Role of Testosterone and its Metabolites in the Differentiation of the Mammary Gland in Rats

Goldman, Alvin I.; Shapiro, Barry A.; Neumann, F.

doi:10.1210/endo-99-6-1490

Cited by 41 publications

(24 citation statements)

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“…However, our studies were not designed to determine whether hyperandrogenemia by itself could produce virilism of the mammary gland in ovary-intact adult female rats. It is known that in fetal rats with little or no circulating estrogens, androgens are critical determinants in the differentiation of the mammary gland to the male phenotype (Goldman et al, 1976). Also, androgen treatment of ovariectomized rats that do not have circulating ovarian hormones results in virilism of the female mammary gland (Sourla et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Androgen Dependent Mammary Gland Virilism in Rats Given the Selective Estrogen Receptor Modulator LY2066948 Hydrochloride

Rudmann¹,

Ir²,

Robbins³

et al. 2005

Toxicol Pathol

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A selective estrogen receptor modulator (SERM) is a nonsteroidal compound with tissue specific estrogen receptor (ER) agonist or antagonist activities. In animals, SERMs may produce morphologic changes in hormonally-sensitive tissues like the mammary gland. Mammary glands from female rats given the SERM LY2066948 hydrochloride (LY2066948) for 1 month at ≥ 175 mg/kg had intralobular ducts and alveoli lined by multiple layers of vacuolated, hypertrophied epithelial cells, resembling in part the morphology of the normal male rat mammary gland. We hypothesized that these SERM-mediated changes represented an androgen-dependent virilism of the female rat mammary gland. To test this hypothesis, the androgen receptor antagonist flutamide was co-administered with LY2066948 (175 mg/kg) to female rats for 1 month. Female rats given SERM alone had hyperandrogenemia and the duct and alveolar changes described here. Flutamide cotreatment did not affect serum androgen levels but completely blocked the SERM-mediated mammary gland change. In the mouse, a species that does not have the sex-specific differences in the mammary gland observed in the rat, SERM treatment resulted in hyperandrogenemia but did not alter mammary gland morphology. These studies demonstrate that LY2066948 produces species-specific, androgen-dependent mammary gland virilism in the female rat.

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Section: Discussionmentioning

confidence: 99%

Androgen Dependent Mammary Gland Virilism in Rats Given the Selective Estrogen Receptor Modulator LY2066948 Hydrochloride

Rudmann¹,

Ir²,

Robbins³

et al. 2005

Toxicol Pathol

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“…From these results, since any endocrine disrupting activity of lindane is clearly weak, adverse effects might not have been expected in this study. A large number of investigations have shown effects of endocrine disruptors detected by examining AGD, nipple development, sexual maturation, estrous cycle, spermatogenesis, and sex organ weights (Aoyama and Suzuki, 2003;You et al, 2002;Ashby et al, 1997;Sharpe et al, 1995;Newbold et al, 1983;Yamasaki et al, 2005;Chamness et al, 1979;Clevenger et al, 1998;Gray et al, 1993Gray et al, , 1994Goldman et al, 1976;Rhees et al, 1997). Therefore, further studies using other chemicals, which have more definite endocrine disrupting activity, are considered necessary to establish the validity of the new protocol.…”

Section: Assessment Of the Test Methodsmentioning

confidence: 99%

Evaluation of a Two-Generation Reproduction Toxicity Study Adding Endopoints to Detect Endocrine Disrupting Activity Using Lindane

et al. 2005

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-A two-generation reproduction toxicity study in rats adding extra endpoints to detect endocrine disrupting activity was conducted using lindane by dietary administration at 0, 10, 60, and 300 ppm, for investigation of its utility. The extra endpoints included anogenital distance (AGD), nipple development, sexual maturation (vaginal opening and preputial separation), estrous cycle, spermatogenesis, sex organ weights, and blood hormone concentrations (thyroid and sex hormones). F1 offspring were examined for emotionality (open field test), motor coordination (rotarod test), as well as learning and memory (pole-climbing test). Hepatic drug-metabolizing enzyme activities were also measured. The results revealed general toxicological effects on parental animals, influence on reproductive function, and altered development of offspring; however, they did not demonstrate any distinct changes in the extra endpoints for detection of endocrine disrupting activity. Adult toxicity was observed in both F0 and F1 animals, including suppressed body weight gain and reduced food consumption in both sexes, and deaths of females at 300 ppm. Convulsions and irritability were observed during the perinatal period in pregnant F1 females given 300 ppm. Pathological examination revealed increased liver weights and centrilobular hepatocellular hypertrophy in both sexes and generations at 10 or 60 ppm and above; in addition, increased kidney weights and increased hyaline droplets in the proximal tubule epithelium, and basophilic renal tubules in males were noted at 10 ppm and above. Pituitary weights were decreased in F0 females and in F1 males and females and adrenal weights were increased in F1 males and females at 300 ppm; however, no histological changes were observed, and manifestations suggesting endocrine disrupting activity related to these changes were lacking. Hypertrophy of the thyroid follicular epithelium in F0 females at 300 ppm and in F1 males at 60 and 300 ppm, and decreases in T3 and/or T4 in both sexes and generations at 300 ppm were presumed to be secondary changes associated with the induction of hepatic drug-metabolizing enzymes. Blood hormone analysis revealed no changes in sex hormones attributable to lindane in males or females. Hepatic drug-metabolizing enzyme activities were increased dose-dependently from 10 ppm in both sexes and generations, with the rise in BROD activity being the most prominent. There were also increases in MROD, EROD, T-6β-OH, and T4-UDP-GT activities (BROD >> EROD > MROD, T-6β-OH, T4-UDP-GT). This suggests that while lindane most strongly induces CYP2B, it also upregulates a number of other drug metabolizing enzymes, such as CYP1A, CYP3A, and UDP-GT. As for effects on reproductive function, lack of maternal behavior, including lactation and retrieval behavior, and consequent total litter loss were observed in F1 dams at 300 ppm. There were no effects of lindane on the estrous cycle, spermatogenesis, mating, fertility, pregnancy, or parturition. Neonatal toxicity was observed in bot...

