Key Laboratory of Agro-Product Quality and Safety, Institute of Quality Standards and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences, Beijing, 100081, China.
Key Laboratory of Agro-Product Quality and Safety, Institute of Quality Standards and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences, Beijing, 100081, China; Faculty of Printing and Packaging and Digital Media, Xi' an University of Technology, Xi'an, 710048, China.
Environ Pollut. 2023 Sep 15;333:122030. doi: 10.1016/j.envpol.2023.122030. Epub 2023 Jun 17.
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',4,4',5,5'-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 μM 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.
人类不断地暴露于环境和食物中的复杂化学混合物中，而不是暴露于单一污染物中。内分泌干扰物（EDCs）的复杂联合毒性的潜在机制仍主要未被探索。在这项研究中，选择了两种代表性的 EDCs，即 2,2',4,4',5,5'-六氯联苯（PCB153）和莠去津（ATZ），通过代谢组学和转录组学的综合分析来探索它们在环境暴露浓度下对 MCF-7 细胞增殖的联合效应。结果表明，1μM ATZ 和 PCB153 联合暴露使 MCF-7 细胞生长速度显著加快了 18.2%。通过 UHPLC-QTOF/MS 检测到的 400 多种代谢物用于观察二元混合物引起的代谢差异。代谢组学分析验证了 ATZ 和 PCB153 单独或联合暴露可以对代谢产生相加作用，并导致糖酵解、嘌呤代谢和 TCA 循环的显著破坏，这为细胞增殖提供了能量需求和生物合成底物。与 PCB153 和 ATZ 单独暴露相比，在嘌呤和嘧啶代谢途径中观察到了联合作用。根据转录组学分析，己糖激酶 3（HK3）和细胞色素 P45019 亚家族 A1（CYP19A1）被鉴定为差异表达基因。通过整合代谢组学和转录组学分析，在 MCF-7 细胞中，ATZ 和 PCB153 通过潜在干扰 CYP19A1 的下游转录信号，在低剂量下诱导了增殖效应。此外，分子对接表明 PCB153 和 ATZ 直接影响 CYP19A1。总之，关键代谢物和差异表达基因的调节可以提供有助于揭示 PCB153 和 ATZ 影响 MCF-7 细胞增殖的机制的信息。
