Effect of chronic oestrogen administration on androgen receptor expression in reproductive organs and pituitary of adult male rat (original) (raw)
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Andrologia, 2010
Following chronic (15 or 30 days) treatment with oestradiol 3-benzoate (75 μg rat−1 day−1 in 100 μl of olive oil) to adult rats, androgen receptor (AR) expression was analysed simultaneously in testis, epididymis, seminal vesicle, prostate and pituitary utilising three independent tools i.e. immunohistochemistry, Western blotting and RT-PCR. All the five organs showed higher AR transcriptional activity gradually increasing from 15 to 30 days of oestrogen treatment. However, the AR protein expression either through immunostaining or Western blotting demonstrated a significant decline in all the reproductive organs. In the pituitary, on the other hand, the decline coincided with a distinct breakdown of the AR protein into two bands with increasing duration of treatment. Serum and intra-testicular testosterone levels were found significantly lowered. Spermatogenesis was adversely affected with concurrent decrease in weights of testis and accessory sex organs. Decrease in testis weight was consistent with the reduction in the number of maturing germ cells per tubule. Despite the decrease in weight, accessory sex organs like epididymis, seminal vesicle and prostate were completely devoid of any apoptotic cells which were characterised only in testis and pituitary. Seminiferous epithelium demonstrated a marked increase in the number of germ cells undergoing apoptosis. However, the rate of cell apoptosis was much higher in the pituitary than in the testis at the end of 30 days treatment. It is therefore concluded that degradation of AR protein expression after oestrogen treatment is probably directly linked to an increase in cell apoptosis both in testis and pituitary.
APMIS, 2001
The effects on reproductive tract development in male rats, of neonatal exposure to potent (reference) oestrogens, diethylstilboestrol (DES) and ethinyl oestradiol (EE), with those of two environmental oestrogens, octylphenol and bisphenol A were systematically compared. Other treatments, such as administration of a gonadotrophin-releasing hormone antagonist (GnRHa) or the anti-oestrogen tamoxifen or the anti-androgen¯utamide, were used to aid interpretation of the pathways involved. All treatments were administered in the neonatal period before onset of puberty. The cellular sites of expression of androgen receptors (AR) and of oestrogen receptor-a (ERa) and ERb were also established throughout development of the reproductive system. The main ®ndings were as follows: (i) all cell types that express AR also express one or both ERs at all stages of development; (ii) Sertoli cell expression of ERb occurs considerably earlier in development than does expression of AR; (iii) most germ cells, including fetal gonocytes, express ERb but not AR; (iv) treatment with high, but not low, doses of potent oestrogens such as DES and EE, induces widespread structural and cellular abnormalities of the testis and reproductive tract before puberty; (v) the latter changes are associated with loss of immunoexpression of AR in all affected tissues and a reduction in Leydig cell volume per testis; (vi) none of the effects in (iv) and (v) can be duplicated by treating with high-dose octylphenol or bisphenol A; (vi) none of the reproductive tract changes in (iv) and (v) can be induced by simply suppressing androgen production (GnRHa treatment) or action (¯utamide treatment); and (vii) the adverse changes induced by high-dose DES (iv and v) can be largely prevented by co-administration of testosterone. Thus, it is suggested that many of the adverse changes to the testis and reproductive tract induced by exposure to oestrogens result from a combination of high oestrogen and low androgen action. High oestrogen action or low androgen action on their own are unable to induce the same changes.
Molecular and Cellular Endocrinology, 2001
Androgens are important for the structural and functional integrity of the testis and the prostate and this may in part be mediated by the aromatisation of testosterone to oestradiol. The aim of the present study was to establish an in vivo model that would allow the identification of genes, the expression of which was regulated acutely by androgen and/or oestrogen in the male reproductive system. In rats in which the Leydig cells were ablated by administration of ethane dimethane sulfonate (EDS) 6 days earlier, testosterone esters (T) were administered from day 0 (To), and additional animals were administered either T, 17b-oestradiol benzoate (EB) or diethylstilbestrol (DES) for 1 or 4 h on day 6 after EDS-treatment. Nuclear immunoexpression of the androgen receptor (AR) was reduced or absent from the testis but unaffected in the ventral prostate following these treatments. ERb immunoexpression in these tissues was unchanged. Northern blot analysis showed that EB and DES as well as T administration 4 h earlier could modulate mRNA expression of two androgen-responsive genes, C3 and SGP-2, in the prostate. The co-administration of T or EB with the AR antagonist, flutamide, or with the ER antagonist, ICI 182,780 (ICI), did not block the suppression of SGP-2 mRNA expression by T or EB. In contrast, the upregulation of C3 mRNA expression by T was successfully antagonised by both flutamide and by ICI. A preliminary evaluation of the expression of three Sertoli cell and five germ cell mRNAs revealed that their expression was not steroid regulated. Our results support the hypothesis that the action of testosterone in the male reproductive system may in part be mediated by its conversion to oestradiol. This in vivo model should prove of value in future studies to identify androgen and oestrogen regulated genes in the male reproductive system.
