Lamartiniere Coral A, Jenkins Sarah, Betancourt Angela M, Wang Jun, Russo Jose
Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama.
Horm Mol Biol Clin Investig. 2011 Mar 1;5(2):45-52. doi: 10.1515/HMBCI.2010.075.
Bisphenol A (BPA) is a synthetically made chemical used in the production of polycarbonate plastics and epoxy resins. Recent studies have shown over ninety percent of humans investigated have detectable BPA concentrations. Yet, the biggest concern for BPA is exposure during early development because BPA has been shown to bind to the estrogen receptors (ER) and cause developmental and reproductive toxicity. We have investigated the potential of perinatal BPA to alter susceptibility for chemically-induced mammary cancer in rats. We demonstrate that prepubertal exposure to low concentrations of orally administered BPA given to lactating dams resulted in a significantly decreased tumor latency and increased tumor multiplicity in the dimethylbenz[a]anthracene (DMBA) model of rodent mammary carcinogenesis. Our data suggested that the mechanism of action behind this carcinogenic response was mediated through increased cell proliferation, decreased apoptosis, and centered on an up-regulation of steroid receptor coactivators (SRCs) 1-3, erbB3, and increased Akt signaling in the mammary gland.Also, we demonstrate that prenatal exposure to BPA shifts the time of susceptibility from 50 days to 100 days for chemically-induced mammary carcinogenesis. Proteomic data suggest that prenatal BPA exposure alters the expression of several proteins involved in regulating protein metabolism, signal transduction, developmental processes, and cell cycle and proliferation. Increases in ER-alpha, SRCs 1-3, Bcl-2, epidermal growth factor-receptor (EGFR), phospho-IGF-1R, phospho-c-Raf, phospho-ERKs 1/2, phospho-ErbB2 and phospho-Akt are accompanied by increase in cell proliferation. We conclude that exposure to low concentrations of BPA during the prenatal and early postnatal periods of life can predispose for chemically-induced mammary cancer.
双酚A（BPA）是一种合成化学物质，用于生产聚碳酸酯塑料和环氧树脂。最近的研究表明，在接受调查的人类中，超过90%的人可检测到双酚A浓度。然而，双酚A最令人担忧的是在早期发育过程中的暴露，因为双酚A已被证明可与雌激素受体（ER）结合并导致发育和生殖毒性。我们研究了围产期双酚A改变大鼠化学诱导性乳腺癌易感性的可能性。我们证明，在啮齿动物乳腺癌发生的二甲基苯并[a]蒽（DMBA）模型中，给哺乳期母鼠口服低浓度双酚A，青春期前暴露会导致肿瘤潜伏期显著缩短，肿瘤多发性增加。我们的数据表明，这种致癌反应背后的作用机制是通过增加细胞增殖、减少细胞凋亡介导的，并且以乳腺中类固醇受体共激活因子（SRCs）1 - 3、erbB3的上调以及Akt信号增强为中心。此外，我们证明产前暴露于双酚A会将化学诱导性乳腺癌的易感性时间从50天转移到100天。蛋白质组学数据表明，产前双酚A暴露会改变几种参与调节蛋白质代谢、信号转导、发育过程以及细胞周期和增殖的蛋白质的表达。雌激素受体α、SRCs 1 - 3、Bcl - 2、表皮生长因子受体（EGFR）、磷酸化胰岛素样生长因子1受体（phospho - IGF - 1R）、磷酸化c - Raf、磷酸化细胞外信号调节激酶1/2（phospho - ERKs 1/2）、磷酸化表皮生长因子受体2（phospho - ErbB2）和磷酸化Akt的增加伴随着细胞增殖的增加。我们得出结论，在生命的产前和产后早期暴露于低浓度双酚A会易患化学诱导性乳腺癌。
