Organophosphate pesticide exposure and differential genome-wide DNA methylation

Kimberly C Paul; Yu-Hsuan Chuang; Myles Cockburn; Jeff M Bronstein; Steve Horvath; Beate Ritz

doi:10.1016/j.scitotenv.2018.07.143

Organophosphate pesticide exposure and differential genome-wide DNA methylation

Sci Total Environ. 2018 Dec 15:645:1135-1143. doi: 10.1016/j.scitotenv.2018.07.143. Epub 2018 Jul 21.

Authors

Kimberly C Paul¹, Yu-Hsuan Chuang², Myles Cockburn³, Jeff M Bronstein⁴, Steve Horvath⁵, Beate Ritz⁶

Affiliations

¹ Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA, USA. Electronic address: kimberlyc.paul@gmail.com.
² Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA, USA.
³ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, CA, USA.
⁴ Department of Neurology, David Geffen School of Medicine, Los Angeles, CA, USA.
⁵ Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Department of Biostatistics, UCLA Fielding School of Public Health, Los Angeles, CA, USA.
⁶ Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA, USA; Department of Neurology, David Geffen School of Medicine, Los Angeles, CA, USA. Electronic address: britz@ucla.edu.

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 epigenetic changes associated with OP exposure, using untargeted analysis of genome-wide DNA methylation data.

Methods: In a population-based case control study of Parkinson's disease (PD), we assessed ambient OP exposure via residential and workplace proximity to commercial applications. We investigated associations between OP exposure and genome-wide DNA methylation (Illumina 450 k) in 580 blood samples (342 PD patients, 238 controls) and 259 saliva samples (128 patients, 131 controls). To identify differential methylation related to OP exposure, we controlled for age, sex, European ancestry, and PD status; in addition, we stratified by disease status.

Results: We identified 70 genome-wide significant CpGs, including cg01600516 in ALOX12 (cor = 0.27, p = 1.73E-11) and two CpGs in HLA genes, cg01655658 (cor = -0.24, p = 2.80E-09) in HLA-L (pseudogene) and cg15680603 (cor = 0.20, p = 7.94E-07) in HLA-DPA1. Among the 70 CpGs located in 41 genes, 14 were also differentially methylated in saliva samples. The most overrepresented pathway was the nicotinic acetylcholine receptor signaling pathway (fold enrichment = 15.63, p = 1.01E-03, FDR = 1.64E-01). Expanding to a larger number of genes (CpG p < 5E-04, FDR < 2.25E-01; 1077 CpGs, 662 genes), the most enriched pathway shifted to the muscarinic acetylcholine receptor 1 and 3 signaling pathway (p-value = 5.36E-04, FDR = 4.73E-02). When we stratified by PD status, results were similar. Of the 70 significant CpGs, 63 were detected among both patients and controls and 7 were only associated with OP exposure among patients.

Conclusions: This study finds chronic low-level OP exposure is associated with differential DNA methylation in blood and saliva, both in elderly population controls and PD patients. Our study results suggest that long-term sub-acute OP exposure influences methylation in genes enriched for muscarinic and nicotinic acetylcholine receptor pathways.

Keywords: Acetylcholine receptor pathways; DNA methylation; EWAS; Organophosphates.

MeSH terms

Aged
Case-Control Studies
DNA Methylation*
Environmental Exposure*
Epigenesis, Genetic
Humans
Organophosphates / toxicity*
Pesticides / toxicity*

Substances

Organophosphates
Pesticides

Abstract

MeSH terms

Substances

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