposing to apical abscess formation (Emily, 1991). This can be prevented by using a dental drill, bur, small hacksaw blade, or embryotomy wire under sedation or general anesthesia to bring the teeth into occlusion (Brown and Donnelly, 2012; Emily, 1991). A speculum, otoscope, or small tongue depressor may assist in visualizing the site (Harkness et al., 2010). Rats with malocclusion require routine monitoring and regular retrimming (Emily, 1991). Incisors without apposition may be removed, although the extraction procedure may prove challenging due to the length of the tooth roots (Brown and Donnelly, 2012). Personnel working with rats should be trained to recognize the 1:3 ratio of upper to lower incisor crown length to avoid an inappropriate diagnosis of malocclusion (Bilhun, 1997; Lennox and Bauck, 2012). Because spontaneous malocclusion without a history of trauma may have a genetic component, affected animals should not be used for breeding (Harkness et al., 2010; Sharp and LaRegina, 1998). It should be noted that yellowing on the rostral aspect of rodent incisors follows iron deposition and is a normal physiological phenomenon (Brown and Donnelly, 2012), not to be confused with

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discoloration associated with tooth death (Harkness et al., 2010). Periodontitis is not uncommon in older rats. Misaligned incisors can accumulate food fragments at the eruption site and lead to periodontitis. Fibers and chaff from oat and barley have also been associated with increased inflammatory oral disease severity, especially at the level of the first molar (Robinson et al., 1991). Madsen (1989) reported that such chaff predisposes rats to foreign body reactions that can lead to tooth loss, oropharyngeal/oronasal fistulation, and subsequent gastrointestinal air distension, as well as epithelial hyperplasia, metaplasia, and squamous cell carcinoma.

B. Megaesophagus and Gastrointestinal Impaction Sporadic cases of idiopathic megaesophagus have been reported in several stocks and strains (Harkness and Ferguson, 1979). This neuromuscular disorder is characterized by flaccid esophageal enlargement, frequently presenting with feed or bedding accumulation and leading to anorexia or choke (Harkness et al., 2010). Some reports suggest a heritable etiology (Baiocco et al., 1993; Ruben et al., 1983). Fatal esophageal impaction has been implicated in several strains, including Wistar (Hla:(WI)BR; Harkness and Ferguson, 1979), BDE/HAN (Deerberg and Pittermann, 1972), F344 (COBS CD F/CrlBR (Will et al., 1979)), and LongeEvans (Baiocco et al., 1993), and was thought to be the cause of 21% mortality in a Srl:BHE rat colony (Ruben et al., 1983). The condition is associated with various feed formulations, including powdered (Harkness and Ferguson, 1979) and highbulk diets (Will et al., 1979). Will et al. (1979) described a female predilection for acquiring esophageal impaction on standard laboratory diet in F344 rats. In one case report, terminal pneumonia reportedly followed pharyngeal paresis/paralysis-induced dysphagia, a sequela to a large pituitary tumor (Dixon and Jure, 1988). Clinical signs depend on the chronicity of the lesion. In cases of esophageal impaction, rats may display ptyalism, anorexia, dehydration, perioral dermatitis, dyspnea, weakness, emaciation, asphyxiation, or sudden death (Harkness et al., 2010; Ruben et al., 1983; Will et al., 1979). Contrast esophagram reveals thoracic esophageal enlargement (Baiocco et al., 1993). At necropsy, the esophagus may be greatly distended and impacted with material; evidence of bronchopneumonia is frequently present due to aspiration of ingesta (Harkness and Ferguson, 1979). The esophageal musculature is generally thin and atrophied, with inflammation, necrosis, and myenteric ganglion cell loss (Baiocco et al., 1993; Ruben et al., 1983).

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Younger rats are prone to intestinal impaction following ingestion of softwood bedding (Kohn and Barthold, 1984). In one report, the death of 42.9% of suckling rats was attributed to fine particles in sawdust bedding causing obstruction at the ileocecal junction (Smith et al., 1968). Like other species, the use of appropriate analgesia in laboratory rats is a scientific and ethical imperative. The m-opioid agonist buprenorphine has been used with great success to mitigate pain in rats (Johnson, 2016; Seymour et al., 2016; Taylor et al., 2016; Waite et al., 2015). Note, however, that a dose-related gastric distension secondary to ingested bedding following oral or systemic administration of this analgesic has also been described (Bender, 1998; Bosgraaf et al., 2004; Clark et al., 1997, 1995). The incidence of such pica has been estimated at 2%e3%; the effects may commence within 30 min of administration and may be lethal (Jacobson, 2000). In addition, there may also be stock or strain variability with the degree of pica that is exhibited (Thompson et al., 2004). Use of the lowest effective dose and limiting access to readily ingestible bedding following administration of this opioid has been suggested (Flecknell et al., 1999; Jablonski et al., 2001; Jacobson, 2000; Roughan and Flecknell, 2002). In addition, the frequency of the behavior may be reduced by an analgesic strategy that uses decreased dosing intervals when possible (Foley et al., 2011; Schaap et al., 2012). Note that pica in rats may be a response to any gastrointestinal irritation and discomfort, similar to emesis in other species, and may warrant further investigation into causation (Mitchell et al., 1976, 1977; Takeda et al., 1993; Thompson et al., 2004).

C. Trichobezoars Trichobezoars, or hairballs, are generally less common in laboratory rats than in other species such as rabbits. Feeding a casein-based semipurified diet to a WistareKyoto (WKY/NHsd) rat colony resulted in a gastric trichobezoar prevalence of 100% (KrugnerHigby et al., 1996). These rats presented with nonspecific signs of illness, anorexia, and evidence of abdominal pain resolving after conversion to a standard laboratory feed. Gastric trichobezoar development in this colony may have had a genetic component, as Spraguee Dawley rats on the same feed failed to develop clinically significant hairballs. However, others have also reported an increased incidence of trichobezoars in Spraguee Dawley rats fed semisynthetic diets compared with commercial feeds, perhaps related to ulcerative gastritis development (Anastasia et al., 1990). Calorie restriction increases the incidence of intestinal obstruction by trichobezoars, possibly due to increased grooming

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(Masoro et al., 1989), reaching an incidence of 8.4% in an F344 rat colony (Maeda et al., 1985).

D. Gastrointestinal Ulcerative Diseases As noted earlier, traumatic injuries in the upper gastrointestinal tract may be an adverse consequence of oral gavage (Bonnichsen et al., 2005; Brown et al., 2000; Murphy et al., 2001; Nolte et al., 2016; Turner et al., 2012). Technician training, animal acclimation, and minimizing duration of restraint are important considerations when performing this procedure (Turner et al., 2012). Punctate erosions and ulcerations are occasionally seen in the glandular or nonglandular stomach (Fig. 16.7). Gastric ulcer formation appears to be an agerelated phenomenon (Anver and Cohen, 1979), with the incidence varying greatly with strain. Rates for gastric erosions and/or ulcerations have been documented to range between 0.6% (Goodman et al., 1979) and 1.7% (Biology Databook Editorial Board, 1985) for F344, 4.1% (Goodman et al., 1980) and 4.9% (Biology Databook Editorial Board, 1985) for OsborneeMendel, and 1.9% in SpragueeDawley rats (Biology Databook Editorial Board, 1985). Such lesions have been reported in WAG/ Rij, BN/Bi/Rij, and their F1 hybrids (Burek, 1978). Nonspecific stressors, such as those mimicked by immobilization, may result in gastric ulceration (Brodie, 1962; Brodie and Hanson, 1960; Mikhail and Holland,

FIGURE 16.7 Gastric ulceration, evident as black hemorrhagic foci on the mucosal surface of the glandular stomach. Image courtesy of the Unit for Laboratory Animal Medicine, University of Michigan.

1966). Wright et al. (1981) reported a significant increase in multifocal gastric ulcers in diabetic Bio Breeding (BB) Wistar (Bb1:(WI)) rats at a rate of 32.1% versus 9.7% in nondiabetic littermates and none in Wistar controls. The incidence was greater in rats dying spontaneously, suggesting that uncontrolled diabetes led to the formation of stress ulcers. Gastric ulceration is associated with both incidence and severity of CPN (Iwasaki et al., 1988). In one survey, 79% of the cases with gastric ulceration also had severe nephropathy; rats with less severe nephropathy had fewer gastric ulcers, suggesting a relationship with nephropathy-induced uremia (Maeda et al., 1985). Anastasia et al. (1990) described a positive correlation between gastric ulceration and feeding semisynthetic diets, noting that rats on such diets consumed more calories than those fed standard laboratory chow. Reduced gastric inflammation and ulceration is seen in dietaryrestricted rats (Masoro et al., 1989; Shimokawa et al., 1993), which is probably due to reduced nephropathy associated with calorie restriction. Nonsteroidal antiinflammatory drugs (NSAIDs) have been safely used in rats for analgesia under numerous conditions and on many occasions, but in some circumstances with varied efficacy (Caro et al., 2014; Johnson, 2016; Seymour et al., 2016; Waite et al., 2015). The rat may be uniquely susceptible among rodents to gastrointestinal ulceration following NSAID administration (Wilhelmi, 1974), leading to this species’ use in determining the “ulceragenic dose-50 (UD50)” of antiinflammatory compounds (Liles and Flecknell, 1992). For example, a single oral dose of indomethacin results in jejunal epithelial injury within 3e6 h (Nyga˚rd et al., 1994). Inadvertent overdose of rats with flunixin meglumine resulted in fatal perforating ulcers in the jejunum, ileum, and cecum within 4 days after administration (King and Miller, 1997). Other nonsteroidal antiinflammatory agents may also affect the gastrointestinal system (Lamon et al., 2008; Laudanno et al., 2000) and a prudent awareness of careful dosage and management should exist (Shientag et al., 2012). As such, consideration should be given to the use of NSAIDs that are more targeted to the COX-2-specific isoform, with careful attention to therapeutic dosing (Bourque et al., 2010; Burukoglu et al., 2016; Engelhardt, 1996; Mahaprabhu et al., 2011). Rats administered nonphysiological or irritating solutions may also develop erosive or ulcerative conditions of the gastrointestinal tract. These inflammatory conditions can lead to scarring and strictures followed by obstructive lesions and death (Brors, 1987). In addition to its predilection for inducing peritonitis and adynamic ileus (see later), the intraperitoneal or subcutaneous administration of chloral hydrate can cause gastric ulceration (Ogino et al., 1990).

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Multifocal ulcerative typhlocolitis has been reported in Chester Beatty hooded Rowett nude rats (CBH-rnu/rnu) presenting with intermittent, mild diarrhea and subclinical hematochezia (Thomas and Pass, 1997), although the familial history suggested a heritable predisposition, and unidentified infectious etiology could not be excluded because the disease surfaced only after removal of the colony from microbiological isolator housing.

E. Intestinal Dilatation The cecum in germ-free rats can reach up to five times normal size. This is due to the increased luminal osmotic pressure, disruption in the mucosal soluteewater resorption mechanisms because of reduced ion availability and vasoactive compounds, and subsequent smooth muscle atony (Kohn and Barthold, 1984). Increased fluid and semisolid ingesta buildup within the lumen leads to cecal wall thinning (Pollard and Kajima, 1970), predisposing older animals to volvulus and torsion (Kohn and Barthold, 1984). A 630-degree torsion at the ileocecalecolic junction was reported in two male, nonaxenic, SpragueeDawley (Caw:(CFE(SD) SPF)) rats (Pollock and Hagan, 1972). Lipman et al. (1998) described a spontaneous mutation resulting in dilatation of the cecum and proximal colon (familial megacecum and colon), heritable as an autosomal recessive disorder.

