Teratogenesis in Livestock

C H A P T E R

72 Teratogenesis in Livestock Robert W. Coppock, Margitta M. Dziwenka O U T L I N E Introduction

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Embryology of Domestic Animals

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Teratogenic Viruses Introduction Bunyaviruses Aino Virus Akabane Virus Cache Valley Virus Rift Valley Fever Virus Flaviviridae Bovine Virus Diarrhea Virus Border Disease Virus Hog Cholera Virus Japanese B Encephalitis Virus Orbivirus Teratogenic Plants Introduction Apiaceae Apocynaceae Dennstaedtiaceae Fabaceae Liliaceae Pinaceae Poaceae Rosaceae Solanaceae

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INTRODUCTION There are multiple agents that cause teratogenic effects in livestock. These range from viruses, chemicals, poisonous plants, and nutrient deficiencies to manipulation of embryos. Birth defects can occur by different mechanisms (Giavini and Menegola, 2012). It is estimated that the majority of teratogenic effects in livestock are Reproductive and Developmental Toxicology http://dx.doi.org/10.1016/B978-0-12-804239-7.00072-X

Nutritional Links With Fetal Development and Teratology Intrauterine Growth Minerals and Vitamins Manganese Deficiency CoppereMolybdenum IodinedThyroid Vitamin A

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Mycotoxins

1401

Pesticides

1401

Drugs Parasiticide Drugs

1401 1402

Environmental Chemicals and Factors Polyhalogenated Aromatic Hydrocarbons Mercury Fetal Endocrine Disruption Altered Sex Ratio In Vitro Fertilization Systems Diagnosis

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Concluding Remarks and Future Directions

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References

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underreported and go undiagnosed. The investigation for a suspected teratogen requires a very systematic and multifaceted approach including many experts’ examinations including a thorough history of potential exposures and multiple sample collections and testing. The teratogens, which have been identified, have generally been endemic in an area or have been reproduced under laboratory conditions. For example, many of the

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Copyright © 2017 Elsevier Inc. All rights reserved.

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72. TERATOGENESIS IN LIVESTOCK

congenital defects of the central nervous system of calves are not diagnosed (Leipold et al., 1993). Many congenital defects, regardless of the cause, are not compatible with life and end in loss of the conceptus (Leipold, 1984). Dennis (1993) reported that congenital defects in sheep occur in 0.2e2% of the lambs born, and of these, 50% are stillbirths. In horses, it is estimated that 2e3% of aborted fetuses and stillborn foals have anomalous anatomical development (Whitwell, 1980). Many animal breeders assume that the birth defects are genetically inherited in origin, and this assumption results in underreporting. Reporting and investigating congenital defects is essential if the etiology is to be established. Epigenetic and environmental factors can cause birth defects and pathophysiological effects in endocrine and biochemical functions. Six basic principles of teratology have been described initially in 1959 by Wilson and are still applicable. These include genetic susceptibility, time of exposure, pathogenesis of the defective development, definition of abnormal development, chemical nature of the teratogen, and dosage (Panter and Stegelmeier, 2011). Species and breeds differ in their sensitivity to teratogenic substances. For a particular teratogen, some species are resistant and others are sensitive. This likely reflects differences in xenobiotic metabolism and embryologic and fetal development factors. The stage of gestation in which the insult occurs is important in determining the organ systems that is vulnerable. It is estimated that many teratogenic effects are not compatible with embryonic fetal life and end in resorption, abortion, or mummification. Many pharmaceutics and biologics labeled for use in livestock have disclaimers for safety in pregnant females because they have not been evaluated for teratogenic effects.

EMBRYOLOGY OF DOMESTIC ANIMALS A brief review of mammalian embryological development provides a background for teratology in the context of gestational timing of organogenesis and development. The gestational stage at which the exposure occurs can determine the terata observed in the fetus. Early in development, vertebrate embryos pass through a stage where they are all anatomically similar and only later in development do the species-specific differences become apparent (Table 72.1). Prenatal development is divided into four main periods: fertilization, blastogenesis, embryogenesis, and fetogenesis (Szabo, 1989). Fertilization is the union of the male and female germ cells to form a zygote. The zygote undergoes a series of rapid cell divisions known as cleavage and then develops into a hollow blastocyst that implants in the uterine endometrium. The timing and process of implantation varies between species and may be delayed in some species to

allow for favorable environmental conditions at parturition. The developmental environment is able to create alterations in the epigenetic settings that can cause long-term changes in homeostasis, meaning that the environment during development can have an important impact on the health and epigenetic phenotype expression of the offspring (O’Neill, 2015). An example is a freemartin female calf (XX maleness) born twin to a bull calf (XY normal) (Harikae et al., 2012). There are two major points of epigenetic reprogramming which occur; the first is during the formation of the primordial germ cells and the second occurs after fertilizations. In the majority of domestic species, such as the cat, dog, cattle, horse, sheep, and swine, the blastocyst develops to a point where it fills the majority of the uterine cavity. This is known as central or superficial implantation. Embryogenesis is the period when organ formation and differentiation occurs. All vertebrate embryos develop into three sheets of cells or germ layers, and it is from these that all tissues and organs later develop. The outermost layer is the ectoderm from which the neural tissues, epidermis, and some of the bony and connective tissue structures of the head will develop. The middle layer or mesoderm consists of a more loose population of cells that will eventually form the majority of the muscles, skeletal structures, and urogenital and cardiovascular systems. The endoderm is the deepest layer and forms the lining of the digestive tract and respiratory system, and the organs related to digestion. It is important to note that almost all the organs or tissues in the body develop from more than one germ layer or from different parts of the same germ layer (Noden and de Lahunta, 1985). Embryonic development proceeds in a rostral to caudal fashion; therefore, many of the organs/tissues present in early organogenesis are associated with the head and neck (Noden and de Lahunta, 1985). Many vertebrate embryos are very similar at the stage of development when the primordial structures of the majority of the organ systems are present. Differences between species in developmental rates and genetic expressions may be responsible for the varying responses observed to the same environmental insult (Szabo, 1989). The body of the embryo is covered by the ectodermal epithelium, and beneath this layer is the hollow neural tube that runs down the dorsal midline (Noden and de Lahunta, 1985). The neural tube has a number of enlarged vesicles located rostrally, which are the early manifestations of the brain. Another hollow tube is located near the ventral midline and will develop into the gastrointestinal system, and layers of endoderm and ectoderm close the rostral and caudal ends of this tube. The more rostral end is the pharynx and is already specialized in the embryo with lateral outpouchings that extend to the ectoderm and are known as pharyngeal pouches. The remaining tissues present at this stage in the embryo are

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TABLE 72.1

Comparison of Major Prenatal Events in Domestic Animals (Day Postconception)

