Evidence of sex reversal in the gonads of chicken embryos after oestrogen treatment as detected by expression of lutropin receptor.
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In chicken embryos, there is a difference between the sexes in the onset of lutropin receptor mRNA expression in the gonads. The effects of oestrogen on lutropin receptor expression were studied to investigate the mechanism controlling this difference. Lutropin receptor mRNA expression was detected in the ovaries of sesame oil-treated control female embryos on day 12 of incubation, while no expression was found in the testes of the male controls. Oestradiol administration to genetically male embryos before sexual differentiation resulted in gonadal sex reversal which was characterized histologically by the proliferation of cortical cords and the presence of lacunae. Lutropin receptor expression was detected in the feminizing testis on day 12 of incubation. Administration of aromatase inhibitor (CGS 16949 A) to genetically female embryos before sexual differentiation inhibited the formation of cortical cords, although a relatively weak expression of lutropin receptor was detected. These results indicate that early expression of the lutropin receptor is regulated by oestrogen. (+info)
Estrogen-inducible, sex-specific expression of brain-derived neurotrophic factor mRNA in a forebrain song control nucleus of the juvenile zebra finch.
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The expression of brain-derived neurotrophic factor (BDNF) mRNA is increased significantly within the high vocal center (HVc) of male but not female zebra finches from posthatching day 30-35 on. The population of HVc cells expressing BDNF mRNA included 35% of the neurons projecting to the nucleus robustus of the archistriatum (RA). In the RA and in RA-projecting neurons of the lateral portion of the magnocellular nucleus of the anterior neostriatum, BDNF mRNA was expressed at very low levels in both sexes. The BDNF-receptor trkB mRNA was expressed in the RA, in RA-projecting neurons of lateral portion of the magnocellular nucleus of the anterior neostriatum, and in the HVc, except in most of its RA-projecting neurons. Premature stimulation and an inhibitory effect on the normal increase of the BDNF mRNA expression in juvenile males occurred after treatments with 17beta-estradiol and the aromatase inhibitor fadrozole, respectively. The up-regulation of the BDNF expression in the HVc could be a mechanism by which estrogen triggers the differentiation of cells within and connected to the HVc of male zebra finches. (+info)
Evaluation of the EDSTAC female pubertal assay in CD rats using 17beta-estradiol, steroid biosynthesis inhibitors, and a thyroid inhibitor.
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The Endocrine Disrupter Screening and Testing Advisory Committee has recommended the female pubertal onset assay as a Tier I test to detect potential endocrine-disrupting chemicals (EDs). We evaluated this assay's ability to detect EDs acting through various mechanisms. In two similar experiments, weanling female rats were dosed for 20 days by gavage with vehicle (0.5% methocel) or the following test compounds (mg/kg/day): 17beta-estradiol (E2; 0.1, 2, or 4), ketoconazole (KETO; 24, 50, or 100), finasteride (FIN; 20), testolactone (TL; 220), fadrozole (FAD; 0.6, 1.2, or 6.0) or 6-propylthiouracil (PTU; 240). In vehicle-treated females, mean age at pubertal onset, as evidenced by vaginal opening (VO), varied interexperimentally from 32.3+/-1.6 days to 33.5+/-1.8 days. At 0.1 mg/kg E2, age at VO was reduced slightly to 31.0+/-1.6 days, but not significantly (alpha=0.05). Higher E2 doses (2.0 and 4.0) reduced age at VO to 28 days. KETO delayed VO, but this delay was significant only at 100 mg/kg (39.7+/-2.4 days). FIN and TL had no effect on age at pubertal onset; however, FAD significantly delayed VO. PTU delayed VO to 34.2+/-1.1 days and altered thyroid weight, histology, and hormone levels. With each compound, significant changes in age at VO were accompanied by decreased uterine or ovarian weights. Thus, although this assay did not detect TL or lower doses of E2 (0.1 mg/kg) or KETO (< or = 50 mg/kg), it was capable of detecting EDs operating through a variety of mechanisms. (+info)
Drug and hormone interactions of aromatase inhibitors.
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The clinical development of aromatase inhibitors has been largely confined to postmenopausal breast cancer patients and strongly guided by pharmacological data. Comparative oestrogen suppression has been helpful in circumstances in which at least one of the comparitors has caused substantially non-maximal aromatase inhibition. However, the triazole inhibitors, letrozole and anastrozole, and the steroidal inhibitor, exemestane, all cause >95% inhibition. Comparisons between these drugs therefore require more sensitive approaches such as the direct measurement of enzyme activity by isotopic means. None of these three agents has significant effects on other endocrine pathways at its clinically applied doses. Pharmacokinetic analyses of the combination of tamoxifen and letrozole have revealed that these drugs interact, resulting in letrozole concentrations approximately 35-40% lower than when letrozole is used alone. (+info)
Oestrogen regulates male aggression in the non-breeding season.
