Pre- and perinatal exposure to bisphenol A (BPA) modifies female and male mammary gland development

M DURANDO; L KASS; EH LUQUE; M MUÑOZ-DE-TORO

Congreso; SETAC LatinAmerica 11thBiennal Meeting; 2015

Endocrine disrupting chemicals (EDCs) have the potential to affect the development and differentiation of the mammary gland (MG). Bisphenol A (BPA) is an EDC that has been shown to elicit long-lasting and profound effects on rodent hormone-dependent tissues after the exposure had ended. Our hypothesis proposes that the exposure to low doses of BPA during the organogenesis and differentiation of the MG impacts negatively on its development promoting the action of chemical carcinogens. Our studies were designed to evaluate: a) the effects of prenatal or perinatal exposure to low doses of BPA on the MG of female and male offspring and b) whether the prenatal exposure to BPA increases the female MG susceptibility to the carcinogen N-nitroso-N-methylurea (NMU). Different time frames and exposition routes were assessed in Wistar rats. Pregnant rats received BPA either subcutaneously until parturition for the prenatal study or in the drinking water until weaning for the perinatal one. In both studies, male and female offspring was sacrificed at different ages and MG development was analyzed. Furthermore, after puberty a group of prenatal BPA-exposed females received a single subcarcinogenic dose of NMU and were sacrificed on adulthood. Male BPA-exposed animals showed a delayed mammary gland development, evidenced by a reduced ductal growth and decreased number of TEBs, independent of BPA route and length of the exposition. In female rats, prenatal exposure to BPA induced a deregulation between proliferation and apoptosis resulting in an increased number of hyperplastic ducts, an augmented stromal nuclear density and an altered endocrine environment with changes in the angiogenic process. Administration of a subcarcinogenic dose of NMU to animals exposed prenatally to BPA increased the percentage of hyperplastic ducts and induced the development of neoplastic lesions. In conclusion, our studies demonstrated that: 1) the male rat MG is sensitive to EDCs, being the prepubertal stage a useful time point to test for potential EDCs effects; 2) prenatal exposure to BPA increases the MG susceptibility to a chemical challenge; 3) BPA exposure induces modifications in the MG endocrine environment that are dose and time-specific; 4) assessing different administration routes, doses and lengths of exposure to EDCs is an important factor, since both the effects on the MG and the moment at which this effect can be appreciable could be different.