Event

Cat

Dog

Cattle

Horse

Sheep

Swine

Morula

e

e

5e7

3e8

3e4

3e4

Blastula

6e8

8e10

8e10

13e14

5e8

5e10

Implantation

12e14

13e14

11e13

e

10e14

10e12

Primitive streak

12e14

14e15

14e18

14e15

13e14

11e12

First somites

13e14

14e16

18e20

15e17

14e15

13e15

First brachial arches

14e15

e

22e24

20e21

17e18

15e17

Neuropore (anterior) closed

e

17e18

23e25

20e22

18e19

5e16

Optic vesicle

14e15

14e15

23e24

e

19e20

16e18

Heart beat

21e22

23e25

21e24

22e25

18e20

19e24

Lens and optic cup

21e22

e

e

26e30

23e25

19e20

Neuropore (posterior) closed

e

18e19

24e25

22e24

19e20

15e16

Forelimb buds

17e18

21e22

24e25

26e28

21e22

16e18

Olfactory pits

20e21

22e23

30e31

e

23e25

20e21

Tail buds

e

19e20

26e30

e

22e23

15e18

Hind-limb buds

18e19

21e22

26e28

28e30

22e23

18e20

Intestinal loops herniate into umbilical cord

20e21

30e32

e

e

e

20e21

Pigment in eye

21e22

25e26

30e31

31e36

24e25

20e21

Tongue

26e27

25e27

44e45

e

e

25e28

Auditory meatus

21e22

24e25

34e35

36e37

25e27

23e26

Vibrissary papillae

23e24

28e30

44e45

e

38e42

28e30

Eyelids forming

24e25

30e32

38e39

38e40

27e28

36e38

Nasomaxillary process

22e24

e

34e35

30e36

30e34

24e28

Pinna

23e24

25e28

38e40

35e40

27e28

28e30

Forelimbs digits separate

24e26

30e35

33e34

35e36

35e38

30e32

Hind limbs digits separate

26e27

32e36

36e38

38e40

e

32e34

Hair follicles on trunk

27e28

42e43

70e76

e

e

55e56

Eyelid closure

30e31

39e40

58e60

60e63

43e45

40e50

Palate closure

31e32

30e35

54e56

46e48

35e38

34e36

Intestinal withdrawal into abdomen

e

35e40

e

e

e

45e50

Hair around eyes and muzzle

35e37

37e38

70e76

96e110

80e90

32e36

External genitalia differentiate

e

33e35

56e60

43e45

41e43

36e55

Birth

60e65

60e65

280e340

330e340

145e155

112e116

Adapted from Szabo, K.T., 1989. Congenital Malformations in Laboratory and Farm Animals. Academic Press, San Diego.

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mesodermal. Future body segments, known as somites, develop in a craniocaudal direction until approximately 40 pairs are formed. The head and tail folds are evident at the 7-somite stage and by the 10-somite stage, the first mandibular process arch and developing pericardium are evident. The second hyoid arches and maxillary and mandibular features are seen in the 14-somite embryo and the anterior neuropore is closed in the 20-somite embryo. The posterior neuropore closes by the 25- to 28-somite stage, and the third pharyngeal arch, optic vesicles, and umbilical cord develop in the later stages. The parts and regions of the body are clearly recognizable as embryogenesis continues and the limb buds subdivide and future digits become evident. The facial processes gradually increase in size and the snout begins to form with closed external nares. The future lens and pigment become evident in the optic vesicle and eyelids and external ears are recognizable. By the end of embryogenesis, all the recognizable features of the species are present (Szabo, 1989). The next period is termed fetogenesis and is defined by rapid growth; however, not all regions of the body grow at the same rate. For example, at the beginning of the fetal period, the head is approximately one-half of the total body length while by the end of the period it is only one-fourth of the length (Szabo, 1989). During this period, the features and structures of the fetus develop and move into their final shape and positions. A comparison of the major prenatal events in domestic animals is presented in Table 72.1. Functional expression of striated muscles has been shown to be important in joint development. Studies in mice have shown that muscle contraction is one mechanism that stimulates joint formation through the Wnt/b-catenin pathway (Kahn et al., 2009). This pathway is important for maintaining joint cell fate leading to cell differentiation that ultimately forms synovial joints. There is evidence that other mechanisms are also involved. Fetal akinesia is considered to be a cause of arthrogryposis with subsequent development of joint contractures (Steinlein, 2007; Green et al., 2013a). Kyphosis, lordosis, scoliosis, and torticollis are also considered to be caused by fetal immobilization progressing to abnormal joint development (Swinyard and Bleck, 1985). The piperidine, pyridine, and quinolizidine alkaloids found in plants can have the structural affinity for the nicotinic acetylcholine receptors. In the fetus, toxic substances that block the nicotinic acetylcholine receptors induce fetal “paralyses,” and the decrease of fetal movement is linked to the toxicokinetics of the toxic agent with variation between breeds of cattle (Green et al., 2013b; 2015). Cleft palate is an orofacial defect and is a malformation that occurs in most domestic species. The formation of the oral palate and related structures depends on

temporal occurrences of sequentially complex events (Buser and Pohl, 2015). Briefly, these events are outgrowth of the vertical palatal shelf from the maxillary prominences, palatal shelf elevation to a position above the tongue, and fusion of the palatal shelves to form the oral nasal barrier. Cleft palate condition is generally caused by extrinsic factors, and these disruptions can be mechanical interferences with structural movement and chemical disruptions in gene expressions. Some chemicals can be specific in only causing cleft palate terata in a species (Hu et al., 2015). There is evidence that the specific orofacial defect that occurs is linked to the timing of exposure to culpable chemicals that perturb Hh signaling of craniofacial development (Heyne et al., 2015). There is also evidence that the tongue causes mechanical interference with elevation and fusion of the palatal shelves and the root causes are faults in genetic expression (Hu et al., 2015; Kouskoura et al., 2016).

TERATOGENIC VIRUSES Introduction The interactions of teratogenic viruses with chemical teratogens have not been studied in livestock. Teratogenic viruses can be an important cause of terata in livestock. The majority of the teratogenic viruses have been studied in livestock species (Table 72.2). Teratogenic viruses as a cause of congenital defects generally can be determined by virological and serological methods.

Bunyaviruses Aino Virus Experimental studies have shown that the Aino virus is teratogenic in cattle. Fetuses injected with Aino virus on days 132e156 of pregnancy had arthrogryposis, hydranencephaly, and cerebellar hypoplasia at birth (Tsuda et al., 2004). Akabane Virus Akabane virus is in the genus Orthobunyavirus and is a member of the Bunyaviridae family. It is widely distributed in temperate to tropical regions of the world. Akabane virus is a recognized teratogen in cattle, sheep, and goats (Charles, 1994; Oberst, 1993). These reports are primarily from Japan, Korea, Taiwan, Australia, Israel, and Turkey. The virus replicates first in the placentome and then in the fetus. The teratogenic effects of in utero Akabane virus infection are secondary to the effects of the virus on the developing nervous system (Swinyard and Bleck, 1985). The affected conceptus show severe muscle atrophy and fixation of the joints by tendon contracture.

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TERATOGENIC VIRUSES

TABLE 72.2

Summary of Teratogenic Viruses

Virus

Species

Terata

Gestation Day

Reference

Aino

Cattle

Arthrogryposis, hydranencephaly, and cerebellar hypoplasia

132e156

Tsuda et al. (2004).

Akabane

Cattle

Arthrogryposis, hydranencephaly, hydranencephaly, and porencephaly

76e173

Charles (1994); Oberst (1993); Kono et al. (2008).

Hydranencephaly, retinal dysplasia

30e105

Maxie and Youssef (2007); Oberst (1993); Vercauteren et al. (2008); Dal Pozzo et al. (2009); Dennis (1993).

Sheep Goats Blue tongue

Cattle Sheep

Border disease

Sheep Goats

Bovine virus diarrhea

Cattle

50e55

Scoliosis, brachygnathism, prognathism, arthrogryposis, hydranencephaly, cerebellar hypoplasia, and hairy fleece

First and second trimester

Oberst (1993); Nettleton et al. (1998).

Hydrocephalus, hydranencephaly, porencephaly cerebellar hypoplasia, microcephaly, demyelination and brachygnathism, retinal dysplasia and atrophy, optic atrophy, cataract, microphthalmia and persistent pupillary membrane, brachygnathism, retarded growth and growth arrest lines, thymic aplasia, pulmonary hypoplasia, hypotrichia to alopecia

75e170

Blanchard et al. (2010); Schlafer and Miller (2007); Dubovi (1994); Maxie and Youssef (2007); Leipold (1984).