F. Injectable Anesthetic-Induced Ileus and Peritonitis Administering various agents to rats via the intraperitoneal route is common, but not without complications (Lee et al., 1994). Intraperitoneal injection of several anesthetic agents can result in life-threatening sequelae. Chloral hydrate concentrations between 125 and 275 mg/mL can result in adynamic ileus, peritonitis, and gastric ulceration (Silverman and Muir, 1993). Clinical signs, including lethargy, unkempt hair coat, anorexia, distended abdomen, constipation, or death, can occur up to 5 weeks after administration, and mortality may exceed 50% of the treated animals (Fleischman et al., 1977). Marked abdominal distension must be differentiated from Tyzzer’s disease (Davis et al., 1985; Kohn and Barthold, 1984). Gross findings include segmental atony and overt distension of the jejunum, ileum, and cecum (Fig. 16.8). Increased intestinal fragility, moderate ascites, and mild to moderate omental, mesenteric, and intestinal adhesions can also occur (Davis et al., 1985; Fleischman et al., 1977; Otto et al., 2015). Although the use of lower concentrations can reduce ileus and inflammatory response to chloral hydrate (Vachon et al., 2000), doses lower than 40 mg/

FIGURE 16.8 Ileus, induced by intraperitoneal injection of chloral hydrate. Rat. In Pathology of Laboratory Rodents and Rabbits, Fourth Edition (Eds., S.W. Barthold, S.M. Griffey and D.H. Percy). 2016, doi: 10.1002/9781118924051.ch02.

mL may produce serositis and other sequelae (Deacon and Rawlins, 1996; Flecknell, 2016; Spikes et al., 1996). Intraperitoneal tribromoethanol (TBE) administration, even at recommended levels of 300 mg/kg, can yield intestinal distension, hepatomegaly, peritonitis, and hepatic capsular fibrosis up to 8 days following injection (Ajadi et al., 2013; Meyer and Fish, 2005; Reid et al., 1999). Fibrous adhesions and ileus following TBE administration have also been reported to result in volvulus (Spikes et al., 1996). Careful attention must be given to dose, preparation, and storage of TBE if its use is deemed appropriate. Although to a lesser extent, intraperitoneal administration of pentobarbital can also result in splenomegaly and moderate peritonitis (Feldman and Gupta, 1976; Spikes et al., 1996).

G. Hepatic and Exocrine Pancreatic Anomalies Hepatodiaphragmatic nodules (HDN) are congenital anomalies resulting from a small mass of liver protruding through, but not perforating, the thin central diaphragmatic tendon into the thoracic cavity (Eustis et al., 1990; Van Zwieten and Hollander, 1997b). Displacement often involves the median or left lateral hepatic lobes (Hall et al., 1992). The diaphragmatic cleft usually results from incomplete fusion of pleuroperitoneal folds (Van Zwieten and Hollander, 1997b). Although HDN is uncommon in most rats, it may occur in 1%e11% of F344 rat colonies (Eustis et al., 1990). Several degenerative hepatic lesions have been described in laboratory rats. Few, if any, are likely to be of clinical significance but may be important in the recognition of experimentally induced changes. These lesions include telangiectasia, periportal hepatocellular vacuolation, hepatocellular necrosis, polyploidy, megalokarya, intranuclear cytoplasmic invagination, intracytoplasmic inclusions, binuclear hepatocytes, foci of sinusoidal dilation, spongiosis, peliosis, areas of

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16. METABOLIC, TRAUMATIC, AND MISCELLANEOUS DISEASES

hepatocellular alteration, EMH, lipidosis, hepatic cysts, and focal granulomas (Barthold et al., 2016; Eustis et al., 1990; Keenan et al., 1995a). Calorie restriction decreases the incidence and severity of many degenerative hepatic lesions (Keenan et al., 1994; Masoro et al., 1989). Bile duct hyperplasia and hepatic cholangiofibrosis are common findings in aging rats (Eustis et al., 1990; Squire and Levitt, 1975). Incidence rates vary with age, strain or stock, sex, and source, and have been reported in 24.5%e98.3% and 12.5% of male and female F344 (Coleman et al., 1977; Goodman et al., 1979),13.4% and 13.1% of male and female OsborneeMendel (Goodman et al., 1980), and 51.9% of male SpragueeDawley (Crl: CD(SD)BR) rats (Cohen et al., 1978). Cholangiofibrosis is uncommon in WAG/Rij and BN/Bi/Rij strains (Burek, 1978). Hyperplastic ductules may become dilated and associated with marked fibrosis, often resulting in the appearance of cirrhosis (Barthold et al., 2016). Exocrine pancreatic acinar atrophy and fibrosis is also a common finding in aging rats (Anver and Cohen, 1979; Kendrey and Roe, 1969; Suttie et al., 2018). As with most degenerative rat lesions, the incidence varies with age, sex, and strain or stock. Rates in OsborneeMendel rats at 109e126 weeks of age have been reported as 2.1% and 0.2% in males and females (Goodman et al., 1980). In F344 rats, the incidence has ranged from 4.9% to 6.9% in males and 3.8% to 5.0% in females of various ages (Coleman et al., 1977; Dixon et al., 1995; Goodman et al., 1979). Up to 40.0% of 12- to 39-month-old male SpragueeDawley (Crl:CD(SD)BR) rats may be affected (Cohen et al., 1978). The pathogenesis of naturally occurring pancreatic atrophy in older rats is largely unknown (Boorman and Eustis, 1997). One curious finding is the presence of pancreatic hepatocytes. These cells, which are microscopically and ultrastructurally identical to hepatocytes, occur spontaneously in rats (Reddy et al., 1984). Increased pancreatic hepatocyte production can be induced by chemical compounds such as 2,6-dichloro-p-phenylenediamine (McDonald and Boorman, 1989), ciprofibrate (Rao et al., 1986; Reddy et al., 1984), and cadmium (Konishi et al., 1990) and by dietary copper depletion (Rao et al., 1986).

VI. URINARY SYSTEM Rats are particularly prone to proximal tubular and renal papillary necrosis following administration of NSAIDs (Alden and Frith, 1991), including salicylate (Kyle and Kocsis, 1985), and acetaminophen (Beierschmitt et al., 1986). Congenital lesions described include persistent urachus in three female Wistar rats (Borra´s, 1983) and ectopic kidney in a female SpragueeDawley

rat (Gupta, 1975). Renal damage can also have iatrogenic origins. For example, vascular catheterization has been reported to cause renal infections (Fonseca et al., 2010). Irregular surface temperatures on a heating source and localized hyperthermia (43 C) resulted in renal damage and hematuria, highlighting the need for careful attention to temperature control in rats undergoing general anesthesia (Roehl et al., 2011).

A. Chronic Progressive Nephropathy End-stage renal disease is the most common agerelated, degenerative condition of laboratory rats and is considered the primary etiology of nonneoplastic mortality (Barthold et al., 2016; Brown and Donnelly, 2012; Ettlin et al., 1994; Otto et al., 2015). It has been noted that other pathological findings are of minor significance by comparison (Owen and Heywood, 1986). Its prevalence in rat colonies has garnered numerous descriptions and terms for this condition, including old rat nephropathy, protein overload nephropathy, chronic renal disease, chronic nephritis, dietary nephritis, glomerulosclerosis, glomerulonephritis, progressive glomerulonephrosis, glomerular hyalinosis, progressive renal disease, chronic progressive glomerulonephropathy, spontaneous nephrosis, and chronic progressive nephrosis, some alluding to the various lesions that develop and others to the condition’s progression (Barthold, 1979; Barthold et al., 2016; Coleman et al., 1977; Rao et al., 1993; Seely and Brix, 2014; Solleveld and Boorman, 1986). The term “chronic progressive nephropathy” has received widespread use and will hereafter be used in this description (Barthold, 1979). Although lesions can be evident at as early as 2e 3 months (Hard and Khan, 2004; Harkness et al., 2010), they tend to be most widespread in rats over 52 weeks of age (Barthold et al., 2016). CPN is more frequently associated with males than with females (Barthold et al., 2016; Ettlin et al., 1994; Kohn and Barthold, 1984; Owen and Heywood, 1986). In one study, CPNassociated mortality occurred from 82 to 188 weeks of age in males, and 85e124 weeks in females (Ettlin et al., 1994). Although the progression of lesions is similar, the reported age of onset, overall incidence rates, and severity vary significantly with stock/strain (Brown and Donnelly, 2012; Goldstein et al., 1988; Gray et al., 1982b, Table 16.3). Some albino stocks and strains (e.g., SpragueeDawley, F344, Wistar) may be more inclined to develop CPN (Gray et al., 1974; Hard and Khan, 2004; Kohn and Barthold, 1984); axenic rats are relatively resistant (Barthold et al., 2016; Harkness et al., 2010; Kohn and Barthold, 1984). Although numerous pathogenic factors are implicated, essentially any nephrotoxic insult eventually

CLINICAL CARE AND DISEASE

TABLE 16.3

Stock/Strain, Gender, and Age Distribution of Moderate or Severe Chronic Progressive Nephropathy. Incidence (%)c of Chronic Progressive Nephropathy 0e25 weeks of Age 26e51 weeks of Age 52e77 weeks of Age 78e103 weeks of Age 104e129 weeks of Age >130 weeks of Age

Stock/Strain

Male

Female

Male

Female

Male

Female

Male

Female

Male

Female

Male

Female

Reference

Fischer 344

90.6

19.1

e

e

e

e

e

e

e

e

e

e

Dixon et al. (1995)

0.0

7.7

25.0

82.5

97.9

e

e

Goodman et al. (1979)

e

e

e

Hall et al. (1992)

100.0

e

100.0

e

Maeda et al. (1985) a

e

100.0

e

e

e

e

99.0

86.0

e

e

Solleveld and Boorman (1986)

e

e

e

100.0

87.0

e

e

Solleveld and Boorman (1986)

e

e

e

e

75.7

36.0

e

e

Goodman et al. (1980)

e

e

e

e

e

99.0

99.0

e

e

Solleveld and Boorman (1986)

e

e

e

e

e

e

93.0

92.0

e

e

Solleveld and Boorman (1986)

e

e

e

e

e

e

96.0

100.0

e

e

Solleveld and Boorman (1986)

33.0

11.0

60.0

18.5

100.0

44.0

e

e

Owen and Heywood (1986)

e

e

e

e

91.4

55.7

e

e

Keenan et al. (1995b)

e

e

e

e

e

e

e

e

e

e

38.7

10.8

e

e

e

e

e

0.0

e

0.0

e

0.0

e

88.6

e

0.0

e

20.0

e

80.0

e

100.0

e

e

e

e

e

e

OsborneeMendel e

e

e

e

e

e

e

e

e

ACI

e

e

e

A28807

e

e

M520

e

e

SpragueeDawley 7.0 e

3.0 e

75.0 e

38.0 e

38.9

Coleman et al. (1977)

Maeda et al. (1985) b

VI. URINARY SYSTEM

CLINICAL CARE AND DISEASE

66.5

100.0

a

Animals in which chronic progressive nephropathy was listed as “cause of death or moribund state.” Animals submitted for scheduled necropsy. Age distributions were not consistent in all references cited. Some references may have stated average age rather than age ranges; such values were approximated in the divisions employed this table. It should also be noted that some references may have used smaller age ranges, or even more divisions among age ranges; these were included with similar age groups for ease of comparison. b c