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Extensive research has focused on territorial aggression during the breeding season and the roles of circulating testosterone (T) and its conversion to 17beta-oestradiol (E2) in the brain. However, many species also defend territories in the non-breeding season, when circulating T-levels are low. The endocrine control of non-breeding territoriality is poorly understood. The male song sparrow of Washington State is highly territorial year-round, but plasma T is basal in the non-breeding season (autumn and winter). Castration has no effect on aggression in autumn, suggesting that autumnal territoriality is independent of gonadal hormones. However, non-gonadal sex steroids may regulate winter territoriality (e.g. oestrogen synthesis by brain aromatase). In this field experiment, we treated wild non-breeding male song sparrows with a specific aromatase inhibitor (fadrozole, FAD) using micro-osmotic pumps. FAD greatly reduced several aggressive behaviours. The effects of FAD were reversed by E2 replacement. Treatment did not affect body condition or plasma corticosterone, suggesting that all subjects were healthy These data indicate that E2 regulates male aggression in the non-breeding season and challenge the common belief that aggression in the non-breeding season is independent of sex steroids. More generally, these results raise fundamental questions about how sexual and/or aggressive behaviours are maintained in a variety of model vertebrate species despite low circulating levels of sex steroids or despite castration. Such non-classical endocrine mechanisms may be common among vertebrates and play an important role in the regulation of behaviour. (+info)
Aromatase inhibitors prevent spontaneous granular cell tumors in the distal female reproductive tract of Sprague-Dawley rats.
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We recently established diagnostic criteria for granular cell changes in the distal female reproductive tract of rats. In a review of control animals from 9 carcinogenicity studies, we found that approximately 23% of animals had granular cell alterations. Because estrogen may play a role in the pathogenesis of granular cell alterations, we reviewed tissue sections from carcinogenicity studies with 2 aromatase inhibitors and found compound-related decreases in the incidence of granular cell changes. Since these aromatase inhibitors selectively prevent the conversion of androgenic steroids to the corresponding estrogens, these data further suggest that estrogen may play a role in the pathogenesis of granular cell tumors of the reproductive tract of rats. (+info)
Evaluation of the male pubertal onset assay to detect testosterone and steroid biosynthesis inhibitors in CD rats.
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The male pubertal onset assay has been recommended by the Endocrine Disrupter Screening and Testing Advisory Committee (EDSTAC) as an alternate Tier I screening assay to detect potential endocrine-active chemicals (EACs). Recently, this assay was evaluated by several laboratories using a variety of dosing schemes. This study used a 30-day dosing period to confirm and extend previous work on the assay's ability to detect steroid biosynthesis inhibitors. Weanling male rats were dosed by gavage from 21 to 50 days of age with vehicle (0.5% methocel) or chemicals from the following EAC classes: an androgen (testosterone propionate [TP], 0.1 or 0.4 mg/kg/day), a broad-spectrum steroid biosynthesis inhibitor (ketoconazole [KETO], 24 mg/kg/day), a 5alpha-reductase inhibitor (finasteride [FIN], 20 or 80 mg/kg/day), a moderately specific aromatase inhibitor (testolactone [TL], 220 mg/kg/day), or a highly specific aromatase inhibitor (fadrozole [FAD], 0.6 or 6.0 mg/kg/day). None of these treatments altered relative thyroid weights. However, TL, KETO, and FIN were positive for endocrine activity based on decreases in one or more reproductive or accessory sex gland organ weights. Of these three inhibitors, only TL significantly increased the age at PPS, indicating that PPS was less sensitive for detecting these EACs. Based on its profile of effects, TL may have been detected as an antiandrogen. TP and FAD were negative in this assay, even at doses that caused effects in other studies. With TP, oral administration limited assay sensitivity such that higher TP doses would be needed for detection. FAD decreased body weight gains, but did not significantly alter any other assay end points; thus, the capacity of this assay to detect aromatase inhibitors remains in question. (+info)
Collaborative work to evaluate toxicity on male reproductive organs by repeated dose studies in rats 4). Fadrozole hydrochloride: an oral 2/4-week male reproductive organ toxicity study.
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Doses of 0, 30 and 60 mg/kg/day of fadrozole hydrochloride (Afema: non-steroidal aromatase inhibitor, antitumor agent) were given perorally by gavage to HanIbm WIST male rats from 6 or 8 weeks of age for 2 weeks, and from 6 weeks of age for 4 weeks. In all treatment groups, reduced weights of seminal vesicle, prostate and epididymis, and degeneration/necrosis of the pachytene spermatocytes in stages VII or VIII seminiferous tubules, were dose-relatedly observed. Effects could also be assessed quantitatively by staging analysis with the result of a reduction in the numbers of stage VII pachytene spermatocytes at 30 and 60 mg/kg/day. Epididymal sperm examination revealed no treatment-related changes in any groups. The effects of 4-week treatment on male reproductive organs were similar to those of 2-week treatment at the same dose levels, except for the weights of seminal vesicle and prostate, which were more reduced by 4-week treatment than by 2-week treatment. There was no notable difference in detectability of toxicity in male reproductive organs between 2-week treatment from 6 weeks of age and 2-week treatment from 8 weeks of age. It was concluded that the changes observed in the rat male reproductive organs following 4 weeks of treatment with fadrozole hydrochloride could be detected also with 2 weeks of treatment. (+info)