双酚A类似物在人乳腺癌裸鼠模型中的代谢活化途径和毒理效应研究

Bisphenol A (BPA) and its analogues (BPXs) are used mainly in the manufacture of chemical products, such as the synthesis of polycarbonates, epoxy resins and thermal paper. The high industrial production and environmental release of BPXs have caused increasing concerns. BPXs have a plenty of transformation pathways in animals, bacteria and plants. Therefore, human are exposed to BPXs almost everywhere. The available result suggests that BPA exposure is closely related to breast cancer. However, the relationship between BPXs exposure and occurrence of breast cancer has not been definite. Mass spectrometry methodology, molecular modeling and molecular biotechnology will be applied to demonstrate the pathway of metabolic activation and toxicological effect of BPXs. The human breast cancer xenograft-bearing nude mice model will be employed to study the changes of metabolic activation pathway after BPXs exposure during the different periods of breast cancer formation. Furthermore, the molecular modeling will be used to explore the change of estrogenic signaling pathway through determining and simulating the binding affinities between the BPXs and estrogenic receptor (ER). Moreover, the energy metabolism analysis of mitochondria will be utilized to prove the BPXs triggers breast cancer cells dysfunction and apoptosis may be meditated via the mitochondrial pathway. Above all, the correlation between BPXs exposure and occurrence of breast cancer will be demonstrated from metabolic regulation and estrogen action mechanism by expected results mentioned above. The results of this proposal will provide strong support for screening of secure alternative of BPXs.

双酚A（BPA）及其类似物（BPXs）广泛用于化工产品的生产，且大范围暴露于生物体。目前，流行病学调查，基因水平、蛋白质水平和代谢产物的分析研究均显示BPA与乳腺癌发病率有关，但BPXs与乳腺癌的关系并不明确。本项目拟开展基于质谱方法学、分子模拟技术和分子生物学的BPXs代谢活化途径和毒理效应研究。拟采用人乳腺癌裸鼠移植模型，考察在乳腺肿瘤潜伏期和成瘤期，BPXs暴露所产生的代谢活化途径的变化特征。为了进一步评估BPXs及其代谢产物的毒理效应，拟采用分子模拟技术，通过模拟计算BPXs及其代谢产物与雌激素受体（ER）的亲和力来阐明其对雌激素信号通路的影响；进一步结合人乳腺癌细胞线粒体能量代谢分析，考察BPXs暴露可能引起的细胞线粒体功能障碍。本项目预期成果可为揭示BPXs暴露水平与乳腺癌发生发展的相关性提供直接证据，进而为BPA安全替代品的筛选提供理论参考。

双酚A（BPA）及其类似物（BPXs）广泛用于化工产品的生产，且大范围暴露于生物体。目前，流行病学调查，基因水平、蛋白质水平和代谢产物的分析研究均显示BPA与乳腺癌发病率有关，但BPXs与乳腺癌的关系并不明确。本项目将分子生物学和质谱为基础的组学研究（包括脂质组学、代谢组学、蛋白质组学等）相结合，对BPXs代谢活化途径和毒理效应进行深入研究。采用人乳腺癌裸鼠移植模型，研究发现双酚S和双酚F具有显著的促进乳腺肿瘤增殖和恶化的效应，伴随着能量代谢产物和代谢网络的异常变化。此外，BPXs暴露还产生显著的肝脏毒性、肾脏毒性、脾脏毒性等效应。细胞水平实验进一步验证了BPXs代谢活化途径的改变，以及引起相关脂质等代谢产物丰度的变化。本项目的成果可为揭示BPXs暴露水平与乳腺癌发生发展的相关性提供直接证据，进而为BPA安全替代品的筛选提供理论参考。