667

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16. METABOLIC, TRAUMATIC, AND MISCELLANEOUS DISEASES

results in CPN. In fact, subtle nephrotoxins can be identified by their ability to augment the onset or severity of the condition (Alden and Frith, 1991). Prolactin administration increases CPN incidence and severity; prolactin secretion by or in association with adrenal or pituitary tumors has been suggested as the rationale for increased CPN seen in these cases (Richardson and Luginbu¨hl, 1976). Facets of the humoral (Bolton et al., 1976; Couser and Stilmant, 1975; Elema and Arends, 1975) and cellular (Bolton et al., 1976) immunological system have also been considered. Dietary factors significantly influence CPN progression. While the effects of some components such as mineral, lipid, and carbohydrate content appear to conflict or play a minor role (Iwasaki et al., 1988; Klahr et al., 1983; Shackelford and Jokinen, 1991; Tapp et al., 1989), others such as protein composition and total caloric content are much more significant (Alden and Frith, 1991; Duffy et al., 2004a; Bras, 1969). The relative importance of these two constituents has been debated for over 4 decades in studies with conflicting results. Diets relatively high in protein contribute to the severity of CPN (Blatherwick and Medlar, 1937; Lalich and Allen, 1971; Rao et al., 1993; Saxton and Kimball, 1941). Rats consuming a diet of 35% protein suffer more marked nephron insult than those fed 20% protein; further protein reduction to 6% essentially prevented CPN (Bertani et al., 1989). Protein content reduction from 23% to 13%e15% significantly reduces the severity of lesions, with or without calorie restriction (Haseman et al., 2003; Rao et al., 2001, 1993). Limiting total dietary protein in rats to as low as 4%e7% has been suggested (Brown and Donnelly, 2012). Reducing dietary protein content in aging F344 rats by time-restricted feeding also decreases CPN development over ad libitum feeding (Maeda et al., 1985). The protein source is also important, as diets using casein or lactalbumin as the sole protein source are more nephropathogenic than diets using other sources, such as soy (Brown and Donnelly, 2012; Iwasaki et al., 1988; Klahr et al., 1983; Saxton and Kimball, 1941; Shimokawa et al., 1993). Similarly, calorie restriction greatly reduces the incidence and severity of CPN (Bras and Ross, 1964; Keenan et al., 2000; Saxton and Kimball, 1941; Shimokawa et al., 1993). Several investigations indicate that calorie restriction has more impact that protein restriction alone (Gumprecht et al., 1993; Masoro et al., 1989; Masoro and Yu, 1989). Regardless of protein intake, feed restriction delays the onset and reduces the severity and development rate of CPN in aging rats and in experimental models in which renal compromise is induced by renal ablation (Maeda et al., 1985; Tapp et al., 1989). Masoro et al. (1989) demonstrated that CPN is less severe in diet-restricted rats even though total protein intake was shown to be 70% greater than in groups fed ad

libitum. Keenan et al. (1995a) found that proteinrestricted diets fed ad libitum had no effect on the incidence of CPN, and nephropathy decreased only when food intake was restricted as well. Dietary restriction initiated at weaning or in young adult rats must continue throughout adulthood to effectively reduce the incidence of CPN; when ceased at 6 months of age, dietary restriction has no effect (Maeda et al., 1985). A current hypothesis on CPN pathogenesis identifies glomerular hypertrophy as the initial pathological consequence of ad libitum feeding (Gumprecht et al., 1993; Keenan et al., 2000). Caloric overload produces hemodynamic and/or glomerular hydrostatic pressure alterations leading to mesangial and glomerular epithelial trauma and proliferation (Fries et al., 1989; Keenan et al., 1995a). This is followed by expansion of the mesangial matrix, basement membrane thickening, and further endothelial damage, leading to glomerulosclerosis, nephron loss, and progressive protein hyperfiltration and tubular damagedthe hallmarks of CPN (Brenner, 1985; Fogo and Ichikawa, 1989; Gumprecht et al., 1993; Keenan et al., 1995a). Clinical signs are usually unapparent until renal decompensation and uremia cause weight loss and lethargy (Barthold et al., 2016). Polydipsia and palpably enlarged kidneys have been used as indicators of CPN (Spangler and Ingram, 1996). Blood urea nitrogen and creatinine values are usually unchanged until disease nears end stage (Coleman et al., 1977; Everitt, 1958; Gumprecht et al., 1993; Maeda et al., 1985). Proteinuria, predominantly albuminuria, has been considered the classical indicator of CPN (Harkness et al., 2010; Palm, 1998; Peter et al., 1986). This finding, which has led to the moniker “protein leakage disease” (Gray, 1986), probably results from an altered composition of the glomerular basement membrane (Abrass, 2000). Perry (1965) reported the change in protein excretion from 25e100 mg/dL at 8 weeks of age to 1000e3000 mg/dL at 12e24 months in Wistar rats. In SpragueeDawley rats, proteinuria levels can rise from 10 mg/day in early stages to 137 mg/day in males and 76 mg/day in females at 18 months of age (Short and Goldstein, 1992), and may exceed a loss of 280 mg/day (Neuhaus and Flory, 1978). Urine protein concentrations measured in potential sires at 4 months of age can be predictive of CPN and CPN-related life span of offspring; this index may be used to select breeding stock for producing progeny with less severe disease (Gray et al., 1982a). In late stages, the urinary protein profile transforms from the normal a-globulinuria to a semblance of serum (Kohn and Barthold, 1984; Perry, 1965). Sequential examination of urine specific gravity reveals decreased concentrating ability (Owen and Heywood, 1986); urine concentration must be considered if protein levels are measured to account for diuresis (Barthold, 1979). When disease

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VI. URINARY SYSTEM

approaches end stage, rats may develop signs consistent with nephrotic syndrome: hypoproteinemia, azotemia, and hypercholesterolemia (Barthold, 1979; Barthold et al., 2016). Compensatory mechanisms persist until very late stage disease with continued nephron loss, eventually resulting in rapid decompensation and death (Harkness and Wagner, 1995). Postmortem examination typically reveals enlarged kidneys with irregular, often pitted renal cortices (Barthold et al., 2016; Short and Goldstein, 1992, Fig. 16.9). Coloration may vary from pale to yellow with mottling and varying amounts of brownish pigmentation (Harkness et al., 2010; Owen and Heywood, 1986). Grossly visible streaks or striations may be appreciated on the cut surface (Barthold et al., 2016). Small cystic structures may be present in the renal cortex (Anver and Cohen, 1979). The histological appearance of CPN depends on the disease’s chronicity, with severity judged by the proportion of nephrons affected (Gray et al., 1982b, Fig. 16.10). Three scales used to grade lesions according to severity are shown in Table 16.4. Mild CPN is characterized by one to several multifocal cross sections of basophilic tubules undergoing varying degrees of regeneration (Dixon et al., 1995). Glomerular hypertrophy and basement membrane thickening progress until the basement membranes of the glomerulus, Bowman’s capsule, and proximal tubule fracture and wrinkle; proximal tubules degenerate and collapse (Kohn and Barthold, 1984). Within affected glomerular tufts, there is mesangial proliferation, adhesion to Bowman’s capsule, and segmental sclerosis (Barthold et al., 2016). Proximal tubules may become dilated with proteinaceous casts, and eosinophilic, periodic acideSchiff-positive and iron-positive droplets evident in the tubular epithelial cells (Barthold et al., 2016; Christensen and Madsen,

FIGURE 16.9 Chronic progressive nephropathy, gross appearance. Note pale, mottled, and dimpled surface of renal capsule. Image courtesy of the Unit for Laboratory Animal Medicine, University of Michigan.

669

FIGURE 16.10 Chronic progressive nephropathy, microscopic appearance. Areas of normal cortical tubules are interspersed with areas with dilated tubules containing eosinophilic proteinaceous material (asterisks), interstitial inflammation, and regenerative tubules characterized by a basophilic appearance and crowded nuclei (arrows). Glomeruli in affected areas have membranous and capsular thickening and varying degrees of sclerosis (arrowhead). H&E staining; bar, 50 mm. Image courtesy of the Unit for Laboratory Animal Medicine, University of Michigan.

1978). Tubules eventually atrophy, which may be accompanied by interstitial fibrosis and inflammatory cell infiltration (Hard and Khan, 2004; Kohn and Barthold, 1984). Renal secondary hyperparathyroidism is frequently observed with chronic CPN. Itakura et al. (1977) described this sequela in 15.6% (24.4% males, 6.7% females) of aged SpragueeDawley rats. Parathyroid glands in rats with end-stage CPN may be hyperplastic (Maeda et al., 1985), leading to osteodystrophy with fibroplasia and osteoid formation of the femur, humerus, vertebrae, scapula, mandible, and parietal bone, and metastatic calcification in the kidney, gastrointestinal tract, lungs, and arterial media (Barthold et al., 2016; Durand et al., 1964; Itakura et al., 1977; Masoro et al., 1989; Owen and Heywood, 1986). Treatment of CPN may be unrewarding and is predominantly palliative, such as fluid therapy and addressing hyperkalemia and anemia if present (Harkness et al., 2010). A low-protein diet and anabolic steroid use has been advocated as with other severe renal disorders (Brown and Donnelly, 2012). Prevention involves a careful balance of the nutritional requirements for sustaining health while adjusting for the deleterious effects of excess dietary calories and protein. Relationships between CPN and several other conditions have been noted. Hard and associates (2013) described the association between CPN and the development of renal tubule tumors. A high rate of PAN correlated with CPN in a mutant colony derived from

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16. METABOLIC, TRAUMATIC, AND MISCELLANEOUS DISEASES

TABLE 16.4

Three Scales Used to Grade the Histological Appearance and Severity of Chronic Progressive Nephropathy in Laboratory Rats.

Grade Reference: Yu et al., 1982

Grade

Reference: Coleman et al. (1977)

Grade Reference: Rao et al. (1993)

1

Minimal severitydprimarily involves 1 glomerular capillary basement membrane and mesangial matrix; an occasional hyaline cast

Thickened glomerular capillary basement membranes and slight mesangial thickening in some glomeruli; a few cortical tubules shrunken, with thickened, wrinkled basement membranes, and lined by enlarged cells containing basophilic cytoplasm and large nuclei

1

Minimaldless than 20% of the cortex and outer medulla affected; a few small foci of tubular cell degeneration and regeneration in the cortex and outer medulla; occasional scattered tubules containing eosinophilic proteinaceous casts.

