Altered Gene Expression during Rat Wolffian Duct Development in Response to in Utero Exposure to the Antiandrogen Linuron

Turner, Katie J.; McIntyre, Barry S.; Phillips, Suzanne; Barlow, Norman J.; Bowman, Christopher J.; Foster, Paul M.D.

doi:10.1093/toxsci/kfg096

Cited by 52 publications

(40 citation statements)

References 53 publications

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“…This is in agreement with previous studies showing that exposure to antiandrogenic compounds in utero results in a high frequency of epididymal malformations when studied in adulthood (17,23,26,27,34). Exposure to LW-flutamide did not result in incomplete WDs at any time point studied.…”

Section: Discussionsupporting

confidence: 93%

The Critical Time Window for Androgen-Dependent Development of the Wolffian Duct in the Rat

2007

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Androgens are thought to separately regulate stabilization and differentiation of the Wolffian duct (WD), but the time windows for these effects are unclear. To address this, fetal rats were exposed to flutamide within either an early window (EW) [embryonic day 15.5 (E15.5) to E17.5], when the WD degenerates in the female, or a later window (LW) (E19.5-E21.5), when the WD morphologically differentiates in the male, or during the full window of WD development (FW) (E15.5-21.5). WDs were examined for abnormalities during fetal (E21.5) or postnatal life, and anogenital distance and prostate presence/ absence were recorded. Exposure to FW-or EW-flutamide, but not to LW-flutamide, induced comparable abnormalities in the fetal WD at E21.5, namely reduced WD coiling, reduced cell proliferation, reduced epithelial cell height, altered epithelial vimentin expression, and reduced expression of smooth muscle actin in the WD inner stroma. Exposure to EW-or FWflutamide, but not to LW-flutamide, resulted in incomplete/ absent WDs in more than 50% of males by adulthood, although such abnormalities were infrequent in fetal life. These findings suggest that androgen action during the EW is sufficient to promote WD morphological differentiation several days later. Because the androgen receptor is expressed in the WD stroma but not in the epithelium during this EW, WD differentiation is likely to be dependent on androgen-mediated signaling from the stroma to the epithelium. In conclusion, the critical window for androgen action in regulating WD development in the rat is between E15.5 and E17.5. This window is also important for prostate formation and anogenital distance masculinization. (Endocrinology 148: 3185-3195, 2007) D URING MAMMALIAN development, before activation of SRY within the somatic cells of the genital ridge, the urogenital tract is initially identical in both sexes, comprising the Mü llerian duct (MD) and the Wolffian duct (WD) (1, 2). In males, after differentiation of the different somatic cell types in the fetal testis, the Sertoli cells secrete anti-Mü llerian hormone to induce MD degeneration, whereas the Leydig cells secrete testosterone, which acts via the androgen receptor (AR) to stabilize and rescue the WD (2, 3). Conversely, in females, the ovaries do not synthesize either androgens or anti-Mü llerian hormone so the WD degenerates and the MD persists (1-3). In males, once the WD is stabilized, it then differentiates to form its adult derivatives; the cranial portion of the WD convolutes to form the adult epididymis, the central portion remains a relatively simple straight duct and forms the vas deferens, whereas the seminal vesicles bud off the distal segment (4, 5). This process is thought to be controlled by androgens because XY males with inactivating mutations in the AR have a female phenotype with intraabdominal testes, no prostate, and a lack of WD-derived tissues (6 -9). In the rat, epididymal differentiation becomes evident between embryonic day 19.5 (E19.5) to E21.5 and is characterized by trans...

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Section: Discussionsupporting

confidence: 93%

The Critical Time Window for Androgen-Dependent Development of the Wolffian Duct in the Rat

2007

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“…For example, loss of epididymal coiling was reported in rat embryos exposed to Di(nButyl) phthalate, which caused a decrease in androgen biosynthesis (36). Similarly, embryos exposed to linuron, a weak AR antagonist, also exhibited decreased epididymal coiling (37). Based on these observations, we initially speculated that the loss of epididymal coiling in the InhbaϪ/Ϫ mutant was the result of defects in systemic androgen production, instead of a direct local effect of Inhba.…”

