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BackgroundBisphenol A (BPA) is widely used in the manufacture of polycarbonate plastics, including infant formula bottles.ObjectivesBased on the reported endocrine disruptor activity of this polyphenol, we hypothesized that exposure to BPA early in life would elicit developmental changes in the mammary tissue and cause a predisposition for mammary cancer.MethodsWe exposed neonatal/prepubertal rats to BPA via lactation from nursing dams treated orally with 0, 25, and 250 μg BPA/kg body weight/day. For tumorigenesis studies, female offspring were exposed to 30 mg dimethylbenzanthracene (DMBA)/kg body weight at 50 days of age.ResultsThe combination of DMBA treatment with lactational exposure to BPA demonstrated a dose-dependent increase in mammary tumor multiplicity and reduced tumor latency compared with controls. In the absence of DMBA treatment, lactational BPA exposure resulted in increased cell proliferation and decreased apoptosis at 50 but not 21 days postpartum (shortly after last BPA treatment). Using Western blot analysis, we determined that steroid receptor coactivators (SRCs) 1–3, Akt, phosphorylated Akt, progesterone receptor A (PR-A), and erbB3 proteins were significantly up-regulated at 50 days of age.ConclusionsThe data presented here provide the first evidence that maternal exposure to BPA during lactation increases mammary carcinogenesis in a DMBA-induced model of rodent mammary cancer. Changes in PR-A, SRC 1–3, erbB3, and Akt activity are consistent with increased cell proliferation and decreased apoptosis playing a role in mammary cancer susceptibility. These alterations provide an explanation of enhanced mammary carcinogenesis after lactational BPA exposure.

Background: Bisphenol A (BPA) is a synthetic compound used to produce plastics and epoxy resins. BPA can leach from these products in appreciable amounts, resulting in nearly ubiquitous daily exposure to humans. Whether BPA is harmful to humans, especially when administered orally in concentrations relevant to humans, is a topic of debate.Objectives: In this study, we investigated the role of chronic oral exposure to BPA during adulthood on mammary carcinogenesis by using a transgenic mouse model that spontaneously develops tumors through overexpression of wild-type erbB2 [mouse mammary tumor virus (MMTV)-erbB2].Methods: MMTV-erbB2 mice were exposed to 0, 2.5, 25, 250, or 2,500 µg BPA/L drinking water from 56 until 112 days of age (for mechanism of action) or 252 days of age (for tumorigenesis). Cellular and molecular mechanisms of BPA action in the mammary gland were investigated via immunohistochemistry and immunoblotting.Results: Only low doses of BPA significantly decreased tumor latency and increased tumor multiplicity, tumor burden, and the incidence of metastasis. All BPA doses significantly increased the cell proliferation index, but only the higher doses also increased the apoptotic index in the mammary gland. At the molecular level, 25 µg BPA/L, but not 2,500 µg BPA/L, increased phosphorylation of erbB2, erbB3, insulin-like growth factor 1 receptor, and Akt in the mammary gland.Discussion: Low, but not high, BPA doses significantly accelerated mammary tumorigenesis and metastasis in MMTV-erbB2 mice. The combined ratio of cell proliferation and apoptosis indices and alterations in protein expression best predicted the ability of each dose of BPA to alter tumorigenesis in this model.

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