2

Mild severitydinvolves glomerular basement membrane and mesangial matrix; tubular proteinaceous casts invariably

2

Grade 1 findings plus scattered dilated 2 tubules lined by atrophic epithelium with occasional hyaline casts, particularly at the corticomedullary junction

Milddapproximately 20%e50% of the cortex and outer medulla affected; focal areas of tubular cell regeneration and degeneration generally larger and more frequent than in grade 1; thickened peritubular basal lamina in some regenerative tubules; eosinophilic proteinaceous casts in cortical and outer medullary tubules, some tubular distension with casts

3

Moderate severitydgrade 2 findings 3 but more extensive, plus thickening of Bowman’s capsule, lymphocyte infiltration, mild interstitial fibrosis

3 Grade 2 findings plus prominent protein casts within cortical, medullary, and papillary tubules; glomerular lesions more pronounced with atrophy of capillary tufts, sclerosis, thickening of Bowman’s capsule, and tubular basement membranes

Moderatedapproximately 50%e75% of the cortex and outer medulla affected; tubular cell degeneration and regeneration, thickening of the basal lamina, and proteinaceous casts more prominent than in grade 2; large number of tubular lumen distended with eosinophilic protein casts; some glomeruli with mesangial proliferation and adhesions of the glomerular tuft to the wall

4

4 Very severedgrade 3 findings but more marked, plus segmental or diffuse glomerular sclerosis; frequent adhesion of glomerular tuft to Bowman’s capsule

4 Grade 3 findings, but more pronounced; adhesions of glomerular tufts to Bowman’s capsule; enlarged nuclei in the tunica media and proliferation of adventitial connective tissue in afferent arterioles of the severely affected glomeruli

Markeddmore than 75% of the cortex and outer medulla affected; foci of tubular cell regeneration and degeneration more numerous and often merged; peritubular basal lamina thickened; frequent interstitial fibrosis and inflammation; many tubules distended with proteinaceous casts; glomerular lesions (adhesions, sclerosis and atrophy of glomerular tuft, etc.), more extensive than in grade 3

E

End stagedwidespread glomerular End sclerosis, obsolescence of glomeruli, stage diffuse interstitial fibrosis, frequent calcification, marked tubular dilation with numerous proteinaceous casts

No normal parenchyma remaining, with widespread glomerular sclerosis, marked tubular dilation, atrophy and hyaline cast formation, and interstitial fibrosis

SpragueeDawley rats developing hypertension, suggesting a relationship between these age-related disorders (Rapp, 1973). Similarly, fawn-hooded rats, another mutant developing hypertension at an early age, may develop CPN at 3 months (Alden and Frith, 1991), related most likely to the development of glomerular hypertension (Provoost, 1994). Systemic hypertension may not be necessary, however, as glomerular capillary

pressure and its effects on the nephron are independent of systemic blood pressure (Anderson et al., 1986). As an additional correlation with a disorder affecting the cardiovascular system, the reduction of CPN following dietary restriction has also been shown to reduce cardiomyopathy (Duffy et al., 2004a; Keenan et al., 1995a; Rao et al., 2001). Interestingly, early lesions of CPN also resemble glomerular lesions associated with

CLINICAL CARE AND DISEASE

VI. URINARY SYSTEM

diabetic glomerulopathy (Velasquez et al., 1990). Thus it is tempting to suggest an interrelationship between two or more of these processes in older rats. Alternatively, the rat kidney might simply be exquisitely sensitive to alterations in systemic and local physiology, with a variety of insults initiating a cascade of events resulting in lesions classically recognized as CPN.

B. Nephrocalcinosis Nephrocalcinosis and intranephronic calculosis are terms used for renal mineralization frequently seen in female rats (Nguyen and Woodard, 1980; Otto et al., 2015). Lesions occur in young rats as early as 3e 5 weeks of age (Hall et al., 1992). A predilection for females suggests a hormonal influence (Rao, 2002). Ovariectomy reduces the development of mineralization, while estrogen administration to either sex induces nephrocalcinosis (Cousins and Geary, 1966; Geary and Cousins, 1969). Some strain differences exist (Du Bruyn, 1970; Ritskes-Hoitinga et al., 1989), with one report indicating up to 77% of female F344 rats between 19 and 21 weeks of age affected (Dixon et al., 1995). The appearance of nephrocalcinosis has historically been related to feeding semisynthetic or purified diets, although rats fed standard laboratory feed also develop lesions (Barthold et al., 2016; Clapp et al., 1982; Hitchman et al., 1979; Nguyen and Woodard, 1980; RitskesHoitinga et al., 1989). The severity of lesions is greater with casein-based semisynthetic diets than in those using lactalbumin (Meyer et al., 1989) or soy protein (Anastasia et al., 1990). Diets with a low concentration of magnesium, high concentration of either calcium or phosphorus, or a low calcium-to-phosphorus ratio may induce typical lesions (Cockell et al., 2002; Ritskes-Hoitinga et al., 1989). Feeding diets with high protein levels (Van Camp et al., 1990) or with a calcium:phosphorus ratio of approximately 1.2 (Clapp et al., 1982; Hoek et al., 1988; Phillips et al., 1986; Ritskes-Hoitinga et al., 1991) assists in preventing lesions. Mineral content and chemical formulations affecting nutritional availability, e.g., solubility and carrier binding, are also involved (Anastasia et al., 1990; Clapp et al., 1982; Woodard, 1971). Dietary chloride, water, lipid, and protein, along with urinary pH, may also play a role (Alden and Frith, 1991; Nguyen and Woodard, 1980; Rao, 2002). There is some controversy on whether dietary changes can induce nephrocalcinosis regression, although reported inconsistencies might reflect analytical method differences and the approaches used to induce the disease (Beynen, 1992; Grimm et al., 1991; National Research Council (U.S.). Subcommittee

671

on Laboratory Animal Nutrition., 1995; Soeterboek et al., 1991). Microscopically, intratubular lithiasis appears as basophilic lamellar deposits of calcium phosphate, or hydroxyapatite (Nguyen and Woodard, 1980), typically occurring in proximal tubules at the corticomedullary junction (Barthold et al., 2016; Clapp et al., 1982; Dixon et al., 1995; Otto et al., 2015). Since standard histological stains may not identify mineral deposition, specific stains such as von Kossa or alizarin red S are suggested (Alden and Frith, 1991). Tubular hyperplasia and fibrosis may also be seen (Ritskes-Hoitinga et al., 1989). Clinical evidence of renal insufficiency, such as albuminuria, may be present only in advanced cases of nephrocalcinosis (Ritskes-Hoitinga et al., 1989). One report evaluating behavior and clinical indices in an experimental model suggested that the disorder may not result in observable discomfort (Soeterboek et al., 1991).

C. Urolithiasis Calculi of struvite, carbonate, phosphate, citrate, oxalate, and combinations of these minerals have been described (Bingel, 2003; Gershoff and McGandy, 1981; Gustafsson and Norman, 1962; Kuhlmann and Longnecker, 1984; Paterson, 1979). The incidence of spontaneous calculus formation in the urinary tract of laboratory rats appears to be quite variable (Table 16.5). Urolithiasis may be more common in males because of the length and relative rigidity of the urethra (Harkness and Wagner, 1995). Hematuria, hemorrhagic cystitis, and/or anuria may be associated with urinary stones (Coria-Avila et al., 2005; Sharp and LaRegina, 1998). If uroliths are present, bacterial infection warrants consideration. In addition, certain strains, such as Zucker diabetic fatty rats, may be more susceptible to bacterial cystitis and subsequent uroliths (Otto et al., 2015). Uroliths may be discovered in the urinary bladder, renal pelvis, ureter, and/or urethra and can result in a thickened bladder wall, ureteral distension, and hydronephrosis (Barthold et al., 2016; Bingel, 2003; Kuhlmann and Longnecker, 1984; Paterson, 1979, Fig. 16.11). Ammonium magnesium phosphate (struvite) calculi ranged in size from minute to over 5 g in one report of SpragueeDawley rats (Paterson, 1979). Similarly, LongeEvans rats have been reported with calculi that varied in size from grit-like to 5 mm (Kinley et al., 2013; Pang et al., 2015). Surgical extraction of urinary bladder calculi and treatment for secondary cystitis may be curative in some cases (Harkness and Wagner, 1995). Microscopic evidence of epithelial hyperplasia and inflammation may be seen in association with urolith location (Kuhlmann and Longnecker, 1984). Urolithiasis

CLINICAL CARE AND DISEASE

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16. METABOLIC, TRAUMATIC, AND MISCELLANEOUS DISEASES

TABLE 16.5

Stock/Strain and Gender Distribution of Urolithiasis in Laboratory Rats. Incidence (%) of Urolithiasis

Stock/Strain

Male

Female

Total (or Gender Not Specified)

Reference

Fischer 344

0.2

0.2

e

Goodman et al. (1979)

0.3

0.3

e

Biology Databook Editorial Board (1985)

OsborneeMendel

0.9

0.0

e

Biology Databook Editorial Board (1985)

SpragueeDawleya

e

e

0.5

Paterson (1979)

SpragueeDawley

7.8

0.3

SpragueeDawleyc

e

e

18.1

Anver et al. (1982)

31.8

18.2

25.0

Magnusson and Ramsay (1971)

b

b

SpragueeDawley

Biology Databook Editorial Board (1985)

a

COBS. Designation not specified. Hap:(SD).

b c

FIGURE 16.11 Urinary calculi within bladder (arrow) causing bilateral hydronephrosis and hydroureters (arrowheads). Image courtesy of the Unit for Laboratory Animal Medicine, University of Michigan.

and crystalluria may be involved in the pathogenesis of uroepithelial proliferative lesions (Alden and Frith, 1991; Boorman and Hollander, 1974). Conversely, epithelial hyperplasia was considered an initiating event in struvite stone formation in a SpragueeDawley rat colony, with degenerating epithelial cells providing a nidus for urolith formation (Magnusson and Ramsay, 1971). Struvite calculi in Lewis and Wistar rats followed dietary retinoid supplementation and possible disruption

to vitamin A metabolism (Kuhlmann and Longnecker, 1984). When combined with lactose as the primary carbohydrate source, vitamin A deficiency has been shown to predispose to weddellite (calcium oxalate dihydrate) or apatite (calcium phosphate) lithogenesis (Gershoff and McGandy, 1981). Other predisposing factors include genotype, metabolic or nutritional imbalances, and dehydration (Harkness et al., 2010). Reportedly, germfree male rats may be more susceptible to urolithiasis than similar females, with 50% and 2%, respectively, diagnosed with calcium citrate and calcium oxalate urinary bladder calculi; administering gut microflora eliminated the increased incidence of stone formation (Gustafsson and Norman, 1962). The authors attributed this predisposition to increased urinary calcium, citrate, and pH in germ-free animals. Table 16.6 summarizes the composition and suspected predisposing factors involving urolithiasis in laboratory rats. It is important to distinguish between uroliths and copulatory plugs. Copulatory plugs, also known as urethral plugs, proteinaceous plugs, bladder plugs, mucoid calculi, or soft calculi, are frequently seen in the urethra or urinary bladder following retrograde ejaculation in male rats (Lee, 1986; Otto et al., 2015). These structures are generally regarded as an agonal change (Barthold et al., 2016); however, some have suggested they are normal structures in healthy rats and are absent only in ill animals (Kunsty´r et al., 1982). Proteinaceous casts were found within the urinary bladder of 1.8% of SpragueeDawley males up to 12 months of age, with no mention of casts in F344 or OsborneeMendel rats (Biology Databook Editorial Board, 1985). Although their relationship to urolith formation is unclear, calcium carbonate calculi may be found incorporated into

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TABLE 16.6

Spontaneous Urolith Composition and Possible Predisposing Factors in Laboratory Rats.a

Composition

Location (in Descending Order)

Suggested Predisposing Factors

Reference

Struvite (magnesium ammonium phosphate)

Urinary bladder, ureter, renal pelvis

Dietary retinoids, vitamin A disturbance

Kuhlmann and Longnecker (1984)

Renal pelvis

Degenerating hyperplastic uroepithelium

Magnusson and Ramsay (1971)

Urinary bladder, renal pelvis

None

Paterson (1979)

Calcium carbonate

Urinary bladder, renal pelvis

None

Paterson (1979)

Calcium phosphate

Renal pelvis

None

Paterson (1979)

Mixed: calcium carbonate and struvite

Urinary bladder, renal pelvis, ureter

None

Paterson (1979)

Mixed: calcium phosphate and struvite

Urinary bladder, renal pelvis

None

Bingel (2003)

Mixed: calcium carbonate, phosphate, and struvite

Urinary bladder

None

Paterson (1979)

Mixed: calcium citrate and calcium oxalate

Urinary bladder

Germ-free status

Gustafsson and Norman (1962)

Mixed: calcium carbonate and calcium oxalate

Urinary bladder

None

Paterson (1979)

a SpragueeDawley rats were described in each report except Kuhlmann and Longnecker (1984), which involved both Lewis and Wistar rats. Stock/strain not identified in Gustafsson and Norman (1962).

copulatory plugs in the urinary bladder of male rats (Paterson, 1979).