Akabane virus can cause arthrogryposise hydranencephaly syndrome in calves (Charles, 1994; Kono et al., 2008). The teratogenic mechanism for arthrogryposis caused by nervous system dysfunction is considered to be decreased limb movement (Van Vleet and Valentine, 2007). Timing of infection is important in expression of teratogenic effects. Hydranencephalic and porencephaly effects generally occur in the fetus when the cow is infected on days 76e104 of gestation. The arthrogryposis deformity (multiple congenital contracture) occurs when the cow is infected on days 103e173 of pregnancy. Vertebral deformities can occur, which include torticollis and scoliosis; these can occur with and without deformed limbs. The association between infection with Akabane virus and teratogenic effects is generally based on serologic evidence. In pregnant cows infected with Akabane virus, fetal infections occur in 20e40% of the cow infections. The Akabane virus is teratogenic in lambs and kids. In sheep and goats, prevalence of abortions is high and lambs are born with arthrogryposis accompanied with hydranencephaly and hydrencephalus. The most sensitive time for teratogenic effects is during the first and second trimester of pregnancy. Prolonged gestation can also be observed and can be an effect of fetal endocrine dysfunction.

Cache Valley Virus The Cache Valley virus (CVV) has been shown to cause hydranencephaly, hydrocephalus, porencephaly, micrencephaly, arthrogryposis, torticollis, and scoliosis in sheep (Chung et al., 1990; Oberst, 1993; Edwards, 1994). The most sensitive interval is gestation days 36e46. The CVV has been identified in malformed lambs in Texas. The LaCross, San Angelo, and Main Drain viruses produce identical congenital defects as the CVV (Edwards et al., 1997). Rift Valley Fever Virus Rift Valley fever virus is considered to be teratogenic in sheep (Oberst, 1993). Vaccination at 30e105 days of pregnancy with modified live virus (Smithburn strain) has been reported to cause hydrops amnii, arthrogryposis, and hydranencephaly in sheep (Bird et al., 2009). Rift Valley fever virus also causes abortion in ruminant species (Pepin et al., 2010).

Flaviviridae Bovine Virus Diarrhea Virus Bovine virus diarrhea virus is in the family Flaviviridae, genus Pestivirus, and is known to be teratogenic

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(Leipold, 1984; Leipold et al.,1993; Oberst, 1993; Baker, 1995; Maxie and Youssef, 2007). Both the cytopathic and noncytopathic strains of the virus are considered to be teratogenic. Exposure of susceptible dams to the virus during days 75e170 of gestation can result in skeletal and neurological defects (Maxie and Youssef, 2007; Blanchard et al., 2010). Neurological and skeletal defects include hydrocephalus, brachygnathism, hydranencephaly, porencephaly, cerebellar hypoplasia, micrencephaly, demyelination and brachygnathism, retarded growth and growth arrest lines, thymic aplasia, and pulmonary hypoplasia. Ocular defects observed with Bovine virus diarrhea are retinal dysplasia and atrophy, optic atrophy, cataract, microphthalmia, and persistent pupillary membrane in the eye, and hypotrichia to alopecia. Border Disease Virus Border disease virus is teratogenic in sheep (Oberst, 1993; Nettleton et al., 1998). Teratogenic lesions reported are scoliosis, brachygnathism, prognathism, arthrogryposis, hydranencephaly, cerebellar hypoplasia, and hairy fleece.

demonstrated in livestock species or laboratory animals. A few plants have been shown to be teratogenic in livestock species or are suspected of being teratogenic in livestock species. Plants of different species that contain the same toxins can produce similar teratogenic effects (Panter et al., 1999a; Molyneux et al., 2007). The stage of gestation when exposure occurs is important as teratogenic effects may only be expressed at a specific stage of embryologic development (Binns et al., 1964). Teratogenic phytotoxins have delayed effects that are not seen for weeks or months later when the plant is no longer obvious in the pasture, or representative harvested or purchased feedstuffs are not available for examination, which makes linkages with causation difficult. Plants contain mixtures of phytotoxins, and the multiple chemical interactions involved in the expression of teratogenic effects are not well understood. Some phytotoxins may be inherently teratogenic and others undergo biotransformation to the ultimate teratogen. The phytotoxins in plants can vary with season, geographical area, and stages of plant growth. Additionally, the concentration of phytotoxins can be distributed unevenly between roots, fleshy parts, and seeds.

Hog Cholera Virus The hog cholera virus is considered to cause teratogenic effects when the fetus is infected on gestation days 13e14. Teratogenic effects are cerebellar and spinal hypoplasia, hydrocephalus, arthrogryposis, and piglets born with congenital tremors (Oberst, 1993). Japanese B Encephalitis Virus The Japanese B encephalitis virus has been reported to cause birth defects in piglets (Radostits et al., 2007).

Orbivirus Blue tongue virus is considered to be a teratogenic virus in cattle and sheep (Dennis, 1993; Maxie and Youssef, 2007; Vercauteren et al., 2008; Dal Pozzo et al., 2009). The congenital defects observed are hydranencephaly (hydrocephalus internus). This lesion is considered to be a type 1 porencephaly. In addition to hydranencephaly, retinal dysplasia has been observed in sheep (Oberst, 1993). The sensitive period for fetal infection is 30e105 days of gestation in cattle and 50e55 days of pregnancy in sheep.

Teratogenic Plants Introduction Chemicals found in plants can be teratogenic in livestock (Burrows and Tyrl, 2001). The majority of teratogenic effects of poisonous plants have been

Apiaceae Poison hemlock (Conium maculatum), in North America, is a nonnative teratogenic plant (Burrows and Tyrl, 2001). It grows well in moist soil and along stream banks, roadside ditches, and cultivated fields and can grow in dense stands (Bischoff and Smith, 2011). Conium maculatum is teratogenic in cattle, pigs, and sheep (Edmonds et al., 1972; Keeler, 1974; Keeler and Balls, 1978; Panter et al., 1985a,b). Coniine and gamma coniceine are the nicotine-like pyridine alkaloids that are considered the teratogenic agents (Burrows and Tyrl, 2001). Coniine predominates in the mature plant and seeds, and gamma coniceine predominates in early growth (Panter et al., 1988a,b). Ewes administered C. maculatum at doses sufficient to cause material toxicity gave birth to lambs that had contracture and lateral deviation of the carpal joint (Panter et al., 1988a). The deviation and flexure of the carpal joint generally resolved with growth of the lamb. Sows administered C. maculatum seeds or plants, dose
1.07 mg of gamma-coniceine/kg body weight, from gestation day 30 to 45 give birth to piglets with lesions of cleft palate and brachygnathia (Panter et al., 1985a). Sows administered C. maculatum seed or plant materials on gestation days 43e61 gave birth to piglets showing arthrogryposis and twisted and malaligned bones in the limbs, and thoracic cage deformity can occur (Panter et al., 1985b). Teratogenic effects consisting of arthrogryposis and spinal curvature were observed in calves when cows were administered C. maculatum on gestation days 50e75 of gestation (Keeler and Balls,

