The harderian gland

Contp. Biochem. Physiol. Vol. 93A, No. 4. Printed in Great Britain

pp. 655-665,

1989 c

0300-9629189 $3.00 + 0.00 1989 Maxwell Pergamon Macmillan plc

MINI REVIEW THE HARDERIAN J.

OLCESE*

and A.

GLAND WESCHE?

Department of Biology, Rhodes College, Memphis, TN 38112, USA (Receiced 19 Jmuary

INTRODUCTION

The Harderian gland is a tubuloalveolar gland located within the ocular orbit of many terrestrial

species, especially those possessing a nictitating membrane. It was first described by Johann Jacob Harder, a noted physician born on 17 September 1656 in Basel, Switzerland. Harder first mentioned this gland in 1694 as occurring in the orbit of the deer, Dama vulgaris (Brownscheidle and Niewenhuis, 1978). Since that time the Harderian gland has been observed in all terrestrial vertebrate classes (Brownscheidle and Niewenhuis, 1978; Sakai, 1981; Shirama et al., 1982). A notable absence to the list of mammals with Harderian glands is the primate. However, the Harderian glands are reported to be rudimentary in monkeys and may even be found in vestigial form in the human fetus from the 11th to the 30th week or occasionally in adults with abnormalities (Kennedy, 1970). The fact that the Harderian gland is primarily found in terrestrial vertebrates lends support to the traditional view (e.g. Davis, 1929) that it evolved with the lacrimal glands in order to lubricate the nictitating membrane and/or cornea, and secondarily the nasopharynx. None the less, investigations over the past few decades have revealed some other, sometimes surprising, morphological, biochemical and physiological features of the Harderian gland. These include sexual dimorphism, photosensitivity, hormone synthesis and perhaps contributions to behavioral thermoregulation. The purpose of this review is to summarize what is currently known about the Harderian gland. Previous reviews on this subject appeared in 1970 (Kennedy) and 1981 (Sakai). It is hoped that the present overview might secure the basis for future progress in understanding the remarkable but heretofore largely neglected Harderian gland. MORPHOLOGY

Located medial and posterior to the eyeball, the Harderian gland in many species is a lobular, tubuloalveolar gland. As seen in Figs 1 and 2 for the *All correspondence should be addressed to: Dr J. Olcese, Institute for Hormone and Fertility Research, Grandweg 64, 2000 Hamburg 54, FRG. tPresent address: University of Tennessee at Memphis, College of Medicine, Memphis, TN 38163, USA.

1989)

Mongolian gerbil, the tubules in the gland form a single duct which opens on or near the nictitating membrane naso-ventrally. The number of lobes in the gland varies from one species to the next. The extraglandular portion of the secretory duct in the gerbil has an ampulla with folded walls between which are clefts that sometimes connect with crypts. Although this is a typical arrangement for a rodent there is considerable variation in other mammals. For example, in the squirrel a single duct opens into the conjunctival sac, whereas in the pig, dog and sheep two ducts are present, and in the rabbit there are several ducts (Kennedy, 1970). Whatever the route of entrance to the eye, the Harderian gland secretions appear eventually to enter the nose and throat via the naso-lacrimal duct. This general anatomical arrangement is seen also in nonmammalian species. In some cases the duct opens into the conjunctival space close to the origin of the lacrimal ducts, while in other species it may open directly into the lacrimal duct (Schwarz-Karsten, 1933). It is perhaps worth noting that in reptiles the nasolacrimal duct opens into the vomeronasal organ of Jacobson (Kennedy, 1970). The morphology of the Harderian gland is typical of exocrine glands with alveoli which lead into tubules. These alveoli, and often portions of the tubules as well, are lined with acinar cells. The mode of secretion by these cells has been a topic of considerable discrepancy in the literature. Since the 1920s it had been held that these secretions were apocrine in nature, analogous to a dermal gland (Cohn, 1955; Tsutsumi ef al., 1966). However, electron microscopical studies by Woodhouse and Rhodin (1963) supported a merocrine mode of secretion. Later studies have substantiated this view (Brownscheidle and Niewenhuis, 1978; Watanabe, 1980; Maxwell et al., 1986). Sakai and Yohro (1981), as well as Johnston et al. (1985) have shown exocytosis to occur in the rodent Harderian gland (see Fig. 3). The secretion of porphyrin pigments by the hamster and rat Harderian gland appears to involve holocrine mechanisms (Hoffman, 1971; Carriere, 1985). The composition of Harderian gland secretions varies greatly between vertebrate classes. In general these secretions are serious or seromucoidal in reptiles (Paule and Hayes, 1958; Burns and Pickwell, 1972; Cowan, 1973; Lopes et al., 1974; SaintGirons, 1982; Saint-Girons, 1986), mucoidal in birds (Maxwell et al., 1986) and lipoidal in mammals, although intermediate forms are not uncommon. For