D. Hydronephrosis Renal pelvis dilation is not an uncommon necropsy finding in many laboratory rats and must be distinguished from polycystic kidneys, pyelonephritis, and renal papillary necrosis (Barthold et al., 2016, Fig. 16.12). Hydronephrosis can be easily visualized radiographically via excretory urogram (Cohen et al., 1970; Lozzio et al., 1967). Analysis of breeding data and the great variation of incidence in different strains and stocks attest to its heritable nature (see Table 16.7). The condition is thought to often be congenital and inherited as an autosomal polygenetic trait with incomplete penetrance in BN/Bi (Cohen et al., 1970; Kota et al., 2008), SpragueeDawley (Van Winkle et al., 1988), and ACI (Cramer and Gill, 1975) rats, and as an autosomal dominant lethal gene when homozygous in the Wistarderived Gunn rat (Lozzio et al., 1967). A subline of Wistar rats was developed by Friedman et al. (1979) that developed hydronephrosis in 95% and 60% of males and females, respectively. Hydronephrosis can also be an acquired condition resulting from ascending infection (Harkness et al., 2010). Hydronephrosis is typically considered incidental and as producing little renal dysfunction (Cohen et al., 1970), although it can be lethal in some cases with

FIGURE 16.12

Hydronephrosis, gross appearance. Image courtesy of the Unit for Laboratory Animal Medicine, University of Michigan.

bilateral involvement (Barthold et al., 2016). Some reports indicate a predilection for the right kidney to be affected (Burton et al., 1979). One hypothesis suggested constriction of the right ureter by the right internal spermatic artery and vein, but surgical resection of these

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TABLE 16.7

Stock/Strain and Gender Distribution of Hydronephrosis in Laboratory Rats. Incidence (%) of Hydronephrosis

Stock/Strain

Male

Female

Total (or Gender Not Specified)

Reference

Fischer 344

2.0

2.0

e

Solleveld and Boorman (1986)

1.1

0.3

e

Biology Databook Editorial Board (1985)

22.0

10.0

e

Solleveld and Boorman (1986)

0.0

4.5

e

Biology Databook Editorial Board (1985)

e

e

3.9

Anver et al. (1982)

e

e

13.9

Anver et al. (1982)

OsborneeMendel

SpragueeDawleya b

SpragueeDawley

c

e

e

2.0

Van Winkle et al. (1988)

d

SpragueeDawley

4.8

4.4

e

Biology Databook Editorial Board (1985)

SpragueeDawleye

1.0

0.4

e

Owen and Heywood (1986)

August Copenhagen Irish (ACI)

48

41

e

Solleveld and Boorman (1986)

7.9

5.3

e

Cramer and Gill (1975)

August (A28807)

3.0

9.0

e

Solleveld and Boorman (1986)

Marshall (M520)

34.0

63.0

e

Solleveld and Boorman (1986)

Wistar (Hla:(WI)BR)

13.9

4.6

e

Burton et al. (1979)

Brown Norway (BN/Bi)

36.8

21.8

e

Cohen et al. (1970)

Lewis  Brown Norway (LBN)

14.8

4.7

e

Treloar and Armstrong (1993)

SpragueeDawley

a

Crl:COBS[R]CD[R](SD). Hap:(SD). c Crl:CD[R](SD)BR. d designation not specified. e CD. b

vessels fails to prevent occurrence (O’Donoghue and Wilson, 1977). Accompanying ureteral dilation is inconsistent (Burton et al., 1979; Fujikura, 1970). Hydronephrosis has been associated with pyelonephritis, renal papillary congestion and hemorrhage, uroepithelial proliferative lesions, and renal pelvic urolithiasis (Burton et al., 1979; Fujikura, 1970; Maronpot, 1986; Solleveld and Boorman, 1986), although urolithiasis does not appear to precede hydronephrosis (Van Winkle et al., 1988). There may be a relationship between hydronephrosis and benign intermittent hematuria seen in Lewis and BN rat crosses subsequent to the rupture of wellvascularized proliferative renal pelvis masses (Treloar and Armstrong, 1993). Renal agenesis is associated with hydronephrosis in the ACI rat. Unilateral renal agenesis has been described in 12%e21% of male and 14%e16% of female ACI rats, with a predilection for the right kidney and concurrent absence or malformation of the ipsilateral adrenal gland and genital organs (Cramer and Gill, 1975; Solleveld and

Boorman, 1986). Interestingly, hydronephrosis occurs in this strain at similar rates, but involving the left kidney (Cramer and Gill, 1975; Fujikura, 1970).

VII. ENDOCRINE SYSTEM Several endocrine gland lesions have been described in rats, especially in older animals. Few, if any, have known clinical significance, but are described as an introduction to the spontaneous disorders of these organs. Neoplasia is the most significant abnormality involving the pituitary gland, which in some reports is cited as the most frequent cause of laboratory rat mortality (Ettlin et al., 1994; Keenan et al., 1995b). Colloid cysts are frequently seen in the pituitary gland of aging rats (Carlton and Gries, 1996). The incidence of cysts varies with age, stock/strain, and specific colony, and occurs in approximately 2.0% of most strains, including F344

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VIII. NERVOUS SYSTEM

and OsborneeMendel rats (Biology Databook Editorial Board, 1985; Coleman et al., 1977; Goodman et al., 1979, 1980). The reported incidence in SpragueeDawley colonies ranges from 1.5% (Biology Databook Editorial Board, 1985) to 12.5%e23.7% (Anver et al., 1982; Cohen et al., 1978). Some pituitary cysts may originate from remnants of Rathke’s pouch, a relatively commonly identified congenital disorder (MacKenzie and Boorman, 1990). Ultimobranchial cysts are a congenital thyroid gland lesion thought to originate from the ultimobranchial body (Hardisty and Boorman, 1990). These are often filled with debris and develop in approximately 8.9% of male and 9.7% of female 19- to 21-week-old F344 rats (Dixon et al., 1995). A spontaneous inherited tertiary hypothyroidism, i.e., secondary to insufficient hypothalamic thyroid-stimulating hormone production, resulting in severe retardation of central nervous system development and death within 30 days of age, has been described in SpragueeDawley rats (Stoica et al., 2007). Thyroid rests are small accumulations of ectopic thyroid tissue often identified in the neck and thoracic midline (Parker and Valerio, 1996a). Similarly, nests of ectopic thymus tissue, termed thymic rests, may be seen histopathologically in the thyroids of rats (Parker and Valerio, 1996b). Spontaneous lymphocytic thyroiditis, an autoimmune disease causing a slowly progressing loss of thyroid function, is a relatively rare finding in most rat stocks and strains (Sandusky and Todd, 1996). Buffalo rats over 30 months of age may present with over 48% incidence (Bigazzi and Rose, 1975). Parathyroid hyperplasia is frequently seen in older rats, primarily as a sequela to CPN (Anver et al., 1982). A brief discussion of this condition can be found in the CPN section. Several lines of the laboratory rat have been propagated to serve as models for human diabetes mellitus, including BB, GotoeKakisaki, Otsuka LongeEvans Tokushima lean, Cohen, obese/SHR, Wistar fatty, SHR/N-cp, BHE, and Zucker fatty (Cheta, 1998; Ktorza et al., 1997; Velasquez et al., 1990). Less is known about the occurrence of this disorder in standard stocks and strains. b cell hyperplasia is frequently seen in rats even as young as 3 months of age; with aging, especially in males, rats may develop islet fibrosis and hyperglycemia (Dillberger, 1994). Glucose metabolism alterations can be identified in rats without islet disease, although dysfunction becomes more severe when morphological changes occur (Anver and Cohen, 1979). Islet changes have also been related to ad libitum feeding (Keenan et al., 1994, 1995a), which also probably predisposes rats to the development of islet cell neoplasia (Dillberger, 1994). Accessory adrenal cortical nodules are frequently seen in aged rats (Hamlin and Banas, 1990). Such nodules were found in 1.3% of female and 1.9% of male

F344 rats ages 19e21 weeks (Dixon et al., 1995). Sinusoidal dilatation and thrombi occur frequently, with up to 32.4% of some SpragueeDawley colonies (Crl: COBS[R]CD[R](SD)) affected (Anver et al., 1982). Other lesions include focal cortical degeneration and adenoma-like cells in the zona fasciculata (Anver and Cohen, 1979).

VIII. NERVOUS SYSTEM A. Hydrocephalus Hydrocephalus appears to be a relatively rare phenomenon in laboratory rats (Kaufmann et al., 2012; Solleveld and Boorman, 1990). Reported incidences have ranged from 0.4% in F344 (Biology Databook Editorial Board, 1985) to 1.4% in SpragueeDawley rats (Anver et al., 1982). Spontaneously developing mutant lines with much higher incidence of hydrocephalus have been described (D’Amato et al., 1986; Kohn et al., 1981).

B. Degenerative Changes and Radiculoneuropathy Spontaneous degeneration in both the central and the peripheral nervous systems is a frequent finding in aging rats (Barthold et al., 2016). Radiculoneuropathy, also known as spinal nerve root degeneration, degenerative myelopathy, spinal radiculoneuropathy, radicular myelinopathy, proximal demyelination, and spontaneously occurring posterior paralysis, is a longrecognized degenerative disease of aging rats (Anver and Cohen, 1979; Krinke, 1988; Bradley et al., 2018). Lesions are not usually apparent until rats reach 18e 20 months of age (Gilmore, 1972; Van der Kogel, 1977), but may reach 80%e100% in rats surpassing 2 years of age (Anver et al., 1982; Berg et al., 1962). A sex predisposition is unclear (Berg et al., 1962; Burek et al., 1976; Gilmore, 1972). Examination of initial peripheral nerve degeneration suggests an earlier onset in males than in females (Cotard-Bartley et al., 1981). This condition has been reported in a number of stocks and strains, including SpragueeDawley, Wistar, WAG/Rij, BN, and F344 (Biology Databook Editorial Board, 1985; Krinke et al., 1981). Lesions generally occur earlier in life in SpragueeDawley rats compared with Wistar or F344 rats; the latter typically develop less severe disease (Bradley et al., 2018). Because of the number of clinical cases of posterior paresis and paralysis, Cohen et al. (1978) carefully examined the nervous system of 30- to 39-month-old SpragueeDawley (Crl:CD(SD)BR) rats, and discovered radiculoneuropathy in 12% and 95% of the cervical/thoracic and lumbar/sacral nerves, respectively. Although incidence rates are

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16. METABOLIC, TRAUMATIC, AND MISCELLANEOUS DISEASES

approximately 2% in inbred BN/Bi/Rij and WAG/Rij strains, the F1 hybrids of these strains develop lesions in 21% of the offspring (Burek et al., 1976). The principal clinical signs of radiculoneuropathy are slowly advancing rear-limb ataxia or paralysis leading to gradual wasting of the rear-limb musculature, weight loss, and lethargy (Anver and Cohen, 1979; Witt and Johnson, 1990). Other clinical signs include urinary incontinence and constipation (Anver et al., 1982). Hindlimb neurological assessment may reveal proprioceptive defects (Witt and Johnson, 1990). Although lesions may be difficult to appreciate grossly, the key histological feature is swelling of the myelin sheath and demyelination (Krinke et al., 1981). Early in the course of development, axonal atrophy is most commonly seen in distal nerve sections (Kazui and Fujisawa, 1988). Segmental demyelination and remyelination may be disseminated, occurring most regularly in the lumbar ventral spinal roots (Anver et al., 1982; Kazui and Fujisawa, 1988; Krinke et al., 1981; Meeker et al., 2016). Lesions may be prominent in peripheral nerves such as the sciatic (Van Steenis and Kroes, 1971; Witt and Johnson, 1990) and tibial (Cotard-Bartley et al., 1981) nerves, and may also develop in the cauda equina, spinal column white matter, lower brain stem, and, rarely, the dorsal spinal nerve roots (Berg et al., 1962; Burek et al., 1976; Gilmore, 1972). Evidence of Wallerian-type degeneration and myelinated fiber loss is seen in the distal segments of affected nerves (Mitsumori et al., 1981, 1986; Fig. 16.13). Theories regarding the pathogenesis of radiculoneuropathy include obesity-related pressure resulting in

trauma, CPN, and hyperglycemia, although radiculoneuropathy can be found in rats not exhibiting any of these concurrent disorders (Krinke, 1983; Witt and Johnson, 1990). An association with vertebral disc degeneration, protrusion, and rupture, with subsequent spinal cord compression, was suggested by Burek et al. (1976), who also described vertebral bone aseptic necrosis in rats displaying posterior paralysis. A case of intervertebral disc disease resulting in posterior paralysis was noted in a 12- to 18-month-old F344 rat (Coleman et al., 1977).

