Toxicological Sciences: An Official Journal of the Society of Toxicology, 2014, 138(1):21-35.

Coexposure to Phytoestrogens and Bisphenol A Mimics Estrogenic Effects in an Additive Manner

Anne Katchy, Caroline Pinto, Philip Jonsson, et al

Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204-5056; et al

Endocrine-disrupting chemicals (EDC) are abundant in our environment. A number of EDCs, including bisphenol A (BPA) can bind to the estrogen receptors (ER), ERα and ERβ, and may contribute to estrogen-linked diseases such as breast cancer. Early exposure is of particular concern; many EDCs cross the placenta and infants have measurable levels of, eg, BPA. In addition, infants are frequently fed soy-based formula (SF) that contains phytoestrogens. Effects of combined exposure to xeno- and phytoestrogens are poorly studied. Here, we extensively compared to what extent BPA, genistein, and an extract of infant SF mimic estrogen-induced gene transcription and cell proliferation. We investigated ligand-specific effects on ER activation in HeLa-ERα and ERβ reporter cells; on proliferation, genome-wide gene regulation and non-ER-mediated effects in MCF7 breast cancer cells; and how coexposure influenced these effects. The biological relevance was explored using enrichment analyses of differentially regulated genes and clustering with clinical breast cancer profiles. We demonstrate that coexposure to BPA and genistein, or SF, results in increased functional and transcriptional estrogenic effects. Using statistical modeling, we determine that BPA and phytoestrogens act in an additive manner. The proliferative and transcriptional effects of the tested compounds mimic those of 17β-estradiol, and are abolished by cotreatment with an ER antagonist. Gene expression profiles induced by each compound clustered with poor prognosis breast cancer, indicating that exposure may adversely affect breast cancer prognosis. This study accentuates that coexposure to BPA and soy-based phytoestrogens results in additive estrogenic effects, and may contribute to estrogen-linked diseases, including breast cancer.

美国《毒理科学：毒理协会官方刊物》，2014年3月

接触性植物雌激素和双酚A以添加剂的方式模仿了雌激素活性

安妮 凯驰，卡罗琳  平托，菲利普  约翰逊，等

美国德克萨斯州休斯顿大学生物和生物化学学院核受体和细胞信号转导大学中心；等

内分泌扰乱化学物质 (EDC) 在我们的环境中大量存在。很多EDCs，包括双酚 A (BPA) 可以绑定到雌激素受体 (ER)，ERα 和 ERβ，并可能有助于与雌激素相关的疾病，如乳腺癌。早期接触特别令人关注；许多穿过胎盘和婴儿的EDCs具有可衡量的水平例如双酚 A。此外，婴儿经常被喂食含有植物雌激素的基于大豆的配方 (SF)。联合接触外来的植物雌激素的影响很少被研究。在这里，我们广泛地比较了双酚 A，金雀异黄素，和婴儿 SF提取物如何模仿雌激素诱导的基因转录和细胞增殖。我们探究了配体特异性对HeLa-ERα 和 ERβ 记录细胞ER 活化的影响；在乳腺癌 MCF7 细胞中，对增殖、 全基因组基因调控和非 ER 介导的影响；以及共接触是如何影响这些作用的。使用临床乳腺肿瘤的差异性调控基因和菌落浓缩分析来探究生物的相关性。我们证明，共接触双酚 A 和金雀异黄素或 SF，会导致功能性和转录雌激素效应的增强。使用统计建模，我们确定双酚 A 和植物雌激素以添加剂的方式发挥作用。测试化合物的增殖能力和转录影响模仿了 17β-雌二醇，并且由ER 拮抗剂联合治疗消除。每种化合物诱导的基因表达类型集中在预后差的乳腺癌中，表明接触可能会对乳腺癌预后产生不利影响。这项研究强调了双酚 A和大豆基植物雌激素的共接触导致额外的雌激素作用，并可能有助于与雌激素相关的疾病，包括乳腺癌。