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Fig. 1. A light micrograph of the Mongolian gerbil eye and surrounding orbital contents, including the prominent Harderian gland just to the left of the eye (from Sakai and Yohro, 1981, reprinted with permission of the author).

example, Lopes et al. (1974) reported mucous-serous cells in the Harderian gland of certain snakes. The Harderian gland of the nine-banded armadillo is quite unique in having a proximal portion with acini that are mucoidal in their secretion while the larger distal portion of the gland has acini that are lipoidal in their secretions (Weaker, 1981). The lipoidal secretions of the mammalian Harderian gland are the most widely studied. Historically it was believed that the secretions of mammalian Harderian glands were sebaceous or mucous (Kennedy, 1970). By the 1950s it was apparent, however, that these secretions are primarily lipoidal (Cohn, 1955). Since that time the lipid composition of Harderian gland secretions has been analysed in detail. Lin and Nadakavukaren (1981) reported a sexual dimorphism in the chain lengths of fatty acids in hamster Harderian gland secretions. The rabbit Harderian gland, which has two histologically distinct lobules, was described by Jost et al. (1974). Both lobules have a high lipid content and lipid accounts for about 80% of the dry weight of the red lobule. The secretion of the rabbit Harderian gland is actually a complex mixture of various lipids, the main fraction (50% of dry weight) being an unusual lipid, identified as I-alkyl-2,3-diacyl-glycerol (Jost, 1974).

In the mouse the main lipid constituents are glyceryl ether diesters and phospholipids (Watanabe, 1980). There are five major 2,3-alkanediols in the Harderian gland secretions of the Mongolian gerbil (Otsuru et al., 1983; Otsuka et al., 1986). The lipids of the guinea pig Harderian gland are also mostly 1-alkyl-2,3-diacylglycerols and to a lesser extent complex mixtures of phospholipids (Yamazaki et al., 1981; Seyama ef al., 198 1; Seyama et al., 1983). A fatty acid synthetase unique to the guinea pig Harderian gland has been isolated and characterized also (Seyama et al., 1981). Histologically, the Harderian gland is fairly typical of exocrine glands. Several studies in birds have been made, for example in the turkey (Maxwell et al., 1986). The turkey Harderian gland consists mostly of secretory epithelia surrounded by myoepithelial cells. The secretory cells are characterized by abundant occasional microvilli, ribosomes, mitochondria, rough endoplasmic reticulum and a complex Golgi apparatus. Secretory vesicles are membrane-bound, apical in location and contain a mucoidal secretion. The mammalian Harderian gland possesses two epithelial cell types, generally known as type A and type B, as well as myoepithelial cells and occasionally melanocytes. Typically Type A cells are more numerous and contain large (up to 2.5 pm diameter)

The Harderian

Fig. 2. The gerbil Harderian

gland

gland

651

the convergence of numerous tubules to form a single, large near the eye (from Sakai and Yohro, 1981, reprinted with permission of the author).

showing

duct which opens at the top of the photograph

secretory vacuoles containing a lipid-like substance and granular filamentous material (Brownscheidle and Niewenhuis, 1978; Watanabe, 1980). These seem to be associated with membrane-bound clusters of tubules (Lin and Nadakavukaren, 1979). Type B cells contain numerous, smaller (maximum diameter 1.7 pm) secretory vacuoles often possessing border laminations, large numbers of mitochondria, extensive endoplasmic reticulum, and a prominent Golgi apparatus (Brownscheidle and Niewenhuis, 1978). Both cell types may have short microvilli which extend into the lumen (Bucana and Nadakavukaren, 1972a, b; Brownscheidle and Niewenhuis, 1978; Abe et al., 1980). Both sex differences and daily rhythms of Harderian gland morphology have been reported

for the neonatal rat (Feria-Velasco et al., 1983). In the female rabbit the different cell types are found in separate lobules of the gland (Jost et al., 1974). In rodents, however, if both cell types are found they are mixed within the same alveoli (Grafflin, 1942; Brownscheidle and Niewenhuis, 1978). Similar findings were reported for the male mouse (Woodhouse and Rhodin, 1963; Watanabe, 1980). Variations do occur however, for example, only one cell type is found in the Harderian gland of the Mongolian gerbil (Sakai and Yohro, 1981; Johnston et al., 1983), while in the plains mouse an additional third cell type was described to contain two nuclei and mitotic figures (Johnston et al., 1985). Perhaps the best studied Harderian glands are

