Gao Ke, Hua Kai, Wang Shiyuan, Chen Xi, Zhu Tong
Key Laboratory of Beijing on Regional Air Pollution Control, Department of Environmental Science, Beijing University of Technology, Beijing, China; SKL-ESPC and BIC-ESAT, College of Environmental Sciences and Engineering, Peking University, Beijing, China.
Key Laboratory of Beijing on Regional Air Pollution Control, Department of Environmental Science, Beijing University of Technology, Beijing, China.
J Hazard Mater. 2025 May 5;488:137395. doi: 10.1016/j.jhazmat.2025.137395. Epub 2025 Jan 25.
Minimal study focused on the association between mixed pollutants in atmospheric particulate matter (PM) and their reproductive health risks. Utilizing a novel quantitative structure-activity relationship (QSAR) integrated machine learning algorithms, we evaluated the mixed reproductive health risks associated with phthalates (PAEs) and organophosphates (OPEs) exposure by assessing the affinities of these compounds binding to estrogen receptors (ER) and androgen receptors (AR). The mixed toxicity equivalent factor (TEF) and mixed toxicity equivalent quantity (TEQ) by the QSAR model were all smaller than the sum TEF and TEQ of individual PAEs and OPEs, which may be due to the antagonistic effect of PAEs and OPEs monomers on reproductive toxicity. Based on network toxicology approach, a total of 590 potential targets associated with PAEs and OPEs affecting sex hormones were initially identified, with an additional 50 core targets, including AR and ER. Di-2-ethylhexyl phthalate (DEHP), triphenyl phosphate (TPHP) and mono-(2-ethylhexyl) phthalate (MEHP) were key components to disrupt AR and ER signaling pathway, and was confirmed by molecular docking analysis. In addition to ER and AR, serine/threonine kinase 1 (AKT1) and heat shock protein 90α family A member 1 (HSP90AA1) might be key targets for reproductive toxicity, which have hardly mentioned before. Our study provided precious information on the mixed reproductive exposure risk of PAEs and OPEs in PM, and innovatively explored the potential mechanisms of PAEs and OPEs affecting human reproductive health using network toxicology.
极少有研究关注大气颗粒物（PM）中的混合污染物与其生殖健康风险之间的关联。利用一种整合了机器学习算法的新型定量构效关系（QSAR），我们通过评估这些化合物与雌激素受体（ER）和雄激素受体（AR）结合的亲和力，来评估与邻苯二甲酸酯（PAEs）和有机磷酸酯（OPEs）暴露相关的混合生殖健康风险。QSAR模型得出的混合毒性当量因子（TEF）和混合毒性当量（TEQ）均小于单个PAEs和OPEs的TEF和TEQ之和，这可能是由于PAEs和OPEs单体对生殖毒性的拮抗作用。基于网络毒理学方法，最初共鉴定出590个与PAEs和OPEs影响性激素相关的潜在靶点，另有50个核心靶点，包括AR和ER。邻苯二甲酸二（2-乙基己基）酯（DEHP）、磷酸三苯酯（TPHP）和邻苯二甲酸单（2-乙基己基）酯（MEHP）是破坏AR和ER信号通路的关键成分，分子对接分析证实了这一点。除了ER和AR，丝氨酸/苏氨酸激酶1（AKT1）和热休克蛋白90α家族A成员1（HSP90AA1）可能是生殖毒性的关键靶点，此前鲜有提及。我们的研究提供了关于PM中PAEs和OPEs混合生殖暴露风险的宝贵信息，并创新性地利用网络毒理学探索了PAEs和OPEs影响人类生殖健康的潜在机制。
