Integrating epidemiological and bioinformatics analyses identified the effects of organophosphate pesticides accelerating biological aging

BACKGROUND: With the intensification of population aging worldwide, aging has become a widely studied area, which is related to various environmental factors. However, the associations and underlying mechanisms of OPPs with biological aging remain unclear. MATERIALS AND METHODS: In this cross-sectional NHANES study, a total of 9,795 participants were included in discovery cohort and 2,494 were in validation cohort. The multiple linear regression models and restricted cubic spline (RCS) were performed to investigate the associations between OPPs and biological aging acceleration. Two sample Mendelian randomization investigated the causal relationships between OPPs, epigenetic clock acceleration, and telomere length. We presented the expression landscape of key targets in various organs through single-cell sequencing analysis, then conducted GO, KEGG, and intercellular communication network analysis. In vitro experiments, quantitative real-time PCR (qPCR) and western blot (WB), RNA interference (RNAi), and flow cytometry (FC) explicated the important targets and potential mechanisms. RESULTS: This study showed that a consistent increase in exposure to OPPs since 2007, and OPPs metabolites significantly associated with biological aging acceleration with non-linear relationships, which were significantly mediated by C-reactive protein. MR results showed that OPPs exposure was significantly associated with epigenetic age acceleration (1.813[0.349, 2.076]), PhenoAge acceleration (0.658[0.202, 1.019]), and Telomere length (-0.327[-0.479, - 0.252]). The overlap of TWAS and network toxicology revealed that 12 target genes were intersected in OPPs and aging, and single-cell transcriptome showing the peptidyl-serine phosphorylation, cell cycle and apoptosis pathways. EGFR and STAT3 activation by OPPs promoted biological aging through inflammation-mediated pathways and phosphorylation-induced apoptosis activation. CONCLUSION: OPPs are associated with accelerated biological aging, which may be mediated by inflammation-mediated pathway and phosphorylation mediated activation of apoptosis. This evidence informs public health interventions against environmental aging drivers.