TLR4 as a Potential Target of Me-PFOSA-AcOH Leading to Cardiovascular Diseases: Evidence from NHANES 2013–2018 and Molecular Docking

Zhilei Mao; Yanling Chen; Haixin Li; Qun Lu; Kun Zhou

doi:10.3390/toxics12100693

Toxics (Sep 2024)

TLR4 as a Potential Target of Me-PFOSA-AcOH Leading to Cardiovascular Diseases: Evidence from NHANES 2013–2018 and Molecular Docking

Zhilei Mao,
Yanling Chen,
Haixin Li,
Qun Lu,
Kun Zhou

Affiliations

Zhilei Mao: Changzhou Maternity and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou 213003, China
Yanling Chen: State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China
Haixin Li: Changzhou Maternity and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou 213003, China
Qun Lu: Department of Prenatal Diagnosis, Women’s Hospital of Nanjing Medical University, Nanjing 210004, China
Kun Zhou: State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China

DOI: https://doi.org/10.3390/toxics12100693
Journal volume & issue: Vol. 12, no. 10
p. 693

Abstract

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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’ 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 p < 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. 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.

Published in Toxics

ISSN: 2305-6304 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Technology: Chemical technology
Website: http://www.mdpi.com/journal/toxics/

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