Multiomics reveals new biomarkers and mechanistic insights into the combined toxicity effects of 2,2 & PRIME;,4,4 & PRIME;,5,5 & PRIME;-hexachlorobiphenyl and atrazine exposures in MCF-7 cells*

文献类型： 外文期刊

第一作者： Lu, Yu-Shun

作者： Lu, Yu-Shun;Wen, Xing;Chen, Ju;He, Xiao-Rong;Qiu, Jing;Qian, Yong-Zhong;Xu, Yan-Yang;Wen, Xing;Chen, Ju;He, Xiao-Rong;Yu, Jiang

作者机构：

关键词： PCB153; Atrazine; MCF-7 cell; Combined effect; Metabolism; Transcriptomic

期刊名称：ENVIRONMENTAL POLLUTION （ 影响因子：8.9； 五年影响因子：9.5 ）

ISSN： 0269-7491

年卷期： 2023 年 333 卷

页码：

收录情况： SCI

摘要： Humans are constantly exposed to complicated chemical mixtures from the environment and food rather than being exposed to a single pollutant. The underlying mechanisms of the complicated combined toxicity of endocrine disrupting chemicals (EDCs) are still mainly unexplored. In this study, two representative EDCs, 2,2 & PRIME;,4,4 & PRIME;,5,5 & PRIME;-hexachlorobiphenyl (PCB153) and atrazine (ATZ), were selected to explore their combined effects on MCF-7 cell proliferation at environmental exposure concentrations by an integrated analysis of metabolomics and transcriptomics. The results showed that 1 & mu;M ATZ and PCB153 combined exposure significantly accelerated MCF-7 cell growth by 18.2%. More than 400 metabolites detected by UHPLC-QTOF/MS were used to observe metabolism differences induced by binary mixtures. Metabolomics analysis verified that ATZ and PCB153 exposure alone or in combination could have an additive effect on metabolism and induce significant disruption to glycolysis, purine metabolism and the TCA cycle, which provide energy demand and biosynthetic substrates for cell proliferation. Compared to PCB153 and ATZ exposure alone, a combined effect was observed in purine and pyrimidine metabolic pathways. Hexokinase 3 (HK3) and cytochrome P450 19 subfamily A1 (CYP19A1) were identified as differentially expressed genes based on transcriptomic analysis. By integrating metabolome and transcriptome analysis, the proliferation effects of ATZ and PCB153 were induced at low doses in MCF-7 cells through potential interference with the downstream transcription signaling of CYP19A1. Furthermore, molecular docking indicated that PCB153 and ATZ directly affected CYP19A1. Altogether, the regulation of pivotal metabolites and differentially expressed genes could provide helpful information to reveal the mechanism by which PCB153 and ATZ affect MCF-7 cell proliferation.

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