In Utero Exposure to Bisphenol A Alters the Development and Tissue Organization of the Mouse Mammary Gland1

Abstract

Exposure to estrogens throughout a woman's life, including the period of intrauterine development, is a risk factor for the development of breast cancer. The increased incidence of breast cancer noted during the last 50 years may have been caused, in part, by exposure of women to estrogen-mimicking chemicals that are released into the environment. Here, we investigated the effects of fetal exposure to one such chemical, bisphenol A (BPA), on development of the mammary gland. CD-1 mice were exposed in utero to low, presumably environmentally relevant doses of BPA (25 and 250 microg/kg body weight), and their mammary glands were assessed at 10 days, 1 mo, and 6 mo of age. Mammary glands of BPA-exposed mice showed differences in the rate of ductal migration into the stroma at 1 mo of age and a significant increase in the percentage of ducts, terminal ducts, terminal end buds, and alveolar buds at 6 mo of age. The percentage of cells that incorporated BrdU was significantly decreased within the epithelium at 10 days of age and increased within the stroma at 6 mo of age. These changes in histoarchitecture, coupled with an increased presence of secretory product within alveoli, resemble those of early pregnancy, and they suggest a disruption of the hypothalamic-pituitary-ovarian axis and/or misexpression of developmental genes. The altered relationship in DNA synthesis between the epithelium and stroma and the increase in terminal ducts and terminal end buds are striking, because these changes are associated with carcinogenesis in both rodents and humans.

Induction of mammary gland ductal hyperplasias and carcinoma in situ following fetal bisphenol A exposure

“…At 4 months of age, these animals had a significant increase in lateral branching [30]. By 6 months of age, we observed an overall increase in epithelial structures including terminal ends and a premature appearance of alveolar buds, normally associated with pregnancy in the mouse [31]. More importantly, BPA exposed mice that were ovariectomized prepubertally showed an enhanced sensitivity to estradiol demonstrated by an increase in the number of TEBs, TEB area, TEB density and ductal extension [30,32].…”

Bisphenol A alters the development of the rhesus monkey mammary gland

“…BPA binds to estrogen receptors α and β (13) and to membranebound estrogen receptors (14) and, thus, affects various functions at all levels of biological complexity in estrogen target organs (15)(16)(17)(18)(19)(20)(21). Animal studies showed that BPA exposure at or below the reference dose of 50 μg/kg per day (http://cfpub.epa.gov/ncea/iris/index.…”

“…More importantly, BPA exposure during gestation and organogenesis produces effects that alter the structure and function of target organs (24). In particular, these low environmentally relevant developmental exposures caused changes in the tissue organization of the mouse mammary gland observed during fetal development (25), and further changes manifested long after the end of exposure at puberty (18,26) and in adulthood (18,(26)(27)(28)(29)(30). Female mice exposed to BPA during gestation also displayed a heightened response to estrogen compared with unexposed controls (31) and developed intraductal hyperplasias, i.e., a precancerous lesion (28).…”

Endocrine Disruptors and Breast Cancer Risk - Time to Consider the Environment

“…Invasive cancers were observed in those animals exposed to low doses of BPA when they were further challenged by a sub-carcinogenic dose of the chemical carcinogen N-nitroso-N-methylurea at puberty (Durando et al, 2007). BPA was also reported to increase the number of terminal end buds lateral branching and epithelial density, the presence of secretory products within the alveoli and increased stromal cell nuclear density (Markey et al, 2001;Munoz-de-Toro et al, 2005;Durando et al, 2007). Furthermore, BPA has been shown to cross the placenta in rodents and increase the bioavailability of estrogens at the fetal circulation (Richter et al, 2007).…”