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J. OLCESEand A. Wascur

Fig. 3. Electron micrograph showing exocytosis in the gerbil Harderian gland (from Sakai and Yohro. I98 I, reprinted with author’s permission).

those of the golden hamster. This is certainly due, in part, to the report by Christensen and Dam (1953) and Woolley and Worley (1954) that there is a histological sexual dimorphism in the Harderian glands of this species. Males possess both type A and type B cells, while females possess only type B cells. This interesting feature was later confirmed by Hoffman (1971) as well as Bucana and Nad~avukaren (1972). Additionally, Hoh and coworkers (1984) have reported a pronounced sexual dimorphism in Harderian gland proteins which they attribute to the tubular clusters found only in the male hamster. Most interesting of all perhaps is the finding by Lin and Nadakavukaren (1979) that the male gland changes histologically into that of a

female (i.e. in having one cell type only) when the animals are castrated. Furthermore, blinding can inhibit this castration effect (Clabough and Norvell, 1973). This implies that the Harderian gland may be a target for androgens in the hamster, and that light may have an influence on this gland, topics addressed in more detail later in this review. INNERVATION

Autonomic nerve fibers have been found in the Harderian glands of the golden hamster (Bucana and Nadakvukaren, 1972a, b; Norvell and Clabough, 1972), rabbit (Kuehnel, 1971), rat (Huhtala et al., 1977; Brownscheidle and Niewenhuis, 1978), mouse

The Harderian gland (Watanabe, 1980) and gerbil (Sakai and Yohro, 1981). In those mammalian species studied the Harderian gland alveoli appear to receive cholinergic innervation (Gardiner et al., 1962; Brownscheidle and Niewenhuis, 1978) with clear vesicle-containing nerve terminals either within (for rabbits, hamsters) or near (for rats, mice and gerbils) the basal laminae of the secretory cells. The cholinergic nerves are thought possibly to influence melanocytes in the gerbil Harderian gland, whereas adrenergic innervation is probably associated with vascular functions (Sakai and Yohro, 1981). Huhtala and co-workers (1977) reported that the cholinergic fibers to the rat Harderian gland derive from the pterygopalatine ganglion, which likewise innervates the lacrimal glands (Ruskell, 1971). The contribution of fibers from the pterygopalatinate ganglion to the Harderian glands of the pigeon and goose also has been noted (Gienc and Kuder, 1985; Gienc and Zaborek, 1985). It has been suggested that the cholinergic innervation of the duck Harderian gland may regulate blood flow and hence glandular activity in this species (Fourman and Ballantine, 1967). Adrenergic (dense-core vesiclecontaining) terminals have been found in association with blood vessels in the Harderian glands of hamsters (Norvell and Clabough, 1972; Bucana and Nadakavukaren, 1972b), mice (Strum and Shear, 1982a) and rats (Huhtala et al., 1977). Recently, peptidergic innervation of the rat Harderian gland has been demonstrated. Using immunohistochemical techniques, Tsukahara and Jacobowitz (1987) found positive reactions to neuropeptide-Y, neurotensin, calcitonin-gene-related peptide and especially to vasoactive intestinal polypeptide (VIP) and cholecystokinin. Some VIP-like immunoreactive nerves appeared to be co-localized with acetylcholinesterase-positive nerves. Ruehle (1981) found the rat Harderian gland to take up radiolabelled oxytocin and lysine vasopressin. Subsequently, it was shown that oxytocin, arginine vasopressin and neurophysins are present in the rat Harderian gland and undergo a day-night rhythm (Gauquelin et al., 1988).

