Perinatal Exposure to Bisphenol-A Alters Peripubertal Mammary Gland Development in Mice

Abstract

Developmental exposure to estrogenic chemicals induces morphological, functional, and behavioral anomalies associated with reproduction. Humans are exposed to bisphenol-A (BPA), an estrogenic compound that leaches from dental materials and plastic food and beverage containers. The aim of the present study was to determine the effects of perinatal exposure to low, environmentally relevant doses of BPA [25 and 250 ng BPA/kg body weight (bw).d] on the peripubertal development of the mammary gland. BPA exposure enhanced the mammary glands' sensitivity to estradiol in ovariectomized CD-1 mice. In their intact 30-d-old littermates, the area and numbers of terminal end buds relative to the gland ductal area increased whereas their apoptotic activity decreased. There was a positive correlation between ductal length and the age at first proestrus; that was reduced as the BPA dose increased, suggesting that BPA exposure slows down ductal invasion of the stroma. There was also a significant increase of progesterone receptor-positive ductal epithelial cells that were localized in clusters, suggesting future branching points. Indeed, lateral branching was significantly enhanced at 4 months of age in mice exposed to 25 ng BPA /kg bw.d. In conclusion, perinatal exposure to environmentally relevant BPA doses results in persistent alterations in mammary gland morphogenesis. Of special concern is the increased terminal end bud density at puberty as well as the increased number of terminal ends reported previously in adult animals, as these two structures are the sites at which cancer arises in humans and rodents.

Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells

“…Epidemiological studies suggest a positive correlation between blood levels of chemicals with estrogenic activity, such as organochlorine pollutants, and breast cancer incidence among women, implying that the growing risk of contracting mammary cancer may be linked to the wide distribution of synthetic xenoestrogens (12,13,(44)(45)(46)(47). On the other hand, beneficial health effects have been attributed to the dietary intake of natural phytoestrogens in food of plant origin (17,18).…”

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

“…In these mice, BPA caused a decreased invasion of the stromal compartment, increased number of terminal end buds (TEBs) relative to the ductal area, decreased apoptosis and increased numbers of cells expressing progesterone receptor in the pubertal mammary gland [30]. At 4 months of age, these animals had a significant increase in lateral branching [30].…”

“…In these mice, BPA caused a decreased invasion of the stromal compartment, increased number of terminal end buds (TEBs) relative to the ductal area, decreased apoptosis and increased numbers of cells expressing progesterone receptor in the pubertal mammary gland [30]. 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].…”

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).…”