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TERATOGENIC VIRUSES

1978). Administering per gavage fresh poison hemlock or gamma coniine to cattle on gestation days 40e75 caused teratogenic lesions of arthrogryposis and scoliosis in live calves. Teratogenic effects were not observed in foals born to mares administered coniine on gestation days 45e75 (Keeler et al., 1980). The plant tissue and seeds from C. maculatum administered on gestation days 30e60 were observed to be teratogenic in goats with the seeds remarkably producing more teratogenic effects (Panter et al., 1990a,b). The congenital effects observed were multiple congenital contractures that included torticollis, scoliosis, lordosis, arthrogryposis, over extension, and flexure and rigidity of the joints. Ribcage abnormalities were also observed. Apocynaceae The Apocynaceae family contains the xerophilous tree Aspidosperma pyrifolium. This tree grows in the semiarid regions of Brazil and causes abortions and premature parturition in goats (Riet-Correa et al., 2012). Kids born premature generally die. Feeding trails have shown that 4e10 g of fresh leaves/kg body weight fed for 18e30 days causes abortions. Abortions in ewes and cows grazing range lands containing A. pyrifolium have not been reported. Feeding studies have not been conducted in pregnant ewes and cows. Dennstaedtiaceae Bracken fern (Pteridium spp.) is found throughout the United States and in most areas of the world. The ingestion of bracken fern by pregnant dams has been associated with retarded fetal development in rats and mice (Burrows and Tyrl, 2001). The toxic principle is ptaquiloside, but this effect does not appear to have been reported for livestock species. Fabaceae Genera that contain teratogenic species include Astragalus, Oxytropis, and Lupinus. Astragalus lentiginosus, Astragalus pubentissimus, and Oxytropis sericea are teratogenic in sheep and cattle, and Astragalus mollissimus has been incriminated as a teratogen in horses (James et al., 1969; McIlwraith and James, 1982; Panter et al., 1989; Panter and Keeler, 1990; James et al., 1994a; Radostits et al., 2007). Skeletal defects and limb contractures were observed in lambs born to ewes fed Astragalus and Oxytropis spp. at various times from gestation days 1e120 (James et al., 1967, 1969; Keeler et al., 1967). Other teratogenic effects in lambs are weak lambs with decreased nursing vigor and decreased cardiac function (James, 1972; Panter et al., 1987, 1999a,b; James et al., 1994a). Neuroaxonal dystrophy, neurovisceral cytoplasmic vacuolization, vacuolization of the thyroid acinar epithelium, kidney proximal tubular cells, hepatocytes, and adrenal cortical cells have been observed

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in fetuses from ewes fed A. lentiginosus (James, 1972; Hartley and James, 1973, 1975). Astragalus lentiginosus and A. pubentissimus have been observed to be teratogenic in cattle. The teratogenic substance in species of Astragalus and Oxytropis is reported by some authors to be swainsonine. However, plants in Australia that contain swainsonine have not been reported to be teratogenic in sheep and cattle, suggesting that a mixture of compounds may be required for the teratogenic effect (Keeler, 1988). Studies have showed that the teratogenic effects of aminoacetonitrile and a,g-diaminobutyric acid in sheep and aminoacetonitrile in cattle are similar to teratogenic effects of Astragalus and Oxytropis spp. (Keeler et al., 1967; Keeler and James, 1971). Species of Lupinus are teratogenic and cause “crooked calf disease” characterized by arthrogryposis, kyphosis, scoliosis torticollis, and cleft palate (Shupe et al., 1967, 1968; Panter et al., 2002). Species shown to be teratogenic are Lupinus arbustus, Lupinus caudatus, Lupinus formosus, Lupinus sericeus, and Lupinus laxiflorus (Panter and Keeler, 1990; Panter et al., 1998). The most sensitive period for teratogenic effects in cattle is gestation days 40e70, and limb contractures can occur at later times in gestation (Shupe et al., 1967; Panter et al., 1998). A number of compounds have been proposed as being the teratogenic agents, but rather than a specific chemical, the overall effect of a mixture of plant chemicals decreasing fetal movement could be the mechanism of action (Keeler et al., 1969; Keeler and Panter, 1989; Burrows and Tyrl, 2001). The putative teratogens are anagyrine and ammodendrine, and studies have shown that body condition of the cow can alter their toxicokinetics (Keeler and Panter, 1989; Lee et al., 2008). The alkaloid profile of Lupinus sulphureus was reported as varying between geographic regions (Cook et al., 2009). Thus, a number of variables can affect the teratogenic effects of lupines. Milk from goats feeding on lupine has been incriminated as a teratogen causing bilateral radial hemimelia, red cell aplasia, and persistent azygous vein in a human baby (Ortega and Lazerson, 1987). The mother, during pregnancy, was sick on several occasions after drinking goat milk. One goat gave birth to a kid with deformities similar to crooked calf disease, and a pregnant bitch that drank goat’s milk subsequently gave birth to pups with abnormal limbs. Other plants in the Fabaceae family have been shown to be teratogenic. The leaves of Leucaena leucocephala, a tropical shrub legume, are high in protein and are used as forage. In a feeding trial in pigs, L. leucocephala at 10% of the diet was considered to cause abortions and polypodia of pectoral limbs (Wayman et al., 1970). Mimosa ophthalmocentra and Mimosa tenuiflora have been shown to be teratogenic in cattle, sheep, goats, and rats (Riet-Correa et al., 2012). High occurrences of embryonic deaths were observed to occur in goats after

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administration of M. tenuiflora during the first 30 days of pregnancy (Dantas et al., 2012). In some regions of Brazil, the occurrences of terata can vary from 1% to 100% of the kids and lambs affected. Higher incidence occurs when feeding grain and grain by-products after the dry season. This may be because of the “flushing” effect of the grain including estrus-ovulation and pregnancy concurrent with browsing on M. tenuiflora. The terata observed include palatoschisis, arthrogryposis, kyphosis, scoliosis, torticollis, hyperlordosis, acephaly, bicephaly, hydranencephaly, and variations of these malformations. Liliaceae Plants in the Liliaceae family (lily) are known or suspected to be teratogenic (Burrows and Tyrl, 2001). Western false hellebore (Veratrum californicum) fed to ewes on gestation days 10e15 caused cyclopian-type or holoprosencephaly terata (Binns et al., 1962, 1964; Shupe and James, 1983). Holoprosencephaly-type terata has been observed in foals born to mares that graze Veratrum eschscholtzii (Shupe and James, 1983). Holoprosencephaly is caused by impaired midbrain cleavage of the fetal forebrain and the most severe forms result in cyclopia. Prolonged gestation may occur and is considered to be caused by the absence of a fetal pituitary gland (Burrows and Tyrl, 2001). Deformities of the limbs can occur in lambs if the ewes are exposed on gestation days 28e32. Lambs may also be born with tracheal stenosis. Feeding V. californicum after gestation day 15 can cause abnormal brain development in sheep (James, 1974). Under field conditions, V. californicum consumed by pregnant ewes also causes early embryonic death and the only observed clinical sign is open (nonpregnant) ewes (Keeler, 1990). Species of Veratrum contain the alkaloids jervine, cyclopamine (11-deoxojervine), and cycloposine (3-glucosyl-11deoxojervine), and these compounds are known to be teratogenic (Keeler, 1984). Chemical structure of cyclopamine is shown in Fig. 72.1. Jervine has been identified in Zigadenus spp. giving this species teratogenic potential (Burrows and Tyrl, 2001). The primary teratogens are cyclopamine and jervine, and the critical exposure time is gestation days 13e15 (Molyneux et al., 2007; Welch et al., 2009). Cyclopamine in unstable at pH <2 and in Lewis acids, and under these conditions, it aromatizes to form veratramine (Heretsch et al., 2010; Heretsch and Giannis, 2015). Some cyclopamine enters the intestine and is absorbed. The dried root of V. californicum contains about 2.34 g of cyclopamine/kg of plant material. The mechanism of action is considered to be cyclopamineinduced faults in the cascade of events that occur during fetal development in the hedgehog-signaling pathway (Heretsch et al., 2010; Heretsch and Giannis, 2015). The hedgehog gene (hh), a key regulator in embryonic development, is essential and is highly conserved. Three unique