BIOCHEMISTRY

The most pronounced and widespread aspect of sexual dimorphism associated with the rodent Harderian gland is in terms of porphyrin content, with the female gland having a significantly greater content of these pigments (Kennedy, 1970; Brownscheidle and Niewenhuis, 1978). Porphyrins are complex, ringed molecules that serve as prosthetic groups in many proteins, including hemoglobin, myoglobin, catalase, peroxidase and cytochrome-c. These porphyrin compounds-mostly protoporphyrin IX (the immediate precursor of heme)-are produced in the secretory epithelium (Tomio and Grinstein, 1968; Carriere, 1985). A tricarboxylic porphyrin, termed “harderoporphyrin” is produced by the rat Harderian gland also (Kennedy, 1970). This compound has been identified as 4,6,7-tri(2-carboxyethyl)-l,3,5,8-tetramethyl-2-vinyl-porphyrin (Jackson et al., 1976). It has been suggested that porphyrin pigments are found along with lipids in

659

the secretory vacuoles of the epithelial cells and are thus released into the lumina (Brownscheidle and Niewenhuis, 1978). However, electron microscopical examination of the rat Harderian gland has shown the protoporphyrin IX crystals to be localized in the cytoplasm (Carriere, 1985). Porphyrin pigments typically fluoresce bright red under ultraviolet light. The sexual differences in this fluorescence intensity were first noted in the mouse Harderian gland by Strong (1942) and later by Cohn (1955). Quantification of this phenomenon has been reported as well (Shirama et al., 1981b; Johnston et al., 1985). The pigment in mice was first determined to be protoporphyrin by Bittner and Watson (1946). This was confirmed by Johnston and co-workers (1985) who found protoporphyrin to be the predominant porphyrin form (approximately 95%) in the Australian plains mouse, although copro- and hexaporphyrins were detected also. Later, ultrastructural studies of the Harderian glands of the male mouse suggested that these pigments are found in the secretory vacuoles of the less numerous type B cells (Watanabe, 1980). Watanabe further speculated that type B cells are responsible for pigment secretion while type A cells are responsible for lipid secretion only. However, fluorescence techniques showed porphyrins in the mouse to be associated with lipid droplets in the more numerous type A cells as well as being present in the lumina (Strum and Shear, 1982a). Thus, the origin of porphyrins in the mouse Harderian gland remains unclear. Johnston et al. (1983) measured protoporphyrin and small amounts of coproporphyrin in the Harderian glands of both the male and female Mongolian gerbil with female glands containing more than twice the porphyrin content of male glands. These investigators reported also that these pigments were visible only as solid intraluminal accretions. Porphyrin sexual dimorphism has been observed also in the hamster Harderian gland (Christensen and Dam, 1953; Woolley and Worley, 1954). This dimorphism was later confirmed by Lin and Nadakavukaren (1979) who found granular pigments in the glands of female hamsters but not in males. However, this failure to detect porphyrins in male hamsters may have been due in part to fixation techniques (Spike et al., 1986b). Woolley and Worley (1954) showed that castrated male hamsters, as well as males, treated with estrogens had Harderian gland porphyrin levels similar to those of intact female hamsters. Furthermore, an absence of porphyrins was noted in the female Harderian gland after administration of testosterone. These observations were confirmed by Hoffman (1971) and Payne et al. (1977a) as well as by Lin and Nadakavukaren (1979) who demonstrated that this phenomenon has ultrastructural correlates. Castration modified the male Harderian gland toward the female type, while daily administration of testosterone prevented this change. Similar effects have been shown for the mouse (Shirama et al., 198la). These authors reported that castration doubled Harderian gland porphyrin content, while castration plus adrenalectomy increased porphyrin levels to that found in female glands. This could be prevented by testosterone.