C. Idiopathic Epilepsy There are numerous induced rat models of seizure disorders, including multiple strains with enhanced susceptibility to audiogenic seizures (Garcia-Cairasco et al., 2017). The WAG/Rij rat has shown particular promise as a model for absence, or petit mal, epilepsy; after 2e 3 months of age, these rats develop paroxysmal EEG waveforms and characteristic facial twitching (Russo et al., 2016). A relatively high incidence (1.5%) of spontaneous clonic seizures was described in a Wistar rat colony (Crl:(WI)BR) over 16 weeks of age with a predilection for females (2/3% vs. 0.7% in males; Nunn and Macpherson, 1995). These authors surmised that these incidence rates were probably underestimated in the absence of careful and frequent animal observation.

D. Traumatic and Toxic Diseases Rats may present with neurological signs following trauma to the peripheral or central nervous system. Differential diagnoses include encephalitis, otitis interna, arthritis, and pituitary adenoma or other lesions compressing nervous tissue (Harkness et al., 2010). Lethal organophosphate toxicity following accidental exposure to an agricultural insecticide was described in LongeEvans rats presenting with muscle fasciculations, depression, exophthalmos, and ptyalism (Gibson et al., 1987). Careful selection of bedding, with attention to vendor assurances with regard to contaminants such as organophosphates, chlorinated hydrocarbons, aflatoxins, and heavy metals, is prudent (Kohn and Barthold, 1984).

FIGURE 16.13 Radiculoneuropathy, microscopic appearance. Cross section through spinal nerve root axons showing a mildly affected segment (left) with myelin sheath swelling (arrowheads) and a severely affected segment (right) showing lipid deposition as cholesterol clefts (arrows) surrounded by axonal fragmentation/loss and macrophagic inflammation (asterisk). H&E stain; bar, 50 mm. Image courtesy of the Unit for Laboratory Animal Medicine, University of Michigan.

XI. OCULAR SYSTEM While apparently rare, primary or congenital glaucoma occurs in rats (Beaumont, 2002; Goldblum and Mittag, 2002; Heywood, 1975). Secondary glaucoma occurs with regularity in association with hypermature

CLINICAL CARE AND DISEASE

XI. OCULAR SYSTEM

cataract formation (Wegener et al., 2002) and may be a sequela to intraocular inflammation (Heywood, 1975). Persistent pupillary membranes incited unilateral and bilateral buphthalmos in up to 15.3% of a WAG rat colony (Young et al., 1974). Strain-specific, spontaneous intraocular hemorrhage has been described in the development of eyes in young rats through 21 days of age (Inagaki et al., 2014). Orbital plexus puncture remains a common method of blood collection in rats. Numerous authors have reported adverse sequelae to this technique (van Herck et al., 1998), ranging from focal hemorrhages along the penetration path, including within the Harderian gland, periocular musculature, and orbital periosteum (Van Herck et al., 1992), to dacryoadenitis (McGee and Maronpot, 1979), enophthalmos resulting from damage to and contraction of ocular muscles (Van Herck et al., 1992), and optic nerve degeneration and retinal atrophy (Krinke et al., 1988; Le Net et al., 1994). Conversely, a 2014 retrospective analysis identified complications in only 0.6% of rats undergoing this procedure by experienced personnel using a well-defined lateral approach (Sharma et al., 2014). Microphthalmia is uncommon (Cook, 1991), although it may occur with some regularity in F344 rats (Williams, 2002). Inferior ectopic pupil secondary to coloboma and associated with microphthalmia and corectopia was described in Royal College of Surgeons (RCS) rats (Tsuji et al., 2011).

A. Conjunctival and Lacrimal Diseases Conjunctivitis in rats may result from infectious agents (e.g., Pasteurella pneumotropica and sialodacryoadenitis virus) or other, noninfectious, causes such as trauma, foreign bodies, and increased environmental ammonia (Harkness et al., 2010). Lack of protective cilia may predispose nude rats to conjunctivitis and blepharitis from hardwood bedding material (Barthold et al., 2016). Epiphora may also be seen in these circumstances, and may also be a sequela of incisor malocclusion and nasolacrimal duct obstruction (Beaumont, 2002). Like many other species, ranging from anuran amphibians to cetaceans, the rat lacrimal system includes the Harderian gland. The biological function of this enigmatic organ has been the source of extensive study (Payne, 1994; Sakai, 1981). The rat Harderian gland is comparatively large, enveloping much of the caudal aspect of the orbit. It produces a lipid-rich tear film that contains, among other components, porphyrins, which may be involved in photoreception by increasing the quality or quantity of light reception and photoprotection via absorption of deleterious light wavelengths.

677

FIGURE 16.14

Chromodacryorrhea. Image courtesy of the Unit for Laboratory Animal Medicine, University of Michigan.

These pigments provide the characteristic reddish coloration to rat tears, which are easily appreciated when accumulated around the eyes (chromodacryorrhea) and external nares (chromodacryorhinorrhea; Fig. 16.14). Porphyrin staining may be incorrectly reported as “bleeding around the eyes” or “bloody nose,” often accumulates on the forepaws during grooming, and can be differentiated from blood by orange-red fluorescence when viewed under ultraviolet light. These signs may result from any condition producing distress in laboratory rats. Stressors exceeding coping mechanisms, such as immobilization, overcrowding, and infection, can result in chromodacryorrhea within a few minutes (Harkness and Ridgway, 1980). Identifying and treating the underlying cause is necessary for alleviation. Mason et al. (2004) developed a scoring system to quantify overall distress based on the amount of porphyrin staining around the external nares of rats. Sialodacryoadenitis is a prototypical clinical sign associated with rat coronaviral infection. Noninfectious Harderian gland dacryoadenitis has also been described. In one study, marked glandular necrosis with cellular infiltrates and edema probably resulting from the photodynamic properties of porphyrin was noted after as little as 12 h of exposure to highintensity (2500 lux) light (Kurisu et al., 1996). Other studies have identified a causal association between uninterrupted light and Harderian gland damage (Johnson et al., 1979; O’Steen et al., 1978).

B. Corneal Lesions Given its comparatively large size and rostral location, lesions involving the cornea following trauma or

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environmental irritation such as metabolic gases and bedding material are common in rodents. Corneal wounds following general anesthesia have been associated with prolonged periods of inadequate ocular lubrication, leading to desiccation (King et al., 1995). However, lesions ranging from opacities to ulceration may also accompany the use of injectable anesthetics, especially ketamine and xylazine combinations, despite the appropriate use of lubricants, which may also lead to transient lens opacities, mydriasis, and proptosis (Kufoy et al., 1989; Calderone et al., 1986). These probably result from local hypoxia induced by these agents, as evidenced by the protection provided by supplemental oxygen, exhibit strain/stock differences in sensitivity (F344 > Wistar, LongeEvans > SpragueeDawley > Lewis), and are mitigated with the use of the reversal agent yohimbine (Turner and Albassam, 2005). In a report involving another a2 agonist, the authors surmised that exophthalmos may be associated with the systemic hypertensive and ocular hypotonic effect of medetomidine (Smith and Grieve, 2008). In a retrospective analysis of approximately 3000 SpragueeDawley rats (Crl: COBS-CD(SD)BR), corneal dystrophy or calcification along with lenticular opacities (see later) were the most common spontaneous findings in older animals, and hyaloid and fetal membranes within the vitreous of young rats (Taradach et al., 1981). Corneal dystrophy, also known as band keratopathy, is typically the result of trauma or inflammation (Carlton and Render, 1991). It has been described in a variety of rat stocks and strains, including Spraguee Dawley and Wistar (Bellhorn et al., 1988), and as a common finding in F344 rats (Bruner et al., 1992; Losco and Troup, 1988; Whorton and Tilstead, 1984). Although it affects both sexes, it appears more prevalent and severe in males (Bruner et al., 1992; Taradach and Greaves, 1984). Wide incidence ranges (reports vary between 15% and 100%) might be due to the method of detection employed. The lesion typically appears as a superficial, punctate to linear opacity located in the interpalpebral fissure. Microscopically there is focal to segmental thickening and disruption of the basement membrane with mineral deposition. The lesion may be seen in animals as young as 10 weeks of age but fails to progress or increase in severity with age. Severe corneal lesions, such as ulceration, often prove to be therapeutic challenges in small rodents. Wilding et al. (2015) demonstrated the utility of enucleation as a viable treatment option for these undoubtedly painful conditions that would otherwise necessitate euthanasia.

C. Lens Opacities Lens opacities are common lesions reported in many different rat stocks and strains, including Spraguee

FIGURE 16.15 Cataracts. Image courtesy of the Unit for Laboratory Animal Medicine, University of Michigan.

Dawley (Durand et al., 2001; Taradach et al., 1981), Wistar, SHR, RCS (Hess et al., 1985), and BN rats. Several rat strains, such as the Ihara cataract rat and the Shumiya cataract rat, serve as animal models of this disease (Ihara, 1983; Shumiya, 1995). Cataract formation (Fig. 16.15) in these lines ranges from 60% to 100% and shows no sex-based differences. Posterior subcapsular cataracts were described in 32% of Wistar rats over 2 years of age, and tended to occur more frequently in females (Wegener et al., 2002). In contrast, the maximum incidence in a SpragueeDawley rat colony was 9.8% (Durand et al., 2001). In this study, the lenticular opacity was caused by focal epithelial proliferation, which failed to progress. Cataract formation frequently reflects the development of retinal degeneration (Yoshitomi and Boorman, 1990). These conditions are also a common sequela to diabetes mellitus, features that have been well described in the spontaneously diabetic strains such as the WBN/ Kob rat (Miyamura and Amemiya, 1998) and may also develop concurrent with phototoxic retinopathy (Barthold et al., 2016). Similar to other degenerative disorders, calorie restriction delays the onset of cataract formation in BN (Wang et al., 2004), although, interestingly, not in the albino F344 rat, indicating a protective effect of pigmentation (Wolf et al., 2000).