FIGURE 72.1

Chemical structure of cyclopamine.

proteins [Shh (Sonic hedgehog), Ihh (Indian hedgehog), and Dhh (Desert hedgehog)] are encoded by the hedgehog gene and are ligands of membrane-bound Patched protein and indirectly influence the hh responsive genes. After their translation, the hedgehog proteins undergo a biochemical process of maturation and are released from the cell. These active forms of hh-coded proteins are ligands for the Patched protein and activation of dynamic activity in the cell cilium and motor-like trafficking of the Patched and Smoothened protein (Smo). The Smo can exist in different states. The Patched protein is removed from the cilium, likely by lysosomal activity, and SmoC inhibits the activation of Gli2/2. The active Gli factors bind to their nuclear promoters and stimulate the transcription of the hh response genes. In the absence of hh ligand, the Patched1 protein is found at the base of the primary cilia, a tail-like projection of the cell membrane. Patched1 blocks the translocation of the membrane-bound Smoothened receptor. The suppressor of the protein Fused is active and inhibition of the hh signaling occurs. Cyclopamine inhibits the Shoothened proteins, and the hh signaling is shut down. The Shh gene is required for the development of bilateral symmetry and the correct formation of limbs, skeleton, muscles, skin, eyes, lungs, teeth, nervous system, and intestines plus other essential activities. There is interest in cyclopamine and its analogs as antineoplastic drugs (Lee et al., 2014). Pinaceae Pregnant cows consuming ponderosa pine (Pinus ponderosa), in addition to abortion, can give birth to small and sickly calves (James et al., 1994b; Burrows and Tyrl, 2001). The mechanism of action is considered to be alterations in steroid metabolism and necrosis of luteal cells in the corpus luteum. Long-term endocrine disruptions in the offspring, if they occur, are not known. The toxins are in the labdane acid group of chemicals and have been identified as isocupressic

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acid and its acetal and succinyl derivatives. A study has shown that the rumen flora and fauna are important in metabolizing labdane acid compounds, and variations in rumen metabolic activity could explain variations in the susceptibility of cows (Welch et al., 2012). Lodgepole pine (Pinus contorta) and juniper (Juniperus communis) also contain isocupressic acid and cause abortions in cattle (Gardner et al., 1998). Poaceae Six of eight heifers grazing a regrowth of droughtstressed Sudex (Sorghum spp.) gave birth to calves with rigid flexion of the rear limbs. Wallerian degeneration of the spinal cord and ventral and lateral tracts in the medulla and pons were also affected (Seaman et al., 1981). Sorghum spp. have also been associated with musculoskeletal defects in foals. Burrows and Tyrl (2001) were not able to repeat this condition in horses by administering cyanide to pregnant mares. Additional observations are required to define the teratogenic effects of Sorghum spp. Rosaceae Pregnant sows consuming black cherry (Prunus serotina) were observed to give birth to piglets with deformed limbs and agenesis of the tail and anus (Selby et al., 1971). The pregnant dams were eating leaves and bark from black cherry trees.

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observed in piglets born to sows administered N. glauca on gestation days 16e68 (Keeler et al., 1981a,b).

NUTRITIONAL LINKS WITH FETAL DEVELOPMENT AND TERATOLOGY Intrauterine Growth Intrauterine growth retardation (IUGR) is becoming a concern in domestic livestock production and is defined as impaired growth and development of the mammalian embryo/fetus or its organs during development (Wu et al., 2006). IUGR can decrease neonatal survival, stunt postnatal growth, decrease the efficiency of feed utilization, negatively affect whole body composition and meat quality, and impair long-term health (Wu et al., 2006). There are numerous studies showing that the conceptus of eutherians is sensitive to the direct and indirect effects of maternal nutrition. IUGR can be induced by underfeeding, overfeeding, heat stress, disease, and toxic substances in cattle, sheep, horses, goats, sheep, and dogs. Placental and fetal growth are controlled by genetic, epigenetic, and environmental factors. The placenta is important in regulating fetal growth. Low birthweight is associated with decreased neonatal survival. Proteome differences occur in the endometrium and placenta causing pathophysiological changes leading to IUGR (Chen et al., 2015).

Solanaceae Plants in the genera Nicotiana have been shown to be teratogenic. Nicotiana tabacum was associated with an epidemic outbreak of congenital defects in piglets fed tobacco stalks and was later shown to be teratogenic in pigs (Menges et al., 1970; Crowe and Pike, 1973; Crowe and Swerczek, 1974). Wild tree tobacco (Nicotiana glauca) is teratogenic in calves when cows were administered N. glauca on gestation days 45e75 (Keeler, 1979; Keeler et al., 1981a,b). The teratogenic effects were moderate to severe arthrogryposis of the pectoral limbs, abnormal spinal curvature, and rib cage deformity. Nicotiana glauca and anabasine-rich extracts have been shown to be teratogenic in goats when administered on gestation days 32e41 (Panter et al., 1990b; Weinzweig et al., 1999). The teratogenic lesion was cleft palate and decreased fetal movement; hyperflexion of the neck and wedging of the tongue obstructing migration of the palatal shelves were observed (Panter et al., 1990b; Weinzweig et al., 2008). Ewes administered N. glauca on gestation days 34e55 gave birth to lambs that had moderate to severe flexure of the carpal and metacarpal joints, abnormal rotation of the limbs and some lambs had lordosis (Keeler and Crowe, 1984). The less severe flexure resolved within 4e6 weeks. Arthrogryposis has been

Minerals and Vitamins Manganese Deficiency Manganese (Mn) deficiency has been reported to cause congenital defects in calves (Rojas et al., 1965; Hansen et al., 2006). Congenital chondrodystrophy has been reported worldwide and is linked with drought and dietary deficiencies in manganese and zinc (White, 2016). There is failure of the endochondral ossification in the developing fetus. Manganese deficiency can be primary or secondary because of interference of absorption by high levels of iron or other substances in the diet. Pregnant cows and heifers deficient in Mn generally do not show clinical signs of deficiency. A study in beef heifers on the long-term effects of Mn deficiency showed that 17-month-old heifers (bred at 13 months of age) on a diet containing 15.8 mg of Mn/kg of dry matter (DM) gave birth to calves with limb and facial deformities (Hansen et al., 2006). Blood levels of Mn in pregnant heifers on the 15.8 mg of Mn/kg DM ratio were not different from pregnant heifers receiving a diet containing 50 mg Mn/kg DM. Congenital defects in the calves were smaller stature, and some calves had superior brachygnathism. Calves born to heifers on the 15.8 mg

