Perinatal bisphenol A exposure increases estrogen sensitivity of the mammary gland in diverse mouse strains.

Environmental exposure to hormonally active chemicals has coincided with an increase in the incidence in breast cancer (Davis et al. 1993), testicular cancer (Skakkebaek et al. 1998), and other endocrine-related diseases (Sharpe and Skakkebaek 1993). These outcomes are thought to result from extemporaneous exposure to synthetic estrogens during fetal development (Sharpe and Skakkebaek 1993) and have motivated the worldwide formation of government-sponsored committees to evaluate evidence for this hypothesis. For instance, in the United States, the U.S. Environmental Protection Agency (EPA) developed a screening program to test chemicals that may contaminate water and food to assess potential endocrine disruptor activity (Endocrine Disruptor Screening and Testing Advisory Committee 1998). At the request of the U.S. EPA, the National Toxicology Program (NTP) convened a meeting to consider whether environmentally relevant doses of endocrine disruptors caused biological effects. In 2001, the NTP Low-Dose Peer Review Panel published a final report (NTP 2001), which stated that there was “credible evidence for low-dose effects” and suggested that different experimental animal strains may account for reports of both positive and negative effects for the same parameters. In this regard, Spearow et al. (1999) observed that rodent strains selected for high fecundity and rapid growth rates, such as CD-1 mice, are more estrogen resistant than the less fecund C57Bl6. An additional controversy identified by the NTP was the shape of the dose–response curve, which was reported as nonmonotonic for some effects of prenatal xenoestrogen exposure. For example, prenatal methoxychlor exposure altered the response of the adult uterus to 17β-estradiol (E2); low doses increased uterine weight, and higher doses reduced it (Alworth et al. 2002). This type of nonmonotonic response was also observed for other end points with other estrogenic chemicals (Rubin et al. 2001; Vandenberg et al. 2006; vom Saal et al. 1997), arguing that low-dose effects cannot be deduced from effects observed at high doses. Our research focuses on the effects of perinatal exposure to environmentally relevant levels of the xenoestrogen bisphenol A (BPA). In the the present study we examined strain sensitivity and the shape of the estrogen dose–response curve in the context of our ongoing work in the mouse mammary gland. In addition, we explored the effects of perinatal BPA exposure on subsequent estrogen sensitivity at puberty. BPA, a compound used in the manufacture of polycarbonate plastics and epoxy resins, leaches from food and beverage containers (Biles et al. 1997; Brotons et al. 1994) and dental sealants and composites (Olea et al. 1996) under normal conditions of use (Markey et al. 2001b, 2003b). BPA levels have been measured in human urine (Calafat et al. 2005), serum (Takeuchi and Tsutsumi 2002), and maternal and fetal plasma, amniotic fluid, and placental tissue at birth (Ikezuki et al. 2002; Schonfelder et al. 2002). We chose to administer perinatally 0 or 250 ng BPA/kg body weight (bw)/day to mice. Based on data reported by Arakawa et al. (2004), we estimated that this level of BPA should fall within the range of reported human exposures. In the mammary gland, perinatal exposure to BPA alters ductal invasion of the stroma at puberty and increases lateral branching and the number of terminal ends during adulthood (Markey et al. 2001a; Munoz de Toro et al. 2005). Although the mechanisms by which BPA induces developmental abnormalities in the mammary gland are unknown, it is plausible that estrogen receptors (ER), which are expressed in the fetal mammary gland, may mediate BPA-induced effects. In the present study, we compared the response of the mammary glands to E2 in outbred CD-1 mice (the strain we have used previously) with inbred C57Bl6 mice, which have been used in numerous studies involving development of the mammary gland. Different levels of biological complexity within the mammary gland (i.e., tissue organization and gene expression) were examined. We also examined the effects of perinatal BPA exposure on the response to E2 at puberty in both strains.