An Epigenome-Wide Analysis of Ambient Pyrethroid Pesticide Exposures in California's Central Valley

Abstract

Background/Aim Pyrethroid pesticide use is increasing worldwide, although the full extent of associated health effects is unknown. An epigenome-wide analysis study (EWAS) with exploratory pathway analysis may help identify potential pyrethroid-related health effects.Methods We performed an EWAS of chronic ambient pyrethroid exposure using control participants’ blood in the Parkinson’s Environment and Genes Study in California (N=237). We estimated associations of exposure to ambient pyrethroid pesticide applications in the 5 years prior to enrollment with differential methylation at enrollment, using beta regression and an FDR q <0.05 for significance. We normalized methylation values for typeI/II probe bias using BMIQ, evaluated batch effects with SVA, and adjusted for cell count. We also performed gene set overrepresentation analysis on the genes annotated to CpG sites that were associated with pyrethroids at a raw p-value cutoff of 0.05. For gene-set overrepresentation analyses, we controlled for background counts of CpG sites on the Illumina450K chip, and identified Gene Ontology (GO) biological process terms with missMethyl, and OMIM and Glad4U disease-associated gene sets. We used an FDR q< 0.05 to evaluate statistical significance of gene sets. Results 5 CpG sites were differentially methylated in relation to pyrethroid exposures. Two of these sites annotated to genes involved in calcium ion binding, a known primary target of pyrethroid pesticides. We also identified 40 GO terms, 14 of which were neurological/developmental in nature. For disease sets, we identified signals for Alzheimer’s disease, leukemia and several other cancers, diabetes, birth defects, and other diseases. Conclusions Chronic ambient pyrethroid exposure is associated with differential methylation at CpG sites that annotate to a wide variety of disease states and biological mechanisms. While several of the identified diseases and gene processes are consistent with prior research, this EWAS also implicates several previously unidentified diseases for future investigation in relation to pyrethroid exposure.