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of Mn/kg DM diet had lower blood Mn levels. In another study, pregnant Hereford cows (4 years old) were fed a diet containing 16.6 ppm Mn for the proceeding 12 months (Rojas et al., 1965). The cows required four services/conception. The calves born to cows on the low-Mn diet showed enlarged joints, stiffness, twisted legs, and a general physical weakness. The calves also had shortened humeri that had a remarkable reduction in breaking strength. Neonatal knuckling of the pelvic limbs was also observed. Neonatal hepatic Mn levels were 11.84 and 6.94 ppm, respectively, for calves born to control and deficient cows. Neonatal renal levels of Mn were 2.52 and 1.17 ppm, respectively, for calves born to the control and deficient cows. Authors in South Africa, New Zealand, Australia, and Canada reporting field observations have described putative Mn deficiency of pregnant cows causing skeletal deformations in calves (Ribble et al., 1989; Hidiroglou et al., 1990; Staley et al., 1994; McLaren et al., 2007; Cave et al., 2008). Calves showed disproportionate limb to body trunk length (McLaren et al., 2007). The pathology has been described as brachygnathism, bilateral valgus deformity of the forelimbs, fetlock overextension, disproportionate shortening of length-to-epiphyseal diameter of predominantly the proximal limb bones, and reduced range of joint movement, and the vertebral column showed variable kyphosis and lordosis. Carpal bones can be malformed, and disorganization of the growth plates was observed. The mandible showed decreased trabecular bone. Similar observations were described in calves deficient in liver Mn and grazing forage from soil repetitively contaminated with sea water and high in strontium (Staley et al., 1994). Availability of Mn in the diet should be assessed if Mn deficiency is suspected. White (2016) conducted a field study in the Murray Valley of Australia. The herd had a history of congenital chondrodystrophy born to cows grazing unimproved native pasture in hilly landscape. Drought conditions existed at the beginning of the trial. Twenty pregnant cows with body condition of 3.0e3.5 were randomly chosen from a herd of 100 cows (8- to 10-year-old Angus and Angus crossbred). Cows, at the beginning of the study, were treated with ivermectin for parasite control. Supplemented cows were injected subcutaneously with a proprietary product containing copper, zinc, manganese, selenium, and multivitamins at 6-week intervals. Liver biopsies were also done at 6week intervals and assayed for copper, zinc, manganese, and iron. Pasture forage was collected and assayed for minerals and protein. Two cows from the group not receiving supplement had calves with congenital chondrodystrophy and superior brachygnathia, and one cow receiving injectable trace mineral supplement gave birth to a calf with congenital chondrodystrophy and superior brachygnathia.

CoppereMolybdenum Extreme copper (Cu) deficiency has been linked to a congenital defect in lambs known as swayback (Radostits et al., 2007). The Cu deficiency decreases the formation of myelin and causes demyelination, and this process may start in mid-gestation. Lambs may be affected at birth or there may be a delay in the onset of clinical signs. These may be linked to peaks in myelin development at day 90 of gestation and then again around day 20 of the postnatal period. Lambs born severely deficient in Cu can develop swayback in the critical postnatal period (progressive spinal swayback). Lesions are found in the white matter of the cerebrum in lambs affected at birth and in the spinal cord of lambs with delayed onset of clinical signs. Lambs may be stillborn or born small and weak with fine tremors of the head. Some lambs may be bright and alert, but will be uncoordinated with posterior weakness. Excessive molybdenum with sulfate interferes with copper absorption metabolism and causes swayback in lambs (Suttle and Field, 1969). Rumens are unique for excessive molybdenum to causes copper deficiency because tetra-thiomolybdate and other thiomolybdates are formed in the rumen and bindecomplex with copper (Gould and Kendall, 2011). The thiomolybdates are absorbed from the rumen and intestine and inactivate copper-containing compounds by bindingecomplexing mechanisms. Iron in the diet exacerbates the problem by mechanisms not fully understood. Brain structural lesions observed in the cerebral white matter are gelatinous softening and cavitation (Maxie and Youssef, 2007). Histopathology includes Wallerian degeneration in the dorsolateral and ventromedial tracts and other lesions occur. Molybdenum poisoning in lambs is the same as copper deficiency. IodinedThyroid Congenital goiter can be observed and generally is caused by dietary deficiency in iodine and dietary substances that interfere with iodine metabolism. In herds where congenital dietary iodine deficiency is observed, the addition of iodine to the diet stops calves being born with congenital goiter (Andrews et al., 1948; Wither, 1997). Brassica plants can be teratogenic in terms of causing congenital goiter in calves. Iodine deficiency during pregnancy causes alopecia or abnormal hair growth, skin edema, and other skeletal terata. There is putative evidence that high nitrate levels in forage fed to mares can be teratogenic and mimics congenital iodine deficiency (Allen et al., 1996). Full-term and prolonged gestation with immature foals was observed. Pathology observed in foals included hyperplastic thyroid, prognathic mandibulae, osteochondrosis consisting of incorrectly ossified carpal and tarsal bones, flexural deformities of the forelimbs, rupture of common digital

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extensor tendons, and incomplete closure of the abdominal wall. Signs of immaturity included short hair and pliable ears. Thyroid lesions have been observed in the fetuses of ewes that have ingested locoweeds (Hartley and James, 1973). A number of polyhalogenated aromatic hydrocarbons can cause endocrine disruption of the thyroid gland (Zoeller, 2010). Vitamin A Vitamin A deficiency (hypovitaminosis A) during pregnancy causes congenital defects in pigs and cattle (Done, 1968; Szabo, 1989; Wilcock, 2007; Maxie and Newman, 2007; Thompson, 2007). In cattle, abnormal development of the cranial bones and hydrocephalus with herniation of the cerebellum vermis occurs. Congenital blindness can occur and failure of the optic nerve foramen to remodel causes contracture of the optic nerve. In pigs, hypovitaminosis A during pregnancy causes congenital defects including hydrocephalus, compression and herniation of the spinal cord, hypoplasia of eye structures and microphthalmia, supernumerary ears, cleft palate, arthrogryposis, and dysmorphogenesis of skeletal muscle. Additionally, renal dysplasia, pulmonary hypoplasia, diaphragmatic hernia, hepatic cysts, and cardiac and genital malformations can be observed. Pups born to a bitch with hypovitaminosis A can have abnormal skeletal development of the head and spinal column and nervous system deficiencies including deafness and blindness.

to learn and retain spatial memory (Gotardo et al., 2016). Some mothers spent less attention to the newborn and maternaleneonate bonding was reduced. Reduced fetal movement and retrognathia and arthrogryposis have been observed in the fetus and neonates from doe goats fed I. carnea (Gotardo et al., 2012). Swainsonine had been identified in amniotic fluid and milk in rats treated with the aqueous extract of I. carnea (Hueza et al., 2007).

PESTICIDES Teratogenic effects of pesticides in farm animals have been reviewed (Szabo, 1989). Carbaryl is teratogenic to dogs (Smalley et al., 1968). Beagle bitches in a feeding study received doses of w3.13, 50, 25, 12.5, and 6.25 mg of carbaryl/kg body weight. The terata observed in all but the 3.13-mg/kg dose were abdominal and thoracic fissures and varying degrees of intestinal agenesis and displacement. Also observed were skeletal defects including brachygnathia, ecaudate pups, and superfluous phalanges. Several of the pups had multiple defects that were difficult to categorize. Dystocia was observed because of uterine atony. Carbaryl has been shown to be teratogenic in pigs. When administered to pregnant pigs at dietary levels of 4e16 mg/kg, carbaryl caused stillbirths and malformations in piglets. Diazinon administered to pregnant bitches causes increased stillbirths and neonatal deaths in dogs, but was not teratogenic. Diazinon is teratogenic in swine.