D. Retinal Disorders Despite considerable literature (reviewed in Organisciak and Vaughn, 2010; De Vera Mudry et al., 2013) since the landmark description of retinal degeneration associated with light exposure, or phototoxic retinopathy, by Noell et al. (1966), much of the significance of this disorder in contemporary rodent colonies remains obscure but probably underappreciated. Its impact is unquestionable

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XI. OCULAR SYSTEM

in safety studies; evaluating potential retinal toxic effects of test articles is confounded by a lack of standardization in housing and illumination conditions that may result in this disease (De Vera Mudry et al., 2013). Retinal degeneration occurs spontaneously with age in albino rats reared in low light (10e20 lux), which is exacerbated at higher illumination levels (Weisse et al., 1974; Lai et al., 1978; Lin and Esnner, 1987; Yoshitomi and Boorman, 1990). Excessive illumination (e.g., 6000e10,000 lux) of short duration is often employed in experimental conditions, and while the deleterious effects of high-intensity light are apparent, identifying preventive levels is more elusive. O’Steen (1970) reported no retinal damage in rats exposed for 30 days to 194 lux. Other authors have noted that photoreceptor cell damage is initiated within 12 h of exposure to 133 lux (Williams et al., 1985) or 160 lux (Rapp and Williams, 1980) in albino rats reared in dim (3e5 lux) lighting, although levels as low as 30 lux may contribute to lesions seen in older rats (Weisse et al., 1974). Bellhorn (1980) recommended room illumination levels of 323 lux measured 0.91 m from the floor, because it resulted in maximum rack row-level light of 32e40 lux using a prototype room with wire-mesh-fronted stainless steel caging, a standard subsequently adopted in the Guide for the Care and Use of Laboratory Animals (ILAR, 2011). This author also acknowledged that numerous environmental parameters have an impact on the amount of light entering the primary enclosure, including the transparency of caging material, relative cage location, reflectivity of room surfaces, and the angle of

(A)

679

illumination. De Vera Mudry et al. (2013) described further challenges associated with verifying light levels within polycarbonate caging, which varied from 18 to 76 and 30 to 82 lux, depending on cage location and the orientation of the light meter, respectively. Given these confounding factors, these authors recommend animal-level lighting lower than 20 lux, although others suggest levels as low as 5 lux for studies involving the retina (Li et al., 2003). Regardless, rats, which are nocturnal species with eyes tailored to maximize light capture, appear uniquely vulnerable to this disorder. Uveal and retinal pigment is largely protective, although mydriasis accelerates photoreceptor cell degeneration in pigmented rats (Rapp and Williams, 1980; Williams et al., 1985). Grossly, fundic exam reveals hyperreflectivity and narrowing of the retinal vessels (Everitt et al., 1987). Bilateral progressive loss of the outer retinal layers (photoreceptors and their nuclei) is seen in histological sections (Fig. 16.16). Degeneration begins in the superior hemisphere of the retina (Rapp and Williams, 1980; O’Steen and Donnelly, 1982). Although no standard grading scale has been developed, lesions are typically ranked with a fivecategory scale ranging from minimal to severe (De Vera Mudry et al., 2013). The condition has been described in multiple rat stocks and strains; Borges et al. (1990) reported Lewis and Buffalo strains to be more sensitive than Wister and F344. Hubert et al. (1994) reported focal degeneration of outer nuclear layers, using the term “linear focal retinopathy,” in 3% of SpragueeDawley rats over 7 weeks of age via indirect

(B)

FIGURE 16.16 Comparison of normal rat retina and phototoxic retinopathy, photomicrograph (original magnification 400). In the normal retina (A), note the distinct layers comprising (from top) the retinal pigmented epithelium, rod outer segments, rod inner segments, outer nuclear layer (dark-staining round nuclei), outer plexiform layer, inner nuclear layer, and inner plexiform layer. Structures not appearing in this image are the ganglion cell layer and inner limiting membrane. In the light-damaged retina (B), note the loss of essentially all layers caudal to the inner nuclear layer, concurrent with permanent loss of photoreceptors; in this image, the inner plexiform layer, ganglion cell layer (containing capillaries), and inner limiting membrane are visible. Images and description courtesy of Dr. D.K. Merriman. CLINICAL CARE AND DISEASE

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ophthalmoscopic evaluation. Female rats may be more susceptible (O’Steen, 1977), and juvenile rats less than 30 days of age are relatively resistant (Joly et al., 2006). Wenzel et al. (2005) reviewed the molecular pathways that converge to photoreceptor apoptosis. In addition to illumination intensity, other determinants include spectral wavelength of the light source and photoperiod/ duration, as well as animal age, sex, and body temperature (Bellhorn, 1980; Lanum, 1978; Peiffer and Porter, 1991; Wenzel et al., 2005; Joly et al., 2006; Krigel et al., 2016). Most important are the synergetic effects of photoperiod and illumination intensity, with lower intensity light exposure for longer lengths of time producing phototoxicity equivalent to that of higher illumination levels for a shorter duration. Rats housed in areas of greater light intensity, such as a rack’s top row and outer columns, are therefore at greater risk (Rao, 1991). The ambient light intensity during animal development affects the damage-producing threshold later in lifedan approximate 1.3 log unit increase is sufficient to induce phototoxicity (Semple-Rowland and Dawson, 1987). In addition to lowering light intensity, other methods to prevent or delay phototoxic retinopathy include rotating cage position on the rack, using opaque or translucent caging, and providing environmental enrichment devices or nesting material allowing rats to self-regulate light level exposure. Lee et al. (1990) described unilateral lesions similar to phototoxic retinopathy but associated with optic nerve degeneration in approximately 16% of F344 rats between 57 and 64 weeks of age. The RCS rat is a standard model of inherited retinal dystrophy (Chader, 2002; Matuk, 1991). Other retinal conditions include proliferative retinopathy, which is characterized by the growth of new blood vessels in the retina or vitreous body, similar to lesions seen in humans with diabetes mellitus (Matsuura et al., 1999). Preretinal arteriolar loops in which a branch of the central artery extends into the vitreous before descending back into the retina have also been described (Tanaka et al., 1994). In addition to linear focal retinopathy described above, other changes described by Hubert et al. (1994) in a large study of over 6000 untreated Crl:CD(SD)BR rats included coloboma of the optic disc (0.5% incidence) with retinal hemorrhage, retinal folds, optic disc aplasia, and saccular aneurysm of the retinal vessels noted as rare occurrences.

X. MUSCULOSKELETAL SYSTEM Musculoskeletal conditions in rats tend to be iatrogenic or traumatic events following improper handling, fighting, or procedures associated with experimental studies. Given their relatively small size, intramuscular injections are not commonly used in rats. Adverse sequelae have been described following administration

of injectable anesthetic combinations, such as ketamine or ketamine in combination with xylazine or medetomidine, which have been shown to produce edema, muscle necrosis, skin ulcerations, and lameness when administered intramuscularly (Smiler et al., 1990; Sun et al., 2003). Injection of acidic compounds at a pH range of 4e5 at 5- to 10-day intervals resulted in persistent bilateral hyperalgesia, despite a lack of appreciable tissue damage (Sluka et al., 2001). Bilateral temporomandibular joint luxation was discovered presumably following head entrapment in a protective jacket (Shientag et al., 2011). Rats housed on wire-bottomed cages are not only predisposed to pododermatitis (see later), but also to limb entrapment, especially during recovery from general anesthesia (Otto et al., 2015). Osteoarthritis affecting rats generally occurs in animals greater than 1 year of age and may be seen in the tibiotarsal joints, the medial femoral condyles, and the sternum (Berg, 1967; Sokoloff, 1967; Yamasaki and Inui, 1985). There is no apparent sex predilection, but comparisons revealed strain differences, with F344 having greater incidence and severity than Wistar rats (Smale et al., 1995). Gross lesions may not be apparent, but microscopically, osteoarthritis is characterized by erosion of articular cartilage and chondromucoid degeneration. Cyst formation may also be observed. However, others have reported a high incidence in Wistar rats, 27.5% in males by 1 month, and 40.0% and 16.0% in males and females, respectively, by 24 months of age; these authors suggested that joint instability led to synovitis and chondroid metaplasia (Sasaki et al., 1998). Epiphyseal aseptic necrosis may be observed in various bones, most commonly affecting the vertebrae, knee joint, and sternum (Burek et al., 1976; Jasty et al., 1986; Sokoloff, 1967). Approximately 92% of Spraguee Dawley (Crl:CD(SD)BR) rats examined at 180 days of age contained aseptic necrosis of the intersternebral cartilage (Jasty et al., 1986). Osteochondrosis is a disease of young animals characterized by abnormal growth cartilage differentiation (Kato and Onodera, 1987). The incidence is higher in males than in females. Lesions typically begin to develop at around 6 weeks of age and often involve the medial femoral condyle and the humeral head. Microscopically, a thick deep zone with incomplete mineralization of the matrix and small cavity formation is seen. Viable chondrocytes are present around the edges of the cavities but there is a lack of blood vessel invasion from the subchondral bone. Other bone-associated conditions include a report of proliferative lesions of unknown etiology seen in histological sections as new bone formation both inside the marrow cavity and outside the cortex of the bones of the carpal, tarsal, and digital joints (Yamasaki and Houshuyama, 1994). Yamasaki and Anai (1989) described a small group of animals with a congenital

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bony lesion producing a kinked tail. In all animals affected by the trait, abnormal bony and cartilaginous tissue was found between the 18th and the 19th vertebrae causing the tail to curve to the right. In an earlier survey of congenital malformations, “kinky tail” was the most prevalent finding (0.2%; Perraud, 1976). Hypertrophic osteopathy associated with congestive heart failure, multifocal granulomatous pneumonia, and both intra- and extrathoracic neoplasia was described in a Wistar rat (WI/HicksCar) presenting with bilateral metatarsal swelling and hind-limb paresis (Jackson et al., 1997). Osteopetrosis is infrequently identified in aged F344 rats (Leininger and Riley, 1990). Fibrous osteodystrophy is a common sequela to renal disease and secondary hyperparathyroidism (Leininger and Riley, 1990). A rat presenting with severe deviation of the snout and unilateral exophthalmos closely resembled osteitis deformans, or Paget’s disease of bone (Coria-Avila et al., 2008). Skeletal muscle degeneration is frequently observed in the hind limbs of older rats (Greaves et al., 2013), including SpragueeDawley and Wistar, but not F344 (McDonald and Hamilton, 1990). Clinical signs generally occur in rats greater than 24 months of age and vary from posterior gait abnormalities to posterior paresis or paralysis. Urinary incontinence or a loss of posterior muscle mass with resulting change in conformation may also be seen. On gross exam, hind-limb muscles appear brown, shrunken, and soft, especially in comparison with muscles from the cranial portions of the body. Histological appearance varies with disease chronicity. Early stages may be limited to a loss of muscle fiber diameter with or without loss of cross-striations (Berg, 1956, 1967; Van Steenis and Kroes, 1971). Disease progression continues through fragmentation and disintegration of fibers until the terminal collapse of the sarcolemmal sheath. Inflammation is characteristically absent. The etiology of skeletal myodegeneration is unclear, but may be associated with neurogenic atrophy secondary to radiculoneuropathy (Burek et al., 1976; Greaves et al., 2013; Van Steenis and Kroes, 1971). However, one study indicated that muscular atrophy, unlike radiculoneuropathy, could be delayed by calorie restriction (Berg, 1967). A congenital defect is thought to be the cause of hepatic herniation through the diaphragmatic musculature seen infrequently in F344 rats (McDonald and Hamilton, 1990, Fig. 16.17).