Endocrinology, 2002
This study tested the hypothesis that testis/reproductive tract abnormalities induced in the rat by neonatal treatment with diethylstilbestrol (DES) result from disturbance of the androgen-estrogen balance. Male rats were treated neonatally with a dose of DES (0.1 g) that induced either no or small effects on its own or with a dose (10 g) that induced major reproductive tract abnormalities. To allow quantification, the abnormalities chosen for study were distension of the rete testis and efferent ducts and reduction in epithelial cell height in the efferent ducts and vas deferens. To alter the androgenestrogen balance, other rats were treated with DES (0.1 g) in combination with a treatment to suppress either androgen production [GnRH antagonist (GnRHa)] or androgen action (flutamide); other rats were treated with GnRHa or flutamide alone. Testosterone levels were measured to verify the effects of treatment. Combined administration of DES (0.1 g) plus GnRHa or flutamide induced significantly greater distension/ overgrowth of the rete testis and efferent ducts (ED) and a reduction in epithelial cell height of the ED than did DES (0.1 g) administered alone. Neither GnRHa nor flutamide affected rete or ED distension when administered alone, but both significantly reduced ED epithelial cell height. Neonatal treatment with bisphenol-A (100 g) with or without GnRHa had no significant effect on any of these parameters. In contrast to the ED, a reduction in cell height of the vas deferens was induced to an equal extent by DES (10 g), DES (0.1 g) with GnRHa, and GnRHa alone, suggesting greater sensitivity of this tissue to both androgen and estrogen action. The induction of major abnormalities in rats treated with DES (10 g) was coincident with loss of androgen receptor immunoexpression in affected tissues. Reduced androgen receptor immunoexpression was also induced by combined treatment with DES (0.1 g) plus GnRHa or flutamide, whereas treatment with any of these compounds alone had no or only minor effects. These findings suggest that reduced androgen action sensitizes the reproductive tract to estrogens, demonstrating that the balance in action between androgens and estrogens, rather than their absolute levels, may be of fundamental importance in determining normal or abnormal development of some regions of the male reproductive tract. (Endocrinology
Toxicological Sciences, 2007
We investigated the ability of a mixture of three androgen receptor antagonists to induce disruption of male sexual differentiation after perinatal exposure. The aim was to assess whether the joint effects of vinclozolin, flutamide, and procymidone can be predicted based on dose-response data of the individual chemicals. Chemicals were administered orally to pregnant Wistar rats from gestational day 7 to postnatal day 16 (PND16). Changes in reproductive organ weights and of androgen-regulated gene expression in prostates from male rat pups were chosen as endpoints for extensive dose-response studies. With all endpoints, the joint effects of the three anti-androgens were dose-additive. Histological evaluations showed that dysgenesis and hypoplasia of prostates, seminal vesicles, and epididymis were seen with the highest mixture doses. No changes were observed in any single-compound low-dose group for these lesions, nor were there histopathological changes in the testes. Pronounced dysgenesis of external genitals was observed with all doses of the mixture, and severe dysgenesis was seen with a mixture for which the individual compounds caused no effects. A combination of doses of each chemical that on its own did not produce significant reductions in the weights of seminal vesicles and PBP C3 expression, induced a marked mixture effect. Thus, antiandrogens cause additive effects on end points of various molecular complexities such as alterations at the morphological and the molecular level.
Journal of andrology
This study evaluated whether androgen action is altered in rats treated neonatally with diethylstilbestrol (DES) at a dose that induced reproductive tract abnormalities. Rats were treated on alternate days 2-12 with 10 microg DES and studied on Day 18. DES-induced abnormalities included a 70% reduction in testis weight, distension and overgrowth of the rete, distension and reduction in epithelial height of the efferent ducts, underdevelopment of the epididymal duct epithelium, reduction in epithelial height in the vas deferens, and convolution of the extra-epididymal vas. In DES-treated rats, androgen receptor (AR) immunoexpression was virtually absent from all affected tissues and the testis, whereas AR expression in controls was intense in epithelial and stromal cells. The DES-induced change in AR immunoexpression was confirmed by Western analysis for the testis. In rats treated neonatally with 1 microg DES, reproductive abnormalities were absent or minor, except for a 38% reducti...
Biology of Reproduction, 2004
Prenatal exposure to environmental chemicals that interfere with the androgen signaling pathway can cause permanent adverse effects on reproductive development in male rats. The objectives of this study were to 1) determine whether a documented antiandrogen butyl benzyl phthalate (BBP) and/or linuron (an androgen receptor antagonist) would decrease fetal testosterone (T) production, 2) describe reproductive developmental effects of linuron and BBP in the male, 3) examine the potential cumulative effects of linuron and BBP, and 4) investigate whether treatment-induced changes to neonatal anogenital distance (AGD) and juvenile areola number were predictive of adult reproductive alterations. Pregnant rats were treated with either corn oil, 75 mg/kg/day of linuron, 500 mg/kg/day of BBP, or a combination of 75 mg/kg/day linuron and 500 mg/kg/day BBP from gestational Day 14 to 18. A cohort of fetuses was removed to assess male testicular T and progesterone production, testicular T concentrations, and whole-body T concentrations. Male offspring from the remaining litters were assessed for AGD and number of areolae and then examined for alterations as young adults. Prenatal exposure to either linuron or BBP or BBP ؉ linuron decreased T production and caused alterations to androgen-organized tissues in a dose-additive manner. Furthermore, treatment-related changes to neonatal AGD and infant areolae significantly correlated with adult AGD, nipple retention, reproductive malformations, and reproductive organ and tissue weights. In general, consideration of the doseresponse curves for the antiandrogenic effects suggests that these responses were dose additive rather than synergistic responses. Taken together, these data provide additional evidence of cumulative effects of antiandrogen mixtures on male reproductive development.