MYCOTOXINS There are few reports of mycotoxin-linked congenital defects in livestock. Griseofulvin, used as a drug, was found to be teratogenic in cats. Dacasto et al. (1995) reported that pregnant sows exposed to zearalenone in the feed give birth to female piglets with abnormal external genitalia. Mares grazing endophyte-infected fescue can have prolonged gestation and give birth to large weak foals (Porter and Thompson, 1992; Coppock and Jacobsen, 2009). Swainsonine is a mycotoxin, chemically an indolizidine alkaloid, produce by Chaetothyriales and Undifilum spp. and other fungi growing in or on various plant species (Cook et al., 2014; Kristanc and Kreft, 2016). Swainsonine is a potent inhibitor of lysosomal a-mannosidase and Golgi mannosidase II.There is evidence that calystegines produced by the plant Ipomoea carnea enhance the toxicity of swainsonine (Hueza et al., 2005). Behavioral changes were caused in goats fed I. carnea from day 27 to parturition (approximately day 150 of pregnancy) (Gotardo et al., 2011, 2016). Kids from dams fed greater than 3 g of fresh I. carnea/kg body weight had difficulty in standing, recognizing mother and suckling, and reduced ability

DRUGS Some drugs have been reported to be teratogenic in domestic animals. Aspirin had been shown to be teratogenic in cats and dogs (Khera, 1976; Robertson et al., 1979). Aspirin administered per os at 25 and 50 mg/kg body weight to pregnant queens on gestation days 10e20 increased the nonspecific terata in kittens. In dogs, the terata, primarily consisting of cleft palate, micrognathia, anasarca, cardiovascular malformations, and tail anomalies, were observed in pups after the bitch was administered per os 400 mg of aspirin bid/kg body weight on gestation days 15e22. No terata in pups were observed born to bitches given 100 mg of aspirin/kg body weight. Pregnant mares treated with sulfonamides, pyrimethamine, folic acid, and vitamin E gave birth to foals with bone marrow aplasia and hypoplasia, lymphoid hypoplasia, renal hypoplasia, and nephrosis (Toribio et al., 1998). The breeds were Quarter Horse, Thoroughbred and Tennessee Walking Horse. Methallibure causes embryo death and is teratogenic in pigs (King, 1969; Akpokodje, 1971; Akpokodje and Barker, 1971). Methallibure fed to

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pregnant gilts during gestation days 29e50 caused skeletal defects consisting of fixed flexion caused by contracted tendons and the long bones of the limbs were shorter and thicker than normal (King, 1969; Akpokodje, 1971). The heads were disproportionately short with distorted mandibles, bones on the dorsal and dorsolateral sides of the cranium were deformed, and the scalp over the abnormal bones showed complete or partial alopecia. Details of cranial terata in porcine embryos showed the frontal and parietal bones to be affected (Akpokodje, 1971). Arthrogryposis has also been reported for methallibure. Griseofulvin is both a drug and a mycotoxin and is teratogenic in cats (Scott et al., 1975; Coppock and Jacobsen, 2009). Pregnant queens in a cat colony and in homes were administered 500e1000 mg griseofulvin per os weekly for a dermatophyte (Scott et al., 1975). The terata observed included exencephaly, malformed prosencephalon, and hydrocephalus. Skeletal malformations included cranium bifidum, spina bifida, abnormal atlantooccipital articulation, cleft palate, absence of maxillae, absence of tail vertebrae, and cyclopia. Anophthalmia accompanied with absence of optic nerves and rudimentary optic tracts were also observed. Visceral terata were atresia ani, atresia coli, and absence of atrioventricular valves in the heart.

Parasiticide Drugs Some members of the benzimidazole group of parasiticides are teratogenic (Radostits et al., 2007). Parbendazole was studied in several countries and generally concluded to be teratogenic in sheep at the 60-mg/kg body weight and was not teratogenic at the 30-mg/kg body weight (Szabo, 1989). The teratogenic effects include limb contractures; excessive flexion and extension of the joints; absence of the femur, humerus, and ulna; hypoplasia of the digits; and hip displacement (Saunders et al., 1974). Parbendazole was not teratogenic in cattle at the 60-mg/kg body weight (Szabo, 1989). Cambendazole is teratogenic in sheep at the 50-mg/kg body weight. At four times the therapeutic dose, albendazole is teratogenic in sheep (Radostits et al., 2007). Apholate is an insect chemosterilant and alkylating agent and was suspected of being teratogenic in sheep (Younger, 1965). There is evidence that trichlorfon is teratogenic in pigs (Bolske et al., 1978; Knox et al., 1978; Fatzer et al., 1981). Pregnant sows were treated per os with trichlorfon during pregnancy. Piglets were born with cerebellar hypoplasia. The teschen/talfan virus was isolated from liver and spleen in one of the piglets. A diagnostic laboratory observed that treatment of sows with trichlorfon during gestation days 45e63 caused an increase in a syndrome in piglets characterized as ataxia and tremor, a pronounced cerebellar hypoplasia, and a reduction in the size of the spinal cord. This condition was also produced experimentally.

ENVIRONMENTAL CHEMICALS AND FACTORS Polyhalogenated Aromatic Hydrocarbons Contaminants in the environment and feedstuffs are of concern. Hyperplasia of the thyroid gland has been observed in piglets born to sows fed polybrominated biphenyls (Werner and Sleight, 1981). Polychlorinated biphenyl (PCB) congeners have been shown to cause pathophysiological epigenetic effects in goat kids (Lyche et al., 2006). Exposure of does to PCB-153 and PCB-126 during gestation was shown to affect the maternal immunity in the kids. Does were exposed orally from gestation day 60 until delivery at dosages of 98 mg of PCB-153/kg body weight or 49 ng PCB-126/kg body weight. Determining the levels of total immunoglobulin G assessed the effects of prenatal PCB exposure on the postnatal humoral immune responses. The kids were also immunized at 2 weeks of age and the immune responses evaluated. Exposure to PCB-153 exposure suppressed maternal transfer of IgG and neonatal humoral antibody response to specific immunogens. The toxic effects of PCB-153 and 118 were studied in pregnant ewes (Gutleb et al., 2010). The ewes were dosed per os with a corn oil control or with 49 mg PCB-118/kg body weight/day and 98 mg PCB153/kg body weight/day every 3 days starting on the first day of gestation and continuing to gestation day 134. The trabecular bone mineral content at the metaphysis in male fetuses was w30% lower in the PCB-118 group compared with male fetuses in the control group. In the PCB-153 group, the female fetuses showed a 19% reduction in the metaphyseal trabecular cross-sectional area. For the PCB153 group, the diaphysis marrow cavity was smaller in female and male fetuses. This study shows that PCB-153 has an effect of developing bone in sheep. No report was given on thyroid gland histopathology. In Greece, semen from ovine, caprine, bovine, and porcine species was assayed for persistent organic pollutants (POPs) (Kamarianos et al., 2003a). The most common POPs were p,p0 DDE (p,p’-dichlorodiphenyldichloroethylene, 80e100% of samples), gamma-HCB (gamma-hexachlorbenzol, 73.9e100%), and gamma-HCH (gamma-hexachlorocyclohexane, 69.6e100%). The follicular fluid of ovine, caprine, bovine, and porcine species was also assayed in Greece for POPs (Kamarianos et al., 2003b). The most commonly detected POPs were gamma-HCH (90e100% of samples) followed by HCB (80e100%) and p,p0 -DDE (75e90.91%). These studies show that gametes are exposed to POPs before fertilization occurs.

Mercury Methyl mercury had been reported to be teratogenic in cats (Khera, 1973). The teratogenic lesions are

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ENVIRONMENTAL CHEMICALS AND FACTORS

abnormalities of the spinal column, abnormally developed limbs, umbilical hernias, and decreased cell density in the external granular layer of the cerebellum. Elevated levels of mercury were observed in fetal blood and brain.

