Play, copulation, anatomy, and testosterone in gonadally intact male rats prenatally exposed to flutamide

Casto, Joseph M.; Ward, O. Byron; Bartke, Andrzej

doi:10.1016/s0031-9384(03)00120-3

Cited by 63 publications

(63 citation statements)

References 46 publications

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“…These figures on flutamide effect do not explain our results, because at adulthood, flutamide or its active metabolite, 2-hydroxyflutamide, would no longer exist in the males prenatally exposed to flutamide, given the short terminal half-lives of these compounds (Xu et al, 1998). Casto et al (2003) also reported similar results. Reduced non-intromittive mounting without sex hormonal change observed in all treatment groups ( Fig.…”

Section: Discussionsupporting

confidence: 64%

Effects of Flutamide on Sex Maturation and Behavior of Offspring Born to Female Rats Treated During Late Pregnancy

et al. 2004

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-Flutamide, when administered subcutaneously to female rats at doses of 3, 10, or 30 mg/ kg/day during late pregnancy (gestational days 16-21), significantly and dose-dependently decreased anogenital distance (AGD) of the male offspring in each dose group compared to controls. Significant delays in preputial separation were found in males at a dose of 30 mg/kg, but body weight gain was not inhibited. Cryptorchidism and absence of the prostate gland and seminal vesicles were found in males at doses ≥ 10 mg/kg, and testicular hypoplasia at a dose of 30 mg/kg. Hypospadias was noted in all dose groups and vaginal pouches at doses of ≥ 10 mg/kg. The effects on the accessory reproductive organs were severe, although the effects on the testes themselves were mild. However, those effects appeared to become more pronounced with growth, as evaluated on Days 30 and 42 and Weeks 16 to 18. Most of these affected animals displayed cryptorchidism. Male offspring exposed to flutamide in utero showed impairments of sexual behavior as adults in a dose-related manner. Number and frequency of mounts with intromissions was markedly decreased in all treated groups as compared to controls. At 10 mg/kg, no mounting with ejaculation was observed, and at a dose of 30 mg/kg, no mounting with intromission or ejaculation was observed. These changes in sexual behavior were closely associated with abnormalities of the external genitalia. Animals with hypospadias did not display mounts with ejaculation. However, F1 males that copulated at a dose of 3 mg/kg had a normal reproductive function. Histological examination of the reproductive organs revealed degeneration of the seminiferous tubules, hypospermatogenesis, and hypoplasia and inflammation of the seminal vesicles and prostate. Serum levels of FSH, LH, and testosterone in these animals were comparable between control and all dose groups. Therefore, the male reproductive dysfunction seen in the present study could not be attributed to abnormal sex hormone levels during maturation, but to possible demasculinization of the brain and progressively delayed dysmorphorogy of the male genitalia caused by fetal exposure to flutamide.

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Section: Discussionsupporting

confidence: 64%

Effects of Flutamide on Sex Maturation and Behavior of Offspring Born to Female Rats Treated During Late Pregnancy

et al. 2004

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“…This period starts a few days before birth and ends approximately 10 days thereafter [48]. Perinatal alterations in the endogenous gonadal hormone levels induce changes in sexually dimorphic physiologic, neuroanatomic, molecular and behavioral characteristics, independently of the genetic sex of the animals [38, 48, 49, 50]. Similar data were obtained after neonatal exposure to stress [51].…”

Section: Discussionmentioning

confidence: 95%

“…In addition to neonatal castration, in a group of males the effect of intrauterine testosterone (first androgenizing peak) was abolished by treatment of pregnant rats with Flut, a non-steroidal anti-androgen which blocks T and DHT action [29, 49, 63]. Moreover, a third group of males was exposed to embryonic Flut treatment and castrated at birth to abolish both masculinizing peaks.…”

Section: Discussionmentioning

confidence: 99%

Effect of Androgens on Sexual Differentiation of Pituitary Gamma-Aminobutyric Acid Receptor Subunit GABA<sub>B</sub> Expression

