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Genome-wide study of DNA methylation alterations in response to diazinon exposure in vitro.

ABSTRACT: Pesticide exposure has repeatedly been associated with cancers. However, molecular mechanisms are largely undetermined. In this study, we examined whether exposure to diazinon, a common organophosphate that has been associated with cancers, could induce DNA methylation alterations. We conducted genome-wide DNA methylation analyses on DNA samples obtained from human hematopoietic K562 cell exposed to diazinon and ethanol using the Illumina Infinium HumanMethylation27 BeadChip. Bayesian-adjusted t-tests were used to identify differentially methylated gene promoter CpG sites. We identified 1069 CpG sites in 984 genes with significant methylation changes in diazinon-treated cells. Gene ontology analysis demonstrated that some genes are tumor suppressor genes, such as TP53INP1 (3.0-fold, q-value <0.001) and PTEN (2.6-fold, q-value <0.001), some genes are in cancer-related pathways, such as HDAC3 (2.2-fold, q-value=0.002), and some remain functionally unknown. Our results provided direct experimental evidence that diazinon may modify gene promoter DNA methylation levels, which may play a pathological role in cancer development.

SUBMITTER: Zhang X

PROVIDER: S-EPMC3514648 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Genome-wide study of DNA methylation alterations in response to diazinon exposure in vitro.

Zhang Xiao X Wallace Andrew D AD Du Pan P Lin Simon S Baccarelli Andrea A AA Jiang Hongmei H Jafari Nadereh N Zheng Yinan Y Xie Hehuang H Soares Marcelo Bento MB Kibbe Warren A WA Hou Lifang L

Environmental toxicology and pharmacology 20120801 3

Pesticide exposure has repeatedly been associated with cancers. However, molecular mechanisms are largely undetermined. In this study, we examined whether exposure to diazinon, a common organophosphate that has been associated with cancers, could induce DNA methylation alterations. We conducted genome-wide DNA methylation analyses on DNA samples obtained from human hematopoietic K562 cell exposed to diazinon and ethanol using the Illumina Infinium HumanMethylation27 BeadChip. Bayesian-adjusted t ...[more]

PMID: 22964155

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Project description: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.

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Genome-wide study of DNA methylation alterations in response to diazinon exposure in vitro.

Publications

Genome-wide study of DNA methylation alterations in response to diazinon exposure in vitro.

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