Mao Zhilei, Chen Yanling, Li Haixin, Lu Qun, Zhou Kun
Changzhou Maternity and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou 213003, China.
State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
Toxics. 2024 Sep 25;12(10):693. doi: 10.3390/toxics12100693.
Concerns have been raised regarding the effects of perfluoroalkyl substance (PFAS) exposure on cardiovascular diseases (CVD), but clear evidence linking PFAS exposure to CVD is lacking, and the mechanism remains unclear.
To study the association between PFASs and CVD in U.S. population, and to reveal the mechanism of PFASs' effects on CVD.
To assess the relationships between individual blood serum PFAS levels and the risk of total CVD or its subtypes, multivariable logistic regression analysis and partial least squares discriminant analysis (PLS-DA) were conducted on all participants or subgroups among 3391 adults from the National Health and Nutrition Examination Survey (NHANES). The SuperPred and GeneCards databases were utilized to identify potential targets related to PFAS and CVD, respectively. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of intersection genes were performed using Metascape. Protein interaction networks were generated, and core targets were identified with STRING. Molecular docking was achieved using Autodock Vina 1.1.2.
There was a positive association between Me-PFOSA-AcOH and CVD (OR = 1.28, = 0.022), especially coronary heart disease (CHD) (OR = 1.47, = 0.007) and heart attack (OR = 1.58, < 0.001) after adjusting for all potential covariates. Me-PFOSA-AcOH contributed the most to distinguishing between individuals in terms of CVD and non-CVD. Significant moderating effects for Me-PFOSA-AcOH were observed in the subgroup analysis stratified by sex, ethnicity, education level, PIR, BMI, smoking status, physical activity, and hypertension ( < 0.05). The potential intersection targets were mainly enriched in CVD-related pathways, including the inflammatory response, neuroactive ligand-receptor interaction, MAPK signaling pathway, and arachidonic acid metabolism. TLR4 was identified as the core target for the effects of Me-PFOSA-AcOH on CVD. Molecular docking results revealed that the binding energy of Me-PFOSA-AcOH to the TLR4-MD-2 complex was -7.2 kcal/mol, suggesting that Me-PFOSA-AcOH binds well to the TLR4-MD-2 complex.
Me-PFOSA-AcOH exposure was significantly associated with CVD. Network toxicology and molecular docking uncovered novel molecular targets, such as TLR4, and identified the inflammatory and metabolic mechanisms underlying Me-PFOSA-AcOH-induced CVD.
全氟烷基物质（PFAS）暴露对心血管疾病（CVD）的影响已引发关注，但缺乏将PFAS暴露与CVD联系起来的明确证据，且作用机制仍不清楚。
研究美国人群中PFAS与CVD之间的关联，并揭示PFAS对CVD的作用机制。
为评估个体血清PFAS水平与总CVD或其亚型风险之间的关系，对来自美国国家健康与营养检查调查（NHANES）的3391名成年人中的所有参与者或亚组进行了多变量逻辑回归分析和偏最小二乘判别分析（PLS-DA）。分别利用SuperPred和GeneCards数据库识别与PFAS和CVD相关的潜在靶点。使用Metascape对交集基因进行基因本体（GO）和京都基因与基因组百科全书（KEGG）富集分析。生成蛋白质相互作用网络，并使用STRING识别核心靶点。使用Autodock Vina 1.1.2进行分子对接。
在调整所有潜在协变量后，Me-PFOSA-AcOH与CVD之间存在正相关（OR = 1.28，P = 0.022），尤其是冠心病（CHD）（OR = 1.47，P = 0.007）和心脏病发作（OR = 1.58，P < 0.001）。在区分CVD和非CVD个体方面，Me-PFOSA-AcOH的贡献最大。在按性别、种族、教育水平、贫困收入比、体重指数、吸烟状况、身体活动和高血压分层的亚组分析中，观察到Me-PFOSA-AcOH有显著的调节作用（P < 0.05）。潜在的交集靶点主要富集在与CVD相关的途径中，包括炎症反应、神经活性配体-受体相互作用、MAPK信号通路和花生四烯酸代谢。TLR4被确定为Me-PFOSA-AcOH对CVD作用的核心靶点。分子对接结果显示，Me-PFOSA-AcOH与TLR4-MD-2复合物的结合能为-7.2 kcal/mol，表明Me-PFOSA-AcOH与TLR4-MD-2复合物结合良好。
Me-PFOSA-AcOH暴露与CVD显著相关。网络毒理学和分子对接揭示了新的分子靶点，如TLR4，并确定了Me-PFOSA-AcOH诱导CVD的炎症和代谢机制。
