Perinatal Exposure to Environmentally Relevant Levels of Bisphenol A Decreases Fertility and Fecundity in CD-1 Mice

Bisphenol A (BPA) has received heightened attention in the last decade because of its ubiquitous presence. BPA is used in the production of polycarbonate plastics and epoxy resins, including the resins used to coat the inside of food and beverage cans, and for dental composites and sealants (Olea et al. 1996; Vandenberg et al. 2007; Ye et al. 2009). A growing body of evidence supports the chronic nature of human BPA exposure. BPA was detected in the urine of > 92% of Americans tested, with higher levels present in children and adolescents relative to adults (Calafat et al. 2008). BPA has also been detected in maternal (Padmanabhan et al. 2008) and fetal plasma, placenta, and amniotic fluid (Ikezuki et al. 2002; Schonfelder et al. 2002) and in breast milk (Sun et al. 2004). The levels of urinary BPA in premature infants in neonatal intensive care units are approximately 10 times higher than those in the general population (Calafat et al. 2009). BPA has been considered to be a weak estrogen because of its low potency compared with estradiol in assays involving nuclear receptors (Blair et al. 2001; Thomas and Dong 2006). However, low levels of BPA can act additively with other xenoestrogens as well as with natural estrogens (Silva et al. 2002; Soto et al. 1994, 1997; Tollefsen 2002). BPA can also act via membrane receptors to produce effects that are similar in potency to those of estradiol (Welshons et al. 2006; Wozniak et al. 2005). These findings stress the relevance of low-dose exposures, particularly during the perinatal period, when BPA may affect the development of estrogen target organs. Developmental exposure to endocrine disruptors has been postulated to play a role in the increased incidence of malformations of the male genital tract and testicular and breast cancers observed in the European and U.S. populations during the last half century, a time when numerous hormonally active chemicals were introduced into the environment (Diamanti-Kandarakis et al. 2009; Jouannet et al. 2001; Skakkebaek 1998; Skakkebaek et al. 2001). Epidemiological studies of women born in Denmark have suggested that young cohorts had progressively lower total fertility rates that were compensated for by the increased use of assisted reproductive technologies (Jensen et al. 2008). In a laboratory setting, female mice exposed in utero to environmentally relevant doses of BPA have shown advanced puberty (Howdeshell et al. 1999), alterations in estrous cyclicity, and an increase in the percentage of ovarian antral follicles (Markey et al. 2003). Early BPA exposure resulted in increased proliferative activity of epithelial cells in the endometrial glands and increased expression of estrogen receptor-α (ERα) and progesterone receptor in the luminal epithelium of the endometrium and in the subepithelial stroma of exposed mice (Markey et al. 2005). Perinatal exposure of mice to BPA also decreased sex differences in the anteroventral periventricular nucleus of the hypothalamus (Rubin et al. 2006), a nucleus known to be important for the preovulatory luteinizing hormone (LH) surge. In addition, BPA exposure during gestation and lactation accelerated the onset of acyclicity in rats (Rubin et al. 2001). Taken together, these multiple effects of BPA exposure during early development might be expected to compromise overall reproductive success. The above-mentioned effects observed after early exposure to BPA are reminiscent of those observed after fetal exposure to another estrogenic compound, diethylstilbestrol (DES), which was widely prescribed to prevent miscarriages in pregnant women (Newbold 2008). Fetal exposure to DES resulted in oviduct malformations in mice during adulthood (Newbold et al. 1983) and uterine fibroids in women later in life (Baird and Newbold 2005; McLachlan et al. 1980). Early exposure to DES also advanced the age of vaginal opening and the age at first estrous in mice (Honma et al. 2002). In addition, prenatal exposure to DES altered the reproductive capacity of female mice in a forced breeding protocol (McLachlan et al. 1982). This protocol revealed significant effects of DES, even at low doses, in stark contrast with the lack of effect of DES reported in studies that examined only the first pregnancy in DES-exposed females (Honma et al. 2002). Based on the wide variety of effects on the reproductive system caused by fetal and/or neonatal exposure to BPA, and the reproductive effects caused by early exposure to DES, we hypothesized that perinatal exposure to BPA impairs the reproductive function of exposed females (Maffini et al. 2006). In the present study, we tested this hypothesis by assessing fertility and fecundity in BPA-exposed CD-1 mice over a period of 32 weeks in a forced breeding regimen.