Environmental toxicants with the potential to alter fetal development of the reproductive system are of major concern to scientists and the general public alike. In particular, the estrogenic plastic monomer bisphenol A (BPA) is a compound of tremendous concern due to its inclusion in many everyday consumer items including baby bottles and canned foods. While some animal studies have indicated exposure to extremely low doses of BPA (less than 50 µg/kg/day) can result in significant alteration of reproductive endpoints, other studies have found no effects of BPA exposure on reproductive system development. To investigate whether low doses of BPA could affect testis morphogenesis in mice, we conducted a gestational exposure study. Pregnant CD-1 dams (n=3 per treatment group) were orally dosed with corn oil vehicle, 50 µg/kg/day BPA, or 0.5 µg/kg/day BPA from embryonic day 10.5 (E10.5) to E17.5. This time period coincides with sex determination and covers subsequent testis cord organization and expansion. A fourth treatment group received 0.05 µg/kg/day of the known ERalpha agonist diethylstilbestrol (DES) to serve as a positive control. Pups were collected via caesarean section at E19.0, shortly before the time of birth. In utero exposure to BPA or DES did not significantly alter litter size, pup body weight, or anogenital distance compared to vehicle-treated controls. Histological analysis revealed abnormal testis morphology in 50% of testes exposed to 50 µg/kg/day of BPA and 80% of testes in the 0.05 µg/kg/day DES and 0.5 µg/kg/day BPA treatment groups. Dysgenic BPA- and DES-exposed testes contained fewer testis cord cross-sections and increased interstitial area compared to vehicle controls. Underdevelopment of the testis cords was particularly evident near the rete testes, where uncoiled lengths of testis cord appeared as finger-like projections. Thus, our study indicates in utero exposure to BPA doses equal to or below the FDA acceptable daily intake value of 50 µg/kg/day can alter fetal testis development in the mouse. Furthermore, the histological similarities between DES- and BPA-exposed testes suggested BPA-induced changes in testis cord development are likely mediated by ERalpha. Surprisingly, altered testis histology following low-dose BPA or DES treatment was remarkably similar in appearance to the fetal testis cord dysgenesis we observed in conditional knockout (cKO) mice lacking expression of inhibin betaA (Inhba), a subunit of activin A, in the fetal Leydig cells. Loss of fetal Leydig cell-derived activin A leads to decreased Sertoli cell proliferation and subsequent impairment of testis cord expansion. Murine fetal Leydig cells express ERalpha, suggesting exposure to estrogenic compounds could potentially influence fetal Leydig cell expression of Inhba/activin A. We therefore hypothesized that BPA- and DES-induced testis cord dysgenesis results from alteration of fetal Leydig cell expression of Inhba and/or disruption of activin A signaling. We are currently testing our hypothesis by performing quantitative real-time PCR analysis for genes involved in the testicular activin A signaling pathway. This research was supported by NIH 1P20ES018163 and NIH T32ES07326. (poster)
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