Miao Gan, Zhou Chengying, Xu Liting, Zhao Li, Zhang Jingxu, Zhang Ze, Kou Zhe, Ahmed Rifat Zubair, Lu Dawei, Jin Xiaoting, Zheng Yuxin
Department of Occupational Health and Environmental Health, School of Public Health, Qingdao University, Qingdao 266071, China.
Pingdu City Center for Disease Control and Prevention, Pingdu 266700, China.
Environ Health (Wash). 2025 Apr 29;3(7):795-806. doi: 10.1021/envhealth.5c00014. eCollection 2025 Jul 18.
Perfluorochemicals (PFCs) are emergent and persistent organic pollutants with widespread application. Their structural similarity and detection in serum raises substantial concerns regarding their toxicological effects. While the endocrine-disrupting effects of PFCs are well-recognized, the structure-activity relationship with respect to vascular function has not been investigated yet. This study addresses this critical gap by investigating the impact of PFCs on endothelial cell function, a key determinant of cardiovascular health. Through a machine learning-based quantitative structure-activity relationship (QSAR) model, we analyzed 16 structural descriptors for 23 environmentally prevalent PFCs with respect to their binding affinities to endothelial cell receptors. The eXtreme Gradient Boosting (XGBoost) algorithm suggested short-chain PFCs with strong acid groups may as particularly detrimental to endothelial cells, a finding substantiated by subsequent cell culture experiments. We also integrated computational and experimental approaches, providing a detailed understanding of the structure-activity and dose-response relationships of PFCs. Furthermore, the population health risk assessment, linking adverse effect with exposure data, indicated differences in risks across countries due to the global shift in the fluoride industry; the entire Chinese population is at high risk, with risk varying by gender and industrialization level. This study not only elucidates the structure-activity relationship of PFCs on vascular function but also offers a strategic framework for managing toxic PFCs and proposing the development of safer alternatives.
全氟化合物（PFCs）是一类新兴的持久性有机污染物，应用广泛。它们结构相似且能在血清中被检测到，这引发了人们对其毒理学效应的严重担忧。虽然全氟化合物的内分泌干扰效应已得到充分认识，但关于其与血管功能的构效关系尚未得到研究。本研究通过调查全氟化合物对内皮细胞功能（心血管健康的关键决定因素）的影响，填补了这一关键空白。通过基于机器学习的定量构效关系（QSAR）模型，我们分析了23种环境中普遍存在的全氟化合物的16种结构描述符与其与内皮细胞受体的结合亲和力。极端梯度提升（XGBoost）算法表明，带有强酸基团的短链全氟化合物可能对内皮细胞特别有害，后续细胞培养实验证实了这一发现。我们还整合了计算和实验方法，详细了解了全氟化合物的构效关系和剂量反应关系。此外，将不良影响与暴露数据联系起来的人群健康风险评估表明，由于氟化物行业的全球转移，各国的风险存在差异；中国全体人口处于高风险状态，风险因性别和工业化水平而异。本研究不仅阐明了全氟化合物对血管功能的构效关系，还为管理有毒全氟化合物和提出开发更安全替代品提供了战略框架。