et al. 2004

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Previous work demonstrated a sexually dimorphic ontogenic expression of γ-aminobutyric acid receptors (GABA_BR) in rat pituitary. As sex steroids determine sex-specific expression patterns, we now studied the effect of sex hormones on pituitary GABA_BR expression. GABA_BR subunits, measured by Western blot and by semi-quantitative RT-PCR and luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone measured by RIA were determined in two experimental designs: First experimental design: 8- and 15-day-old females (8F, 15F); 8F and 15F treated with 100 µg testosterone propionate (TP) on day 1 of life (8F100TP, 15F100TP), 8- and 15-day-old males (8M, 15M) and 8M and 15M castrated on day 1 (8MC, 15MC). Second experimental design: 8-day-old female and male animals: 8F, 8F100TP, 8F treated with 1 µg/day TP on days 1–4 (8F1TP), 8F treated with the androgen antagonist Flutamide (Flut: 2.5 mg/100 g BW of pregnant mother on days E17-E23) (8F-Flut), 8M, 8MC, 8M treated with Flut as above (8M-Flut) and 8MC-Flut. In these animals, in addition, GABA, glutamate, aspartate and taurine were measured by HPLC in hypothalami and cortex. In the first set of experiments, GABA_B1R mRNA/protein expression was higher in 8F than in 15F, 8M or 15M. In 8F100TP, GABA_B1R mRNA/protein decreased to male levels. TP treatment did not alter GABA_B1R expression in 15F. There was no difference in GABA_B1R expression between 8M and 15M and neonatal castration did not modify its expression. In the second set of experiments, TP (1 µg) or Flut did not modify GABA_B1R in 8F, while 100 µg TP continued to decrease GABA_B1R expression. In 8M, Flut, alone or with castration, increased GABA_B1R mRNA/protein expression to 8F. Hypothalamic GABA content followed the same pattern as pituitary GABA_BR expression in 8-day-old animals, suggesting a cross-regulation. With regard to hormonal levels, 100 µg, but not 1 µg TP altered gonadotropins at 8 days, although both treatments effectively androgenized females as evidenced by lack of cycling. We conclude that androgens, acting pre- and postnatally, decrease pituitary GABA_BR subunit expression.

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“…Moreover, flutamide-exposed tg and wt males exhibited the expected shortened anogenital distance at weaning, comparable to females (data not shown), confirming that this dose was effective in blocking activation of ARs necessary for prenatal masculinization of the external genitalia. This dose has been used to successfully feminize male rats [29][30][31] . Note that neither expression of the transgene nor flutamide affects survival of tg females ( table 1 ).…”

Section: Prenatal Flutamide Rescues Tg Males From Perinatal Death Bumentioning

confidence: 99%

Prenatal Flutamide Enhances Survival in a Myogenic Mouse Model of Spinal Bulbar Muscular Atrophy

et al. 2010

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Background: Spinal bulbar muscular atrophy (SBMA) is caused by a CAG repeat expansion mutation in the androgen receptor (AR) gene, and mutant AR is presumed to act in motoneurons to cause SBMA. However, we found that mice overexpressing wild-type (wt) AR solely in skeletal muscle fibers display the same androgen-dependent disease phenotype as when mutant AR is broadly expressed, challenging the assumptions that only an expanded AR can induce disease and that SBMA is strictly neurogenic. We have previously reported that AR toxicity was ligand dependent in our model, and that very few transgenic (tg) males survived beyond birth. Methods: We tested whether the AR antagonist flutamide could block perinatal toxicity. tg males were treated prenatally with flutamide and assessed for survival and motor behavior in adulthood. Results: Prenatal treatment with flutamide rescued tg male pups from perinatal death, and, as adults, such perinatally rescued tg males showed an SBMA phenotype that was comparable to that of previously described untreated tg males. Moreover, tg males carrying a mutant endogenous allele for AR – the testicular feminization mutation (tfm) – and thus having functional AR only in muscle fibers nevertheless displayed the same androgen-dependent disease phenotype as adults. Conclusions: These mice represent an excellent model to study the myogenic contribution to SBMA as they display many of the core features of disease as other mouse models. These data demonstrate that AR acting exclusively in muscle fibers is sufficient to induce SBMA symptoms and that flutamide is protective perinatally.

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Play, copulation, anatomy, and testosterone in gonadally intact male rats prenatally exposed to flutamide

Cited by 63 publications

References 46 publications

Effects of Flutamide on Sex Maturation and Behavior of Offspring Born to Female Rats Treated During Late Pregnancy

Effects of Flutamide on Sex Maturation and Behavior of Offspring Born to Female Rats Treated During Late Pregnancy

Effect of Androgens on Sexual Differentiation of Pituitary Gamma-Aminobutyric Acid Receptor Subunit GABA<sub>B</sub> Expression

Prenatal Flutamide Enhances Survival in a Myogenic Mouse Model of Spinal Bulbar Muscular Atrophy

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