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Castration of the male hamster also increases the concentration of sodium, copper, iron and manganese in the Harderian gland while decreasing the concentration of molybdenum (Hoffman and Jones, 1981). This change is in the direction of the female gland. Hoffman and Jones (1981) proposed that molybdenum is associated with type A cells (which are found only in males) and correspondingly reduced porphyrin synthesis, while manganese is important for porphyrin synthesis in the type B cells. Although ovariectomy was reported initially to have no effect on the Harderian gland of hamsters (Hoffman, 1971), this endocrine manipulation was later shown to produce extensive degeneration, e.g. the breaking down of tubule walls and invasion of the lumen by neutrophils (Payne et al., 1982; Payne et al., 1985; Spike et al., 1985; Spike ef a/., 1986a). Ovariectomy, as well as androgen treatment, causes increased porphyrin deposits and increased numbers of mast cells in the hamster Harderian gland (Spike et al., 1985). Ovariectomy also produces a significant decrease in porphyrin content in the rat Harderian gland (Ulrich et al., 1974). This would seem to indicate that ovarian hormones, like androgens in the male, are necessary for maintenance of the Harderian gland. Harderian gland porphyrin levels have been shown also to vary with the estrus cycle. In the mouse porphyrin levels are lowest during metestrus and highest at diestrus (Shirama er al., 1981a). However, Payne and co-workers (1977b) have reported that Harderian gland protoporphyrin content in the hamster is highest on the day of estrus (coproporphyrin content remains unchanged). These authors also noted dramatically greater porphyrin content during the summer as compared to the winter months, presumably a consequence of the fact that porphyrin concentrations in the Harderian gland rise considerably during pregnancy and lactation (Payne et al., 1979). Because of the presence of porphyrins in the rodent Harderian gland it has been used as a model for porphyrin and heme biosynthesis. The rate-limiting, mitochondrial enzyme in the production of heme is d-aminolevulinate synthase, the activity of which varies seasonally in parallel with porphyrin content in the female hamster Harderian gland (Moore et al., 1980). Not surprisingly, the activity of this enzyme is higher in the female than in the male Harderian gland (Lin and Nadakavukaren, 1982) and is substantially depressed following ovariectomy (Spike et al., 1983). Sexual differences in the activity of several other heme biosynthetic enzymes in the hamster Harderian gland have been reported (Thompson et al., 1984). Although the incorporation of iron into the protoporphyrin IX molecule leads to hemoglobin and myoglobin synthesis this has never been shown to occur in the Harderian gland. Porphyrins from the Harderian gland may enter the circulation via interstitial blood vessels, lymphatics or the retro-orbital sinus which surrounds the gland (Sakai and Yohro, 1981) and in this way contribute to hemoglobin formation (Payne et al., 1982; Payne er al., 1985). Light and visual system functions appear to influence the Harderian gland porphyrin content also. Wetterberg and Geller (1970) reported that

porphyrin content in the rat Harderian gland increases rapidly at 12 days of age coinciding with the maturation age of the first evoked cortical responses to visual stimuli. Constant darkness or blinding prevents the castration-induced increase of Harderian gland porphyrin content in male hamsters (Wetterberg, 1972). Conversely, blinding of the female hamster decreases Harderian gland porphyrin levels (Hoffman, 1971). Cold exposure as well as thiourea treatments also decreased Harderian gland porphyrin content. Ulrich er al. (1974) reported that constant light or darkness for 35 days significantly decreased Harderian gland porphyrin levels in the rat. These findings were verified by Shirama and co-workers (1977a, b). Similarly, constant light leads to marked decreases in Harderian gland porphyrins as well as epithelial cell damage in mice (Strum and Shear, 1982b). HORMONES

AND THE HARDERIAN

GLAND

As mentioned earlier, the Harderian gland may be a target for gonadal steroids. Much in the manner that androgens influence secretion in rat exorbital glands (Sullivan et al., 1984), estrogens have been reported to inhibit secretion in duck Harderian glands (Gupta and Maiti, 1983). Testosterone, 5-dihydrotestosterone and androstenedione prevent the castration-induced changes seen in the golden hamster (Payne et al., 1975, 1977a). Additionally, testosterone can cause the development of the male type Harderian gland in female hamsters (Sun and Nadakavukaren, 1980). That these steroid effects are probably direct is suggested by the findings that estradiol is accumulated by the Harderian glands of female armadillos (Weaker et al., 1983) and that androgen receptors may occur in the Harderian glands of male golden hamsters (Vilichis et al., 1987). Blinding of female hamsters leads to decreases in Harderian gland weights which can be prevented by removal of the pineal gland (Clabough and Norvell, 1973, 1974). Similarly, short photoperiods lead to a loss of sex differences in the Harderian gland, which can be blocked by pinealectomy (Diloria and Nadakavukaren, 1984). Pinealectomy or ovariectomy can prevent also the blinding-induced conversion of the female Harderian gland into the male-type gland (McMasters and Hoffman, 1984). These studies not only demonstrate the influence of the gonads on the Harderian gland but suggest also that the male type of Harderian gland in the hamster is expressed whenever significant levels of androgens are present. The influence of the pineal gland on the Harderian gland is probably indirect via pineal-mediated photoperiodic effects on the pituitary-gonadal axis, although this has not been adequately addressed (see also below). Evidence that the Harderian gland may serve as an extraretinal phototransducer is also available. Investigations by Wetterberg and co-workers (1970a, b) demonstrated that removal of the Harderian gland in neonatal rats prevent light-induced effects on pineal indoleamine metabolism whereas simply blinding the animals is ineffectual. However, Harderianectomy of adult rats does not have effects on pineal metabolic activity (Reiter and Klein, 1971). The Harderian

