Perinatal exposure to Bisphenol A disturbs the early differentiation of male germ cells.

Understanding the effects of Bisphenol A (BPA) on early germ cell differentiation and their consequences in adult life is an area of growing interest in the field of endocrine disruption. Herein, we investigate whether perinatal exposure to BPA affects the differentiation of male germ cells in early life using a transgenic mouse expressing the GFP reporter protein under the Oct4 promoter. In this model, the expression of GFP reflects the expression of the Oct4 gene. This pluripotency gene is required to maintain the spermatogonial stem cells in an undifferentiated stage. Thus, GFP expression was used as a parameter to evaluate the effect of BPA on early germ cell development. Female pregnant transgenic mice were exposed to BPA by oral gavage, from embryonic day 5.5 to postnatal day 7 (PND7). The effects of BPA on male germ cell differentiation were evaluated at PND7, while sperm quality, testicular morphology, and protein expression of androgen receptor and proliferating cell nuclear antigen were studied at PND130. We found that perinatal/lactational exposure to BPA up-regulates the expression of Oct4-driven GFP in testicular cells at PND7. This finding suggests a higher proportion of undifferentiated spermatogonia in BPA-treated animals compared with non-exposed mice. Moreover, in adulthood, the number of spermatozoa per epididymis was reduced in those animals perinatally exposed to BPA. This work shows that developmental exposure to BPA disturbed the normal differentiation of male germ cells early in life, mainly by altering the expression of Oct4 and exerted long-lasting sequelae at the adult stage, affecting sperm count and testis.

Neonatal exposure to xenoestrogens impairs the ovarian response to gonadotropin treatment in lambs.

Bisphenol A (BPA) and diethylstilbestrol (DES) are xenoestrogens, which have been associated with altered effects on reproduction. We hypothesized that neonatal xenoestrogen exposure affects the ovarian functionality in lambs. Thus, we evaluated the ovarian response to exogenous ovine FSH (oFSH) administered from postnatal day 30 (PND30) to PND32 in female lambs previously exposed to low doses of DES or BPA (BPA50: 50 µg/kg per day, BPA0.5: 0.5 µg/kg per day) from PND1 to PND14. We determined: i) follicular growth, ii) circulating levels of 17ß-estradiol (E2), iii) steroid receptors (estrogen receptor alpha, estrogen receptor beta, and androgen receptor (AR)) and atresia, and iv) mRNA expression levels of the ovarian bone morphogenetic protein (BMPs) system (BMP6, BMP15, BMPR1B, and GDF9) and FSH receptor (FSHR). Lambs neonatally exposed to DES or BPA showed an impaired ovarian response to oFSH with a lower number of follicles ≥2 mm in diameter together with a lower number of atretic follicles and no increase in E2 serum levels in response to oFSH treatment. In addition, AR induction by oFSH was disrupted in granulosa and theca cells of lambs exposed to DES or BPA. An increase in GDF9 mRNA expression levels was observed in oFSH-primed lambs previously treated with DES or BPA50. In contrast, a decrease in BMPR1B was observed in BPA0.5-postnatally exposed lambs. The modifications in AR, GDF9, and BMPR1B may be associated with the altered ovarian function due to neonatal xenoestrogen exposure in response to an exogenous gonadotropin stimulus. These alterations may be the pathophysiological basis of subfertility syndrome in adulthood.

Neonatal exposure to bisphenol A reduces the pool of primordial follicles in the rat ovary.

We evaluated whether exposure to bisphenol A (BPA) disrupts neonatal follicle development in rats. From postnatal day 1 (PND1) to PND7, pups received corn oil (control), diethylstilbestrol (DES20: 20 µg/kg-d, DES0.2: 0.2 µg/kg-d), or BPA (BPA20: 20mg/kg-d, BPA0.05: 0.05 mg/kg-d). We examined follicular dynamics, multioocyte follicles (MOFs) incidence, proliferation and apoptosis rates, expression of steroid receptors (ERα, ERß, PR, AR) and cyclin-dependent kinase inhibitor 1B (p27) in PND8 ovaries. DES20, DES0.2 and BPA20-ovaries showed fewer primordial follicles and increased growing follicles. DES20-ovaries exhibited increased incidence of MOFs. Oocyte survival, AR, PR and apoptosis were not changed. Primordial and recruited follicles from BPA20-ovaries showed higher p27, whereas ERß and proliferation were both increased in recruited follicles. ERα positive primary follicles increased in BPA 20-ovaries. Results show that BPA reduces the primordial follicle pool by stimulating the neonatal initial recruitment, associated with an increased proliferation rate likely mediated by an estrogenic pathway.