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“…First, it served to masculinize the SN B -BC / L A system and maximally rescue SN B motoneurons from apoptosis (Freeman et al, 1996;Ward et al, 1996). Second, it provided a means to distinguish androgenized wild-type females, who do not form nipples in the presence of prenatal testosterone (Goldman et al, 1976), from mosaics (androgenized tf m carriers), who form nipples despite prenatal androgen exposure because of the presence of androgen-insensitive nipple tissue (Freeman et al, 1996).…”

Section: Methodsmentioning

confidence: 99%

Neuronal Size in the Spinal Nucleus of the Bulbocavernosus: Direct Modulation by Androgen in Rats with Mosaic Androgen Insensitivity

2001

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The motoneurons of the spinal nucleus of the bulbocavernosus (SNB) and its target muscles, the bulbocavernosus and levator ani, form a sexually dimorphic circuit that is developmentally dependent on androgen exposure and exhibits numerous structural and functional changes in response to androgen exposure in adulthood. Castration of male adult rats causes shrinkage of SNB somata, and testosterone replacement reverses this effect, but the site at which androgen is acting to cause this change is undetermined. We exploited the X-chromosome residency of the androgen receptor (AR) gene to generate androgenized female rats that were heterozygous for the testicular feminization mutant (tfm) AR mutation and that, as a consequence of ontogenetic random X-inactivation, expressed a blend of androgen-sensitive wild-type cells and tfm-affected androgen-insensitive cells in the SNB. Chronic testosterone treatment of adult mosaics increased soma sizes only in androgen-competent wild-type SNB cells. The size of tfm-affected SNB somata in the same animals did not differ from the size of either the wild-type or tfm-affected SNB neurons in control mosaics that did not receive androgen treatment in adulthood. Because the muscle targets of the SNB are known to be uniformly androgen-sensitive in tfm mosaics, this mosaic analysis provides unambiguous evidence that androgenic effects on motoneuron soma size are mediated locally in the SNB. It is possible that the neuronal AR plays a permissive role in coordinating the actions of androgen. Key words: mosaic; androgen; spinal nucleus of the bulbocavernosus; tfm mutation; soma size; steroid receptorsMost vertebrate motoneurons possess androgen receptors (ARs) (Pfaff, 1968;Sar and Stumpf, 1977;Kelley, 1986;Simerly et al., 1990), making them attractive models of steroidal effects on neuronal structure and function. The spinal nucleus of the bulbocavernosus (SNB), a cluster of motoneurons located in the dorsomedial aspect of lumbar segments 5 and 6, innervates the sexually dimorphic perineal muscles bulbocavernosus and levator ani (BC/LA), which participate in copulatory behavior. Adult male rats have more and larger SNB motoneurons than do females Arnold, 1980, 1981;Schroder, 1980). A perinatal surge of testosterone (T) in males rescues the BC/LA musculature from involution (Cihak et al., 1970) and inhibits apoptosis in the SNB (Nordeen et al., 1985). Exposing females to exogenous androgens during this critical period permanently masculinizes the SNB-BC/LA system (Breedlove and Arnold, 1983). The SNB critical period developmentally precedes AR expression in SNB cells (Jordan et al., 1991), and systemic androgen can rescue genetically androgen-insensitive SNB motoneurons provided that their BC/LA targets remain androgencompetent (Freeman et al., 1996). Furthermore, androgen is unable to rescue the SNB if the BC/LA muscles are treated with anti-androgen (Fishman and Breedlove, 1992) or extirpated (Kurz et al., 1992), indicating that androgen acts indirectly, via actions in the BC/LA, to rescu...

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Role of Testosterone and its Metabolites in the Differentiation of the Mammary Gland in Rats

Cited by 41 publications

References 0 publications

Androgen Dependent Mammary Gland Virilism in Rats Given the Selective Estrogen Receptor Modulator LY2066948 Hydrochloride

Androgen Dependent Mammary Gland Virilism in Rats Given the Selective Estrogen Receptor Modulator LY2066948 Hydrochloride

Evaluation of a Two-Generation Reproduction Toxicity Study Adding Endopoints to Detect Endocrine Disrupting Activity Using Lindane

Neuronal Size in the Spinal Nucleus of the Bulbocavernosus: Direct Modulation by Androgen in Rats with Mosaic Androgen Insensitivity

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