The Harderian

has been implicated also as a detector of photoperiods in the blind mole rat, Spalax ehrenbergi (Pevet et al., 1984). The Harderian gland is much like the pineal gland in being capable of synthesizing the indoleamine hormone, N-acetyl-S-methoxytryptamine (i.e. melatonin). The enzymes necessary for melatonin production, i.e. N-acetyl-transferase and hydroxyindole-0-methyltransferase, are both found to be active in the rodent Harderian gland (Cardinali and Wurtman, 1972; Bubenik et al., 1976a, b; Pang et al., 1977; Damian, 1977; Brammer er al., 1978; Prozialeck et al., 1978; Balemans et al., 1980; Vivien-Roels et al., 1981; Menendez-Pelaez et al., 1988a). Furthermore, melatonin synthesis in the Harderian gland is characterized by circadian rhythms, as shown for the rat (Bubenik et al.. 1978; Reiter et al., 1983; White et al., 1984) for the golden hamster (Pevet et al., 1980; Balemans et al., 1983) for the ground squirrel (Reiter et al., 1981) and for the pigeon (Vakkuri et al., 1985). Pinealectomy has been shown to elevate melatonin levels in the rat Harderian gland (and retina) without interfering with the circadian rhythm (Reiter et al., 1983). Hence the melatonin-producing capacity of the Harderian gland may be influenced by pineal (or other) hormones. Castration and gonadal regression induced by short photoperiods reduces N-acetyltransferase activity in the Harderian gland of male golden hamsters (Menendez-Pelaez et al., 1988b). In this regard Hoffman and co-workers (1985) reported that androgens may influence Harderian gland melatonin content in the hamster. In their study it was shown that castration elevated melatonin in male Harderian glands to female levels. Furthermore, Harderian gland melatonin rhythms were seen only in female hamsters. Exactly what the role for melatonin in the Harderian gland is remains to be established.

gland

661

gland

BEHAVIOR AND THE HARDERIAN GLAND

In rodents the secretions of the Harderian gland are groomed about the face using saliva as a base. The presence of these secretions stimulates exploratory behavior in the gerbil and can trigger grooming in conspecifics (Thiessen and Rice, 1976; Thiessen et al., 1976). Dominant males in pairs groom more frequently and secrete greater amounts of Harderian pheromone while Harderianectomized males are always submissive in paired encounters (Thiessen and Rice, 1976). It has been shown also that male Harderian gland secretions may stimulate proceptive behavior in female gerbils and female gerbils display significantly less often to Harderianectomized males (Harriman and Thiessen, 1985). Since the Harderian glands are influenced directly by the gonads via be that Harderian gland androgens, it may pheromones communicate information to females about the reproductive status of the male. Studies with golden hamsters also support the idea that Harderian gland secretions may function as pheromonal agents. Both sexually-experienced and inexperienced male hamsters are attracted to female Harderian gland smears (Payne, 1979a, b). The attractiveness of these smears does not correlate with protoporphyrin content, nor does it appear to be related to the estrus cycle (Payne, 1979a, b). Female

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Fig. 4. Effect of Harderianectomy on body temperature maintenance by the Mongolian gerbil under cold-wet stress conditions (from Thiessen and Kittrell. 1980, used with author’s permission).

Harderian gland smears, if placed on male hamsters, will inhibit aggression by other males (Payne, 1977). Hence, there appears to exist pheromonal qualities to female Harderian gland secretions as well. Another possible function for Harderian gland secretions may be in thermoregulation. Gerbils prefer to groom at 28°C along a thermal gradient, with the dominant males controlling the zone around this temperature (Thiessen et a/., 1977). Grooming may have a thermoregulatory effect at these temperatures since the Harderian gland secretions are mixed with saliva and spread on bare areas of the face, paws and ears, where it evaporates to remove excess body heat. However, Harderian gland secretions appear to be most important for thermoregulation at cold temperatures. The lipids contained in these secretions are spread throughout the animal’s fur during grooming, which helps to provide insulation. Harderianectomy greatly reduces the gerbil’s ability to withstand cold and wetness, analogous to removing these lipids by shampooing (see Fig. 4; Thiessen and Kittrell, 1980). If animals are shaved, but have oils replaced artificially some restoration of insulation is achieved. The Harderian gland secretions also make the fur darker, thereby increasing solar radiation absorption and heat gain (Pendergrass and Thiessen, 1981; Thiessen et al., 1982). Thermoregulatory effects of Harderian lipids have been reported also for the muskrat (Hat-low, 1984). IMMUNOLOGICAL

