低剂量六氟双酚A对乳腺癌细胞生长的影响及非基因组信号转导机制研究

项目名称： 低剂量六氟双酚A对乳腺癌细胞生长的影响及非基因组信号转导机制研究

项目编号： No.21507078

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 化学工业

项目作者： 雷炳莉

作者单位： 上海大学

项目金额： 20万元

中文摘要： 六氟双酚A（BPAF）属于新型双酚类化合物，作为双酚A（BPA）替代品之一，可能比BPA具有更强的内分泌干扰效应。深入剖析BPAF对机体的内分泌干扰效应机制是准确评价其潜在健康危害的关键。乳腺癌细胞是研究污染物内分泌干扰效应及细胞信号传导通路的理想细胞模型。本项目以人乳腺癌细胞为对象，评估不同剂量BPAF对细胞的增殖能力、细胞凋亡、细胞周期等指标的影响；建立裸鼠乳腺癌细胞移植动物模型，进一步评估活体情况下低剂量BPAF对乳腺瘤细胞生长的影响。重点以PI3K/Akt和ERK1/2通路及下游调控的与细胞生长相关的基因为主要靶点，分析非基因组膜受体GPR30和αvβ3介导BPAF对信号通路的激活情况及对靶基因的调控作用，明确低剂量BPAF促进细胞增殖的关键靶基因。通过非基因组膜受体途径深入研究BPAF的内分泌干扰效应机制可深化对BPAF的毒性认识，为正确评价BPAF的潜在健康危害提供实验依据。

中文关键词： 六氟双酚A；乳腺癌细胞；细胞增殖；膜受体GPR30和αvβ3；分子机制

英文摘要： Six fluorinated bisphenol A (BPAF) belongs to a novel bisphenol compound. BPAF as one of bisphenol A (BPA) replacements has stronger estrogen and thyroidal hormone activities than BPA. It indicated that BPAF may have a stronger endocrine disrupting effect compared with BPA. Therefore, the potential harm of BPAF to human health can not be ignored. The depth analysis on endocrine disrupting effect mechanism of BPAF is the key to the accurate evaluation health harm of BPAF. Breast cancer cell is an ideal cell model to study the endocrine disrupting effects and cell signal transduction pathway of pollutants. Therefore, the human breast cancer cells were selected as the test receptor. The project comprehensively evaluates influence of different dose BPAF on the growth of different breast cancer cells. The evaluated biological effect endpoints included cell proliferation, cell apoptosis, cell cycle, intracellular reactive oxygen species (ROS) and Ca2+ concentration changes. At the same time, the transplantable breast cancer cell animal model of Bal b/c nude mice was established to further study the effect of low dose BPAF on breast cancer cell growth in vivo. The PI3K/Akt and ERK1/2 signaling pathways and their downstream genes associated with cell growth were used as main targets. The activation of BPAF on nongenomic membrane receptor GPR30 and αvβ3 mediated PI3K/Akt and ERK1/2 signaling pathways and the target genes were analyzed. The roles of the target genes and molecular mechanism in low dose BPAF-induced proliferation of breast cancer cells were clarified. The study on the endocrine disrupting effect mechanism of BPAF by nongenomic membrane receptor pathway can strengthen our understanding on the toxicity of BPAF. The results will provide experimental basis to accurately evaluate the potential health harm and health risk of BPAF.

英文关键词： six fluorinated bisphenol A;breast cancer cells;cell proliferation;membrane receptor GPR30 and αvβ3;molecular mechanism