Section: Parameters Of Androgen Action Are Not Affected In the Absencmentioning

confidence: 96%

Essential roles of inhibin beta A in mouse epididymal coiling

Tomaszewski

Joseph²,

Archambeault³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Testis-derived testosterone has been recognized as the key factor for morphogenesis of the Wolffian duct, the precursor of several male reproductive tract structures. Evidence supports that testosterone is required for the maintenance of the Wolffian duct via its action on the mesenchyme. However, it remains uncertain how testosterone alone is able to facilitate formation of regionally specific structures such as the epididymis, vas deferens, and seminal vesicle from a straight Wolffian duct. In this study, we identified inhibin beta A (or Inhba) as a regional paracrine factor in mouse mesonephroi that controls coiling of the epithelium in the anterior Wolffian duct, the future epididymis. Inhba was expressed specifically in the mesenchyme of the anterior Wolffian duct at embryonic day 12.5 before the production of androgens. In the absence of Inhba, the epididymis failed to develop the characteristic coiling in the epithelium, which showed a dramatic decrease in proliferation. This loss of epididymal coiling did not result from testosterone deficiency, because testosterone production and parameters for testosterone action such as testis descent and anogenital distance remained normal. We further found that initial Inhba expression did not require testosterone as Inhba was also expressed in the anterior Wolffian duct of female embryos where no testosterone was produced. However, Inhba expression at later stages depended on testosterone. These results demonstrated that Inhba, a mesenchyme-specific gene, acts collectively with testosterone to facilitate epididymal coiling by stimulating epithelial proliferation.activin ͉ androgen ͉ epididymis ͉ Wolffian duct

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“…Testosterone reaching the Wolffian duct by the luminal compartment up regulates AR levels and induces proliferation of the epithelial cells through mesenchymal-epithelial cell interactions involving paracrine factors (48). At this stage, growth factors and components of the extracellular matrix are proposed to be important mediators from the mesenchyme to the epithelium (49). Recently, it has been suggested that circulating androgens are also important to induce Wolffian duct stabilization and subsequent formation of epididymides, as well as prostatic bud formation, virilization of the urogenital sinus and prostatic development (50).…”

Section: Expression and Physiological Roles Of Androgen Receptor In Tmentioning

confidence: 99%

Androgens and the male reproductive tract: an overview of classical roles and current perspectives

Patrão

Silva

Avellar

2009

Arq Bras Endocrinol Metab

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Androgens are steroid hormones that play key roles in the development and maintenance of male phenotype and reproductive function. These hormones also affect the function of several non-reproductive organs, such as bone and skeletal muscle. Endogenous androgens exert most of their effects by genomic mechanisms, which involve hormone binding to the androgen receptor (AR), a ligand-activated transcription factor, resulting in the modulation of gene expression. AR-induced non-genomic mechanisms have also been reported. A large number of steroidal and non-steroidal AR-ligands have been developed for therapeutic use, including the treatment of male hypogonadism (AR agonists) and prostate diseases (AR antagonists), among other pathological conditions. Here, the AR gene and protein structure, mechanism of action and AR gene homologous regulation were reviewed. The AR expression pattern, its in vivo regulation and physiological relevance in the developing and adult testis and epididymis, which are sites of sperm production and maturation, respectively, were also presented. Arq Bras Endocrinol Metab. 2009;53(8):934-45Keywords Androgen receptor; male reproductive tract; testis; epididymis RESUMOOs androgênios são hormônios esteroides com papel fundamental no desenvolvimento e na manutenção do fenótipo masculino e da função reprodutiva. Esses hormônios também afetam a função de diversos tecidos não reprodutivos, como, por exemplo, o ósseo e musculoesquelé-tico. Os androgênios endógenos exercem a maioria de suas funções por mecanismo genômico, que envolve a ligação do hormônio ao receptor de androgênio (RA), um fator de transcrição ativado por ligante, o que resulta no controle da expressão gênica. Mecanismos não genômicos também têm sido associados aos efeitos induzidos pelo RA. Um grande número de ligantes do RA, esteroidais e não esteroidais, tem sido desenvolvido para o uso terapêutico, incluindo o tratamento do hipogonadismo masculino (agonistas do RA) e de doenças da próstata (antagonistas do RA), entre outras condições patológicas. Neste trabalho, foram discutidas as caracterís-ticas estruturais básicas do RA (gene e proteína), os mecanismos de ação desse receptor, bem como aspectos relacionados à sua regulação homóloga. O padrão de expressão do RA, sua regulação in vivo e relevância fisiológica durante o desenvolvimento e a vida adulta na função do testículo e epidídimo, tecidos responsáveis pela produção e maturação de espermatozoides, respectivamente, também foram discutidos. Arq Bras Endocrinol Metab. 2009;53(8):934-45 Descritores Receptor de androgênio; trato reprodutor masculino; testículo; epidídimo

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Altered Gene Expression during Rat Wolffian Duct Development in Response to in Utero Exposure to the Antiandrogen Linuron

Cited by 52 publications

References 53 publications

The Critical Time Window for Androgen-Dependent Development of the Wolffian Duct in the Rat

The Critical Time Window for Androgen-Dependent Development of the Wolffian Duct in the Rat

Essential roles of inhibin beta A in mouse epididymal coiling

Androgens and the male reproductive tract: an overview of classical roles and current perspectives

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