Fetal Endocrine Disruption Exposure in utero to pharmacological levels of hormones and xenobiotics that have endocrinological effects can alter the endocrinology of the fetus (Padmanabhan and Veiga-Lopez, 2014). The expression of endocrine disruption may not occur until certain stages of the life history. Studies have been done in sheep on the endocrine and endocrine teratogenic effects of exposure to multiple POPs after the spreading of sewage sludge on pasture lands. During mating and gestation, sheep were pastured on lands that had received municipal sewage sludge and control sheep were pastured on lands receiving equivalent inorganic fertilization without sewage sludge (Paul et al., 2005; Fowler et al., 2008; Bellingham et al., 2009, 2010). The fetuses were examined at pregnancy day 110 (145 day gestation). In the treatment group, decreased fetal body weight was observed at gestation day 110 in both male and female fetuses (Paul et al., 2005). In male fetuses, there was a reduction in testicular mass, a reduction in Sertoli and Leydig cell numbers, and a reduction in fetal blood testosterone and inhibin A. Blood levels of folliclestimulating and -luteinizing hormones were not decreased. Observations on the effect of pregnant ewe exposed to sewage sludge on fetal ovarian parameters were done in the same study (Fowler et al., 2008). Fetal exposure to chemicals from sewage sludge reduced numbers of growth differentiation factor (GDF9) and induced myeloid leukemia cell differentiation protein (MCL1)epositive oocytes by 25e26%. There was an increase in pro-apoptotic Bax by 65%, and 42% of protein spots in the ovarian proteome were differently expressed. There was no difference between treatment and control fetuses for normalized ovarian mass. In exposed fetal females, serum prolactin levels were decreased compared with controls and estradiol tended to be lower. In female fetuses from exposed ewes, the ovaries showed histological and associated changes in the transcription of genes critical for fetal ovarian development (Bellingham et al., 2013). There was a reduction in GnRH mRNA expression in the hypothalamus. The hypothalamus and pituitary gland had reduced GnRH receptor and galanin receptor mRNA expression (Bellingham et al., 2010). The neuropeptide kisspeptin (KiSS-1) and its receptor Gproteinecoupled receptor 54 are vital for the central regulation of GnRH neurosecretory activity and timing of puberty (Bellingham et al., 2009). Fetuses from exposed ewes had reduced KiSS-1 expression in the rostral, mid, and caudal regions of the hypothalamus and fewer kisspeptin-immunopositive cells in the pituitary gland

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for luteinizing hormone-b and estrogen receptor-a. These changes suggest that disruption of reproduction would occur in adulthood (Bellingham et al., 2009). The testicles of ram lambs were examined at the time of weaning (4 months old) (Bellingham et al., 2012). For the rams born to ewes exposed to sewage sludge, 5 of 12 ram offspring had decreased germ cell numbers/testis or per Sertoli cell and more anomalous Sertoli celleonly seminiferous tubules. These findings suggest a later life stage of expression of epigenetic effects of endocrine disruption. Sertoli cell numbers/testicle were not changed. Testicular mass was not different from control ram lambs. Ewes grazing pasture lands fertilized with sewage sludge before mating and placed on control pasture after mating had male lambs at 110 days of gestation with increased relative thyroid mass (Hombach-Klonisch et al., 2013). Histological evaluations of the fetal thyroids showed decreased cell proliferation, decreased thyrocyte differentiation, and regions with decreased formation of mature angiofollicular units. Areas of the thyroid gland without follicular organization also had low immunostaining for sodium-iodide symporter suggesting decreased cellular differentiation. Fetal plasma levels of thyroxine and triiodothyronine were not different from controls. These studies show that fetal exposure to mixtures of environmental chemicals may have long-term effects on reproductive capacity. The studies also show there is a likelihood that real-world exposure to chemical mixtures can produce effects that would be different to knowledge gained from laboratory exposure to single chemicals. Also, there is evidence that endocrine disruptors have nonmonotonic metric doseeresponse curve (Gore et al., 2015). Concerns are being expressed regarding the potential epigenetic phenotype expression of environmental perchlorate, polybrominated diphenyl ethers, and other PAHs (Crofton and Zoeller, 2005; Kirk, 2006; Mastorakos et al., 2007). The interactions of different environmental chemicals on the developing thyroid gland are not well understood and need to be considered in risk models used to assess the impact of POPs in cattle (Crofton et al., 2005; Crofton, 2008; Gilbert and Zoeller, 2010).

Altered Sex Ratio Feeding ewes fed a diet enriched with rumenprotected polyunsaturated fatty acids produced more male than female conceptus (Green et al., 2008). The mechanisms for this are unclear. In vitro exposure of bovine oocytes to 30 ng bisphenol A/mL skewed the sex ratio to increased female embryos (Ferris et al., 2016).

In Vitro Fertilization Systems The in vitro systems for fertilization can result in bovine congenital defects (Farin et al., 2006). During

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early embryologic development, abnormalities that are not compatible with fetal life result in abortion. Congenital defects associated with in vitro production and somatic cell nuclear transfer methods are altered fetal body weight; abnormally increased duration of gestation; increased perinatal mortality; increased occurrences of male fetuses; increased fetal edema; altered growth of heart, brain, spinal cord, and skeletal muscle; abnormal biochemical parameters; defects in fetal membranes including abnormal development of the chorioallantoic membranes and blood vessels; alterations in placentome morphology and fetoematernal contact; and increased occurrences of hydrallantois and hydramnios. The “abnormal offspring syndrome” (AOS) has been proposed to more accurately assess the congenital defects from in vitro production and somatic cell nuclear transfer methods to produce bovine embryos. The four types of AOS proposed are:

ownership during the time between exposure and the recognition of the abnormalities. Representative feed from the suspect source may have been consumed and is no longer available for chemical and biological testing, etc. Exposure parameters may be difficult to establish, especially for environmental substances. The teratogenic effect may be livestock species specific and has not been previously reported for a particular agent. The specimens that would provide accurate descriptions of the congenital defects were not presented for professional examination. Casual links between in utero chemical exposure and pathophysiological effects are an emerging area in epigenetic birth defects.

Type I: abnormal development and death of the embryo or early conceptus (early embryonic death/ abortion) before completion of organogenesis (approximately day 42 of gestation in cattle). Type II: abnormal development of the placental membranes and fetus; fetus dies (fetal death/ abortion) between completion of organ differentiation and full term (day 42eday 280 of gestation in cattle). Type III: a full-term fetus and/or placenta with severe developmental abnormalities and no evidence of compensatory response by the fetus/placenta. Parturition is normal (eutocia) or difficult (dystocia). The calves are severely compromised with altered clinical, hematological, or biochemical parameters; death occurs around the time of parturition or during the neonatal period. Type IV: a full-term fetus and/or placenta with moderate abnormalities; however, the feto-placental unit compensates and adapts to the compromising genetic or physiological insults and survives. Parturition is normal (eutocia) or difficult (dystocia). The calves may be normal or abnormal in size for their breed, and they may have clinical, hematological, or biochemical abnormalities.

Congenital and pathophysiological birth defects in livestock are generally underreported. Substances that have been identified as being teratogenic in livestock species, and these etiological links have been established through cooperation of the veterinary and animal science professionals and producers. The interactions between genetic expression and plant, drugs, and environmental chemicals are not well understood. New studies are showing that genetic differences can alter the teratogenic and pathological effects of toxic chemicals through different mechanisms. New studies on endocrine disruption in sheep suggest that some endocrine dysfunctions and some causes of reproductive soundness likely are epigenetic in origin. Compared with rodent studies, teratogenic studies in livestock species are expensive and labor intensive. Emerging research methods using bovine ova can provide new insights into the effects of chemicals on the biochemical and pathological effects that occur after fertilization. It is important that research groups continue to study the teratogenic effects of plants and other substances in livestock species. The interactions between natural toxins, environmental chemicals, especially POPs, and viruses need further study. Additional studies are needed on the mechanisms of teratogens and epigenetic alteration of physiological functions.

CONCLUDING REMARKS AND FUTURE DIRECTIONS

Diagnosis The diagnosis of a chemical or infectious agent as the cause of a congenital defect can be challenging for a variety of reasons. Causal links between the observed congenital defect and a causative agent are often not considered. Infectious agents can be incriminated or diagnosed using serological, microbiological, and histopathological procedures. For chemical teratogens, an accurate history may be difficult to establish as the pregnant females may have moved locations or changed

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