{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T06:05:41Z","timestamp":1789365941122,"version":"build-2803163510"},"reference-count":81,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,9,25]],"date-time":"2024-09-25T00:00:00Z","timestamp":1727222400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Top Talent of Changzhou for \u201cThe 14th Five-Year Plan\u201d High-Level Health Talents Training Project","award":["2022CZBJ088"],"award-info":[{"award-number":["2022CZBJ088"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxics"],"abstract":"<jats:p>Background: 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. Objectives: To study the association between PFASs and CVD in U.S. population, and to reveal the mechanism of PFASs\u2019 effects on CVD. Methods: 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. Results: There was a positive association between Me-PFOSA-AcOH and CVD (OR = 1.28, p = 0.022), especially coronary heart disease (CHD) (OR = 1.47, p = 0.007) and heart attack (OR = 1.58, p &lt; 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 (p &lt; 0.05). The potential intersection targets were mainly enriched in CVD-related pathways, including the inflammatory response, neuroactive ligand\u2013receptor 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 \u22127.2 kcal\/mol, suggesting that Me-PFOSA-AcOH binds well to the TLR4-MD-2 complex. Conclusions: 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.<\/jats:p>","DOI":"10.3390\/toxics12100693","type":"journal-article","created":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T08:20:52Z","timestamp":1727338852000},"page":"693","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["TLR4 as a Potential Target of Me-PFOSA-AcOH Leading to Cardiovascular Diseases: Evidence from NHANES 2013\u20132018 and Molecular Docking"],"prefix":"10.3390","volume":"12","author":[{"given":"Zhilei","family":"Mao","sequence":"first","affiliation":[{"name":"Changzhou Maternity and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou 213003, China"},{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China"},{"name":"Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanling","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China"},{"name":"Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haixin","family":"Li","sequence":"additional","affiliation":[{"name":"Changzhou Maternity and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou 213003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qun","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Prenatal Diagnosis, Women\u2019s Hospital of Nanjing Medical University, Nanjing 210004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China"},{"name":"Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China"},{"name":"Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"132378","DOI":"10.1016\/j.chemosphere.2021.132378","article-title":"Occurrence of selected per- and polyfluorinated alkyl substances (PFASs) in food available on the European market\u2014A review on levels and human exposure assessment","volume":"287","author":"Pasecnaja","year":"2022","journal-title":"Chemosphere"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1016\/j.chemosphere.2012.03.035","article-title":"Perfluoroalkyl and polyfluoroalkyl substances (PFASs) in consumer products in Norway\u2014A pilot study","volume":"88","author":"Herzke","year":"2012","journal-title":"Chemosphere"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"151003","DOI":"10.1016\/j.scitotenv.2021.151003","article-title":"Per- and polyfluoroalkyl substances in water and wastewater: A critical review of their global occurrence and distribution","volume":"809","author":"Kurwadkar","year":"2022","journal-title":"Sci. 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