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 Drinking Water Science and Technology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China.
Faculty of Printing and Packaging and Digital Media, Xi' an University of Technology, Xi'an 710048, China.
Environ Int. 2024 Jun;188:108778. doi: 10.1016/j.envint.2024.108778. Epub 2024 May 26.
With the discovery of evidence that many endocrine-disrupting chemicals (EDCs) in the environment influence human health, their toxic effects and mechanisms have become a hot topic of research. However, investigations into their endocrine-disrupting toxicity under combined binary exposure, especially the molecular mechanism of combined effects, have rarely been documented. In this study, two typical EDCs, perfluorooctanoic acid (PFOA) and 4-hydroxybenzophenone (4-HBP), were selected to examine their combined effects and molecular mechanism on MCF-7 cell proliferation at environmentally relevant exposure concentrations. We have successfully established a model to evaluate the binary combined toxic effects of endocrine disruptors, presenting combined effects in a simple and direct way. Results indicated that the combined effect changed from additive to synergistic from 1.25 × 10 M to 4 × 10 M. Metabolomics analyses suggested that exposure to PFOA and 4-HBP caused significant alterations in purine metabolism, arginine, and proline metabolism and had superimposed influences on metabolism. Enhanced combined effects were observed in glycine, serine, and threonine metabolic pathways compared to exposure to PFOS and 4-HBP alone. Additionally, the differentially expressed genes (DEGs) are primarily involved in Biological Processes, especially protein targeting the endoplasmic reticulum, and significantly impact the oxidative phosphorylation and thermogenesis-related KEGG pathway. By integrating metabolome and transcriptome analyses, PFOA and 4-HBP regulate purine metabolism, the TCA cycle, and endoplasmic reticulum protein synthesis in MCF-7 cells via mTORC1, which provides genetic material, protein, and energy for cell proliferation. Furthermore, molecular docking confirmed the ability of PFOA and 4-HBP to stably bind the estrogen receptor, indicating that they have different binding pockets. Collectively, these findings will offer new insights into understanding the mechanisms by which EDCs produce combined toxicity.
随着越来越多的环境内分泌干扰化学物质（EDCs）对人类健康影响的证据被发现，它们的毒性作用和机制已成为研究的热点。然而，对于它们在二元混合物暴露下的内分泌干扰毒性，特别是联合作用的分子机制，很少有研究报道。在这项研究中，选择了两种典型的 EDCs，全氟辛酸（PFOA）和 4-羟基二苯甲酮（4-HBP），以研究它们在环境相关暴露浓度下对 MCF-7 细胞增殖的联合作用及其分子机制。我们成功建立了一种评估内分泌干扰物二元混合物联合毒性的模型，以简单直接的方式呈现联合作用。结果表明，联合作用从相加到协同，从 1.25×10 M 到 4×10 M 发生变化。代谢组学分析表明，暴露于 PFOA 和 4-HBP 会导致嘌呤代谢、精氨酸和脯氨酸代谢的显著改变，并对代谢产生叠加影响。与单独暴露于 PFOS 和 4-HBP 相比，甘氨酸、丝氨酸和苏氨酸代谢途径中观察到增强的联合作用。此外，差异表达基因（DEGs）主要参与生物过程，特别是内质网靶向的蛋白质，并且显著影响氧化磷酸化和与产热相关的 KEGG 途径。通过整合代谢组学和转录组学分析，PFOA 和 4-HBP 通过 mTORC1 调节 MCF-7 细胞中的嘌呤代谢、三羧酸循环和内质网蛋白质合成，为细胞增殖提供遗传物质、蛋白质和能量。此外，分子对接证实了 PFOA 和 4-HBP 稳定结合雌激素受体的能力，表明它们具有不同的结合口袋。综上所述，这些发现将为理解 EDC 产生联合毒性的机制提供新的见解。
