Metabolome-wide association study of organophosphate pesticide exposure

Abstract

Background: Organophosphates (OP) are widely used insecticides that acutely inhibit acetylcholinesterase enzyme activity. There is great interest in improving the understanding of molecular mechanisms related to chronic OP exposure induced toxicity. We aim to elucidate metabolomic changes associated with OP exposure using high-resolution metabolomics (HRM).Methods: In a population-based case control study of Parkinson's disease (PD), we retrieved serum samples of 178 controls and assessed ambient OP exposure via residential and workplace proximity to commercial applications for each subject. We used liquid chromatography-high resolution mass spectrometry to obtain untargeted metabolic profiles and partial least squares regression to select metabolic features associated with OP exposure. Pathway analyses were employed to identify biologic pathways related to OP exposure. Confounders including age, race/ethnicity, sex were controlled a prior.Results: In total we extracted 8,615 and 4,124 metabolic features from serum samples in hydrophilic interaction (HILIC) chromatography (positive ion mode) and C18 (negative ion mode) columns, respectively. Controlling for confounding factors, 151 and 50 discriminatory metabolic features (HILIC and C18, respectively) were selected (Variable Importance in Projection (VIP) >= 2). Pathway enrichment analysis for discriminatory features associated with OP indicated that in serum fatty acid oxidation and inflammation related pathways were altered, including arachidonic acid, leukotriene, and prostaglandin pathways.Conclusion: This study finds chronic low-level OP exposure is associated with differential metabolomic profiles in serum. Our study results suggest that long-term sub-acute OP exposure influences metabolites enriched for oxidative stress and inflammation pathways.