XI. INTEGUMENTARY SYSTEM A common finding involving the rat integumentary system is a roughened hair coat. While underlying

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FIGURE 16.17 Diaphragmatic hernia, gross appearance. Arrow shows herniation of a portion of a liver lobe through the diaphragm into the thoracic cavity. Image courtesy of the Unit for Laboratory Animal Medicine, University of Michigan.

causes of distress or malaise should be investigated, a rough hair coat may simply be a product of aging and thus not indicative of disease per se. Thinning of the pelage with a gradual buildup of yellowish sebum, growing darker with time, is frequently seen in older rats (Elwell et al., 1990; Otto et al., 2015). Pigmented scales develop along the dorsum, perineum, and tail of older rats, and, while dependent on age, strain, and sex, it does not appear to be related to any specific disease (Tayama and Shisa, 1994). Epidermolysis bullosa disorders, congenital skin diseases affecting the dermoepidermal junction resulting in blister-like lesions filled with blood or serous fluid, have been described in SpragueeDawley rats. Findings in a single litter, characterized by detachment of the epidermis at the lamina lucida, were suggestive of the junction form of the disease (Brenneman et al., 2000). In another report, histopathology and breeding trials were suggestive of dystrophic epidermolysis bullosa, which involves clefting below the basement membrane, inherited in an autosomal recessive manner (Eden et al., 2016). Epidermal inclusion cysts are infrequently identified in rats, occurring typically on the tail, hind limbs, and dorsal midline (Lake et al., 1989). Galactoceles, small masses within the mammary tissue resulting from obstructed and dilated ducts in older female rats, are a primary differential diagnosis for the commonly occurring fibroadenoma (Boorman et al., 1990b).

A. Traumatic and Husbandry-Related Conditions Various noninfectious causes of alopecia have been reported in the rat. While barbering is not as common

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in rats as it is in mice, it can occur (Bresnahan et al., 1983; Militzer and Konerding, 1989). Other causes of alopecia include fighting, excessive mutual grooming associated with high dietary fat content (Beare-Rogers and McGowan, 1973), and mechanical abrasion from feeding cups (Andrews, 1977). A well-recognized cutaneous lesion in rats is the development of scaly skin and single or multiple annular constrictive rings on the tail of suckling or preweanling animals. Edema is frequently seen distal to the constriction and may progress to a dry necrosis of the affected area (Fig. 16.18). This syndrome, commonly known as “ringtail,” although the hind limbs may also be affected, is traditionally attributed to low (below 25%) environmental humidity (Flynn, 1958; Njaa et al., 1957; Totton, 1958), although the condition may occur in environments with higher levels of relative humidity (Taylor et al., 2006). Other potential determinants include environmental temperature, dietary deficiencies, hydration status, and genetic susceptibility (Barthold et al., 2016; Dikshit and Sriramachari, 1958). Crippa et al. (2000) have detailed the histological findings associated with this condition. Daily topical application of lanolin is an effective treatment (Taylor et al., 2006). The tail is frequently used during handling and restraint. Attempts to pick up large rats by the distal tail may lead to skin tears and a degloving injury, also known as “tail slip” (Harkness et al., 2010; Kohn and Barthold, 1984; Fig. 16.19). Fighting may occur among some group-housed rats, with lesions typically occurring near the face or flank (Harkness et al., 2010). Self-trauma plays a pivotal role in the pathogenesis of UD. This condition, which ranges from alopecia to full-thickness ulceration usually presenting on the lateral shoulder or interscapular areas,

FIGURE 16.18 Annular constrictions (“ringtail”). Image courtesy of the Research Resources Facilities, University of Louisville.

FIGURE 16.19 Degloving injury. Image courtesy of the Unit for Laboratory Animal Medicine, University of Michigan.

has long been associated with Staphylococcus aureus infection (Ash, 1971) The importance of self-trauma in either initiating or perpetuating UD has been demonstrated by partial resolution with rear-limb toenail clipping (Fox et al., 1977) and complete recovery following hind-limb toe amputation (Wagner et al., 1977). Numerous topical and systemic antibiotic and antiinflammatory agents have been used to treat this disease in both rats and mice, including maropitant citrate, which interferes with neuropeptides associated with the itchescratch cycle (Williams-Fritze et al., 2011). Adams et al. (2016) described complete resolution with lack of recurrence following hind-limb toenail trimming, providing further evidence that UD may be initiated as a compulsive behavioral disorder, at least in mice. Other causes of self-induced trauma may include ectoparasites or dermatophyte infection. Pododermatitis (poditis, ulcerative pododermatitis, plantar decubitus ulcers, hock ulcers, “sore hocks,” “bumblefoot”) usually presents as nodular swellings, calluses, and decubital ulcers on the plantar surface of the rat foot (Fig. 16.20). These lesions, typically associated with housing in unsanitary conditions or on wirebottomed cages or other hard surface flooring, are the result of pressure-related avascular necrosis, and can progress to granulomas, generalized edema, and regional lymphadenopathy of the affected limb (Honma and Kast, 1989). Lesions, which generally require over a year to develop, are also associated with increased body weight with a possible stock/strain predilection (Peace et al., 2001). Dietary restriction significantly reduces the incidence and severity of pododermatitis, which otherwise may be a common finding in aging animals fed ad libitum (Duffy et al., 2004a). Wounds may become secondarily infected; treatment therefore requires not only improvements in housing, but strict attention to wound care and potentially surgical debridement (Blair, 2013).

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ear tag placement and may be followed by lesions in the contralateral ear within 4 weeks (Kitagaki et al., 2003). Chronic irritation and inflammation caused by the tags may initiate the autoimmune response (Meingassner, 1991).

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FIGURE 16.20 Pododermatitis. Image courtesy of the Unit for Laboratory Animal Medicine, University of Michigan.

A. Auricular Chondritis Characterized by a gross thickening of the pinnae, auricular chondritis (also called auricular chondropathy) is typically bilateral and ranges from focal nodules to diffuse swelling and disfiguration. It has been described in SpragueeDawley (Chiu and Lee, 1984), fawn-hooded (Prieur et al., 1984), and Wistar rats (McEwen and Barsoum, 1990). Histological examination reveals a predominantly granulomatous infiltrate disrupting the normal cartilaginous structures and resulting in multifocal nodular proliferation of cartilaginous tissue (Linton et al., 1994). Differential diagnoses include fibrochondroma, chondroma, and chondrosarcoma (Chiu and Lee, 1984). Swelling may spontaneously wane and regress entirely (Chiu, 1991). This condition has been proposed as a model for the suspected autoimmune-associated human disorder relapsing polychondritis. Similar lesions may be induced in rats via immunization with type II collagen; unlike the spontaneous condition, these animals develop arthritis (Cremer et al., 1981; McCune et al., 1982). A lack of responses to delayed hypersensitivity tests for type II collagen in spontaneous auricular chondritis also suggests that the autosensitization results from other pinnal cartilage proteins (Meingassner, 1991). Although lesions develop in rats without them, spontaneous auricular chondritis is often associated with metal ear tags. Unilateral lesions may occur within 1 week of

The reader is referred to Chapter 6, “Reproduction and Breeding,” for a treatise of the various causes of infertility and methods of enhancing reproductive indices in rat breeding colonies. Similarly, exhaustive lists of congenital malformations described in the rat fetus, which are important considerations in toxicology and teratology studies, and degenerative conditions that may have an impact on reproductive success in aging rats are beyond the scope of this text. Light cycles and total light exposure time can greatly influence the estrus cycle of rats. Constant environmental light may induce polycystic ovaries, endometrial hypertrophy, hyperestrogenism, and persistent estrus (Barthold et al., 2016). Exposure to even low-intensity light during the dark phase of the diurnal cycle induces ovarian atrophy (Beys et al., 1995). Both agenesis, unilateral or bilateral lack of development, and dysgenesis, which may include a mixture of both ovarian and testicular tissues, have been described in the rat ovary (Alison et al., 1990). Both longitudinal and transverse vaginal septa preventing conception or inducing mucometra, metritis, fetal death, and dystocia have also been described in the rat (Barbolt and Brown, 1989; Barthold et al., 2016). Reported incidence rates range from 2% in Wister rats (De Schaepdrijver et al., 1995) to over 6% in Spraguee Dawley rats, the latter rate potentially underestimated in groups for which an impedance meter probe was used to identify estrus cycle stage (Lezmi et al., 2011). Other spontaneous changes in the aging female reproductive tract include ovarian degeneration and cysts (Alison et al., 1990; Meites et al., 1978; Peluso and Gordon, 1992), endometrial cysts and cystic hyperplasia (Brown and Leininger, 1992), hydrometra and pyometra (Franks, 1967), granular cell aggregations in the cervix and vagina (Markovits and Sahota, 2000), vaginal epithelial inclusion cysts (Yuan and Lund, 1991), cystic dilatation of the vaginal fornix (Yoshitomi, 1990), and acinar cellular atrophy and fibrosis of the clitoral gland (Copeland-Haines and Eustis, 1990; Reznik and Reznik-Schu¨ller, 1980). Hematometra, cervical hypertrophy, and uterine prolapse are also seen in female rats (Leininger and Jokinen, 1990). Like other species, rats carrying the X-linked testicular feminized gene (Tfm) are insensitive to androgens, resulting in a pseudohermaphroditism with agenesis of

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male reproductive organs excepting underdeveloped and undescended testes, which are predisposed to developing Leydig’s (interstitial) cell tumors (Allison et al., 1965; Reddy and Rao, 1987; Yarbrough et al., 1990; Zuloaga et al., 2011). Testicular degeneration and atrophy may result from environmental extremes, nutritional or hormonal imbalance, or obstruction within local vasculature or in excretory ducts, and is a common finding in aged animals (Boorman et al., 1990a; Wright, 1987; Yuan and McEntee, 1987). Many changes seen in the male reproductive system are associated with aging. In the testes, these include seminiferous tubule atrophy and edema, dystrophic calcification, spermatocele granuloma, PAN (Takahashi et al., 1992), 1990), and focal interstitial cell hyperplasia (Boorman et al., 1987). Of these, seminiferous tubule atrophy was found to be the most common testicular lesion in 2-year-old SpragueeDawley rats (James and Heywood, 1979). The age of onset of interstitial cell hyperplasia could be significantly delayed by food restriction. Other than prostatic corpora amylacea, lesions within most of the male accessory sex glands are relatively rare and usually consist of either inflammation or atrophy (Bosland, 1992; Parker and Grabau, 1987). Conversely, preputial gland lesions are common in the aging rat and include acinar cell atrophy, fibrosis, duct distension, and inflammation, affecting up to 68% of 112-week-old F344 rats (Copeland-Haines and Eustis, 1990; Reznik and Reznik-Schu¨ller, 1980). In contrast to those conditions occurring primarily in older animals, epididymal granulomas may be found in 12-week-old Spraguee Dawley rats, possibly resulting in outflow obstruction of spermatozoa from the epididymis, producing distension, thinning, and eventually rupture of the ducts resulting in granuloma formation (Yamasaki, 1990).

Acknowledgments The authors acknowledge the contributions by Dr. Steven P. Russell for the previous edition of this work. We are deeply indebted to Dr. Ingrid Bergin for her assistance with the images used in this chapter, along with the contributions by Drs. Stephen W. Barthold and Dana K. Merriman. Finally, we note our appreciation to John Chenault, Tegan Tulloch, Sheila Carpenter, Melissa Carpenter, and Manon Gant, for their assistance.

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