Exposure to the Endocrine Disruptor Bisphenol A Alters Susceptibility for Mammary Cancer.
Exposure to the Endocrine Disruptor Bisphenol A Alters Susceptibility for Mammary Cancer.
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DOI：
10.1515/hmbci.2010.075
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发表时间：
2011-03-01
影响因子：
1
通讯作者：
Russo J
中科院分区：
文献类型：
--
作者：
Lamartiniere CA;Jenkins S;Betancourt AM;Wang J;Russo J
双酚 A (BPA) 是一种合成化学品，用于生产聚碳酸酯塑料和环氧树脂。最近的研究表明，超过 90% 的受调查人类都可检测到 BPA 浓度。然而，BPA 最令人担忧的是早期发育期间的暴露，因为 BPA 已被证明会与雌激素受体 (ER) 结合并导致发育和生殖毒性。我们研究了围产期 BPA 改变大鼠对化学诱发乳腺癌易感性的潜力。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，青春期前给哺乳母鼠口服低浓度的 BPA 会导致肿瘤潜伏期显着缩短并增加肿瘤的多样性。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、减少细胞凋亡来介导的，并集中于乳腺中类固醇受体共激活剂 (SRC) 1-3、erbB3 的上调和 Akt 信号传导的增加。此外，我们还证明，产前接触 BPA 会使化学诱发乳腺癌的易感时间从 50 天变为 100 天。蛋白质组学数据表明，产前接触 BPA 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。 ER-α、SRC 1-3、Bcl-2、表皮生长因子受体 (EGFR)、磷酸-IGF-1R、磷酸-c-Raf、磷酸-ERKs 1/2、磷酸-ErbB2 和磷酸-Akt 的增加伴随着细胞增殖的增加。我们的结论是，在产前和产后早期接触低浓度的 BPA 可能会导致化学诱发的乳腺癌。
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.