Epigenome-Wide DNA Methylation and Pesticide Use in the Agricultural Lung Health Study,Environmental Health Perspectives

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Epigenome-Wide DNA Methylation and Pesticide Use in the Agricultural Lung Health Study
Environmental Health Perspectives ( IF 10.4 ) Pub Date : 2021-9-13 , DOI: 10.1289/ehp8928
Thanh T Hoang ₁ , Cancan Qi _{2,

3} , Kimberly C Paul ₄ , Mikyeong Lee ₁ , Julie D White ₁ , Marie Richards ₅ , Scott S Auerbach ₆ , Stuart Long ₅ , Srishti Shrestha ₁ , Tianyuan Wang ₇ , Laura E Beane Freeman ₈ , Jonathan N Hofmann ₈ , Christine Parks ₁ , , Cheng-Jian Xu _{9,

10,

11} , Beate Ritz _{4,

12} , Gerard H Koppelman _{2,

3} , Stephanie J London ₁

Affiliation

Epidemiology Branch, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Research Triangle Park, North Carolina, USA.
Department of Pediatric Pulmonology and Pediatric Allergy, University Medical Center Groningen, Beatrix Children's Hospital, University of Groningen, Groningen, Netherlands.
Groningen Research Institute for Asthma and Chronic Obstructive Pulmonary Disease, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
Department of Epidemiology, University of California, Los Angeles Fielding School of Public Health, Los Angeles, California, USA.
Westat, Durham, North Carolina, USA.
Biomolecular Screening Branch, National Toxicology Program, NIEHS, NIH, DHHS, Morrisville, North Carolina, USA.
Integrative Bioinformatics Support Group, NIH, DHHS, Research Triangle Park, North Carolina, USA.
Occupational and Environmental Epidemiology Branch, National Cancer Institute, NIH, DHHS, Bethesda, Maryland, USA.
Research Group of Bioinformatics and Computational Genomics, CiiM, Centre for individualized infection medicine, a joint venture between Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.
Department of Gastroenterology, Hepatology and Endocrinology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.
Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands.
Department of Neurology, David Geffen School of Medicine, Los Angeles, California, USA.

Abstract

Background:

Pesticide exposure is associated with many long-term health outcomes; the potential underlying mechanisms are not well established for most associations. Epigenetic modifications, such as DNA methylation, may contribute. Individual pesticides may be associated with specific DNA methylation patterns but no epigenome-wide association study (EWAS) has evaluated methylation in relation to individual pesticides.

Objectives:

We conducted an EWAS of DNA methylation in relation to several pesticide active ingredients.

Methods:

The Agricultural Lung Health Study is a case–control study of asthma, nested within the Agricultural Health Study. We analyzed blood DNA methylation measured using Illumina’s EPIC array in 1,170 male farmers of European ancestry. For pesticides still on the market at blood collection (2009–2013), we evaluated nine active ingredients for which at least 30 participants reported past and current (within the last 12 months) use, as well as seven banned organochlorines with at least 30 participants reporting past use. We used robust linear regression to compare methylation at individual C-phosphate-G sites (CpGs) among users of a specific pesticide to never users.

Results:

Using family-wise error rate ( $p < 9 \times 10^{- 8}$ ) or false-discovery rate ( $false discovery rate less than 0.05$ ), we identified 162 differentially methylated CpGs across 8 of 9 currently marketed active ingredients (acetochlor, atrazine, dicamba, glyphosate, malathion, metolachlor, mesotrione, and picloram) and one banned organochlorine (heptachlor). Differentially methylated CpGs were unique to each active ingredient, and a dose–response relationship with lifetime days of use was observed for most. Significant CpGs were enriched for transcription motifs and 28% of CpGs were associated with whole blood cis-gene expression, supporting functional effects of findings. We corroborated a previously reported association between dichlorodiphenyltrichloroethane (banned in the United States in 1972) and epigenetic age acceleration.

Discussion:

We identified differential methylation for several active ingredients in male farmers of European ancestry. These may serve as biomarkers of chronic exposure and could inform mechanisms of long-term health outcomes from pesticide exposure. https://doi.org/10.1289/EHP8928

中文翻译：

农业肺健康研究中的表观基因组范围 DNA 甲基化和农药使用

摘要

背景：

农药暴露与许多长期健康结果有关；对大多数协会来说，潜在的基本机制还没有很好地建立起来。表观遗传修饰，例如 DNA 甲基化，可能有所贡献。个别农药可能与特定的 DNA 甲基化模式相关，但没有表观基因组关联研究 (EWAS) 评估与个别农药相关的甲基化。

目标：

我们对几种农药活性成分进行了 DNA 甲基化 EWAS。

方法：

农业肺健康研究是一项哮喘病例对照研究，嵌套在农业健康研究中。我们分析了使用 Illumina 的 EPIC 阵列在 1,170 名欧洲血统的男性农民中测量的血液 DNA 甲基化。对于在采血时仍在市场上销售的农药（2009-2013 年），我们评估了至少 30 名参与者报告过去和当前（过去 12 个月内）使用的九种活性成分，以及至少有 30 名参与者的七种禁用有机氯报告过去的使用情况。我们使用稳健的线性回归来比较特定农药使用者与从未使用者之间单个 C-磷酸-G 位点 (CpG) 的甲基化。

结果：

使用全族错误率 ( $p < 9 \times 10^{- 8}$ ) 或错误发现率 ( $false discovery rate less than 0.05$ )，我们在目前销售的 9 种活性成分中的 8 种（乙草胺、阿特拉津、麦草畏、草甘膦、马拉硫磷、异丙甲草胺、甲基磺草酮和毒莠定）和一种禁用的有机氯（七氯）中鉴定了 162 种差异甲基化 CpG。每种活性成分的差异甲基化 CpG 都是独一无二的，并且大多数人观察到与终生使用天数之间存在剂量反应关系。显着的 CpG 富含转录基序，28% 的 CpG 与全血cis基因表达相关，支持发现的功能效应。我们证实了先前报道的二氯二苯基三氯乙烷（1972 年在美国被禁止）与表观遗传年龄加速之间的关联。