Pesticide exposures and 10-year atherosclerotic cardiovascular disease risk: Integrated epidemiological and bioinformatics analysis

Background and purpose: Recent studies link pesticide exposures to cardiovascular disease risk factors. However, research on the combined effects of multiple pesticides on atherosclerotic cardiovascular disease (ASCVD) is limited, particularly in rural areas. Despite advances in toxicogenomics, the mechanisms underlying these effects remain unclear. This study aims to investigate the combined effects and mechanisms of pesticide exposures on ASCVD.

Methods: In the cross-sectional study section, 2291 participants were included. Variables were filtered using machine learning models, and associations between mixed exposure to multiple pesticides and ASCVD were explored using environmental mixed exposure models (weighted quartile sum (WQS) regression and quantile-based g-computation (QGC)). In the bioinformatics analysis section, the GEO, CTD, Malacards, and GeneCards databases were used to retrieve target genes for pesticide exposure and atherosclerotic diseases. Enrichment analysis was then performed to identify the biological pathways associated with these genes.

Results: Three machine models screened 34 pesticides. Single pesticide exposures, such as atrazine, oxadiazon, p,p'-DDE, α-BHC, β-BHC, fenitrothion, malathion, fenitrothion, cypermethrin, cypermethrin, and cypermethrin might increase the 10-year ASCVD risk (all P < 0.05). Total mixed pesticide exposure was positively associated with 10-year ASCVD risk in both the QGC (3.223(2.196, 4.730)) and WQS models (4.642(3.070, 7.020)). Notably, there was a linear relationship between total_QGC (P__overal < 0.001; P__nonlinearity = 0.864) and high 10-year ASCVD risk. In toxicogenomic bioinformatics analysis, we identified 112 potential atherosclerosis target genes affected by pesticide exposure. Pathway enrichment analysis suggests pesticide-induced atherosclerosis is linked to pathways such as metabolic pathways, lipid metabolism, MAPK, AMPK, FoxO signaling, apoptosis, fluid shear stress, endocrine resistance, TNF, and PI3K-Akt. Key genes were identified based on maximal clique centrality, including AKT1, TP53, IL6, BCL2, TNF, JUN, PTGS2, CASP3, MAPK3, and CASP9.

Conclusion: Individual and combined exposure to pesticides increased the 10-year ASCVD risk, especially in patients with T2DM. Mixed levels of pesticide exposure were linearly and positively associated with high 10-year ASCVD risk. The mechanism of atherogenesis by mixed pesticide exposure may involve pathways such as lipid metabolism, MAPK, AMPK, FoxO signaling, apoptosis, fluid shear stress, endocrine resistance, TNF, and PI3K-Akt.