An epigenome-wide association study identifies multiple DNA methylation markers of exposure to endocrine disruptors

Xueling Lu; Eliza Fraszczyk; Thomas P van der Meer; Martijn van Faassen; Vincent W Bloks; Ido P Kema; André P van Beek; Shuang Li; Lude Franke; Harm-Jan Westra; BIOS Consortium; Xijin Xu; Xia Huo; Harold Snieder; Bruce H R Wolffenbuttel; Jana V van Vliet-Ostaptchouk

doi:10.1016/j.envint.2020.106016

An epigenome-wide association study identifies multiple DNA methylation markers of exposure to endocrine disruptors

Environ Int. 2020 Nov:144:106016. doi: 10.1016/j.envint.2020.106016. Epub 2020 Sep 9.

Authors

Affiliations

¹ Department of Epidemiology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands; Laboratory of Environmental Medicine and Developmental Toxicology, Shantou University Medical College, 515041 Guangdong, China.
² Department of Epidemiology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands; Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), 3721 MA Bilthoven, the Netherlands.
³ Department of Endocrinology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands.
⁴ Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands.
⁵ Department of Pediatrics, Section of Molecular Metabolism and Nutrition, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands.
⁶ Department of Genetics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands.
⁷ Laboratory of Environmental Medicine and Developmental Toxicology, Shantou University Medical College, 515041 Guangdong, China.
⁸ Laboratory of Environmental Medicine and Developmental Toxicology, Guangdong Key Laboratory of Environmental Pollution and Health, School of Environment, Jinan University, 511443 Guangdong, China.
⁹ Department of Epidemiology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands. Electronic address: h.snieder@umcg.nl.
¹⁰ Department of Epidemiology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands; Department of Genetics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands; Genomics Coordination Centre, Department of Genetics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands. Electronic address: j.v.van.vliet@umcg.nl.

PMID: 32916427
DOI: 10.1016/j.envint.2020.106016

Abstract

Background: Exposure to environmental endocrine disrupting chemicals (EDCs) may play an important role in the epidemic of metabolic diseases. Epigenetic alterations may functionally link EDCs with gene expression and metabolic traits.

Objectives: We aimed to evaluate metabolic-related effects of the exposure to endocrine disruptors including five parabens, three bisphenols, and 13 metabolites of nine phthalates as measured in 24-hour urine on epigenome-wide DNA methylation.

Methods: A blood-based epigenome-wide association study was performed in 622 participants from the Lifelines DEEP cohort using Illumina Infinium HumanMethylation450 methylation data and EDC excretions in 24-hour urine. Out of the 21 EDCs, 13 compounds were detected in >75% of the samples and, together with bisphenol F, were included in these analyses. Furthermore, we explored the putative function of identified methylation markers and their correlations with metabolic traits.

Results: We found 20 differentially methylated cytosine-phosphate-guanines (CpGs) associated with 10 EDCs at suggestive p-value < 1 × 10^-6, of which four, associated with MEHP and MEHHP, were genome-wide significant (Bonferroni-corrected p-value < 1.19 × 10^-7). Nine out of 20 CpGs were significantly associated with at least one of the tested metabolic traits, such as fasting glucose, glycated hemoglobin, blood lipids, and/or blood pressure. 18 out of 20 EDC-associated CpGs were annotated to genes functionally related to metabolic syndrome, hypertension, obesity, type 2 diabetes, insulin resistance and glycemic traits.

Conclusions: The identified DNA methylation markers for exposure to the most common EDCs provide suggestive mechanism underlying the contributions of EDCs to metabolic health. Follow-up studies are needed to unravel the causality of EDC-induced methylation changes in metabolic alterations.

Keywords: DNA methylation; Endocrine disruptor; Epigenetics; Epigenome-wide association study; Human exposure; Metabolic trait.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

DNA Methylation
Diabetes Mellitus, Type 2* / genetics
Endocrine Disruptors* / toxicity
Epigenesis, Genetic
Epigenome