CONTRIBUTION

There is some evidence that the Harderian gland plays an immunological role in birds. Exogenous antigens that enter the eye can reach the Harderian gland (Burns, 1977). The Harderian gland of chickens contains large numbers of plasma cells and lymphoid cells carrying immunoglobulin determinants (Albini and Wick, 1973; Sundick et al., 1973; Davelaar and Kouwenhoven, 1977; Kittner et al., 1978). When antigens are applied to the conjunctiva, but not when administered systemically, the Harderian gland develops a local immune response (Albini et al., 1974). Several investigators have suggested that the Harderian gland may play a role in the defense mechanisms against viral bronchitis in chickens (Davelaar and Kouwenhoven, 1977; Pejkovski ef

J.

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OLCESEand

al., 1979; Davelaar and Kouwenhoven, 1980a, b; Sivanandan et al., 1986). Harderian gland-derived antibodies have been reported to exist in the salivary fluid of chickens (Ewert et al., 1979). Similar attempts to demonstrate an immunological role for the Harderian gland in mammals have been unsuccessful (Sullivan er al., 1984; Gudmundson et al., 1985). CONCLUSIONS

Despite decades of modest attention answers to the question “what is the physiological role for the Harderian gland” remain clouded by uncertainty. It would appear that the sexual dimorphism of the gland is an important clue to the eventual understanding of Harderian physiology. That this dimorphism is not just biochemical (porphyrin content, melatonin synthesis etc) but morphological also, and that it can be altered by hormonal manipulations would seem to provide biologists with an excellent model to further explore sexual diffentiation, hormone regulation of development, etc. Surprisingly, the most basic of investigations with the Harderian gland have yet to be done. For

example, are there in fact gonadal steroid receptors in the gland? Are there steroid-metabolizing enzymes such as aromatase? Does the Harderian gland, which is clearly exocrine but perhaps endocrine as well, really secrete hormones, e.g. melatonin? What is the ultimate fate of porphyrin in the Harderian gland? These fundamental issues will need to be addressed (in addition to the many others) before the continually-accumulating data on the Harderian gland begin to coalesce into a coherent pattern. Nearly 300 years after the “discovery” of the Harderian gland we might then finally reach agreement on the significance of this fas~iRating structure. REFERENCES

Abe J,, Sugita A., Katsume Y., Yoshizuka M., Tamura N., lwanaga S. and Nisbida T. (1980) Scanning electron microscope observations of the Harderian gland in rats. Kurume Med. J. 27, 239-246. Albini B. and Wick G. (1973) Immuno~lobulin determinants on the surface of chicken lymphoid cells. Inti. Arch. Allergy appl. Immunol.44,804-822. Albini B.. Wick G., Rose E. and Orlans E. (1974) Immunoglobuiin production in chicken Harderian glands. Grit/.Arch. Allerg,~ appi. Immunol. 47, 23-34. Balemans M. G. M.. Pevet P., Legerstee W. C. and Nevo E. (1980) Preliminary investigations on melatonin and S-methoxytryptophol synthesis in the pineal. retina and Harderian gland of the mote rat (Spalax ehrenbergi) and in the pineal of the mouse eyeless. J. Neural Trans. 49, 247-256. Balemans M. G. M., Pevet P., Van Benthem J., HaldarMisra C., Smith I. and Hendriks H. (1983) Day-night rhythmicity in the methylating capacities for different S-hydroxyindoles in the pineal, the retina and the Harderian gland of the golden hamster (~e~oericctu~ auratus) during the annual seasons. J. Neural Trans. 56, 53..72. Bittner J, J. and Watson C. J. (1946) The possible association between porphyrins and cancer in mice. Cancer Res. 6, 337-343. Brammer G. L., Yuwiier A. and Wetterberg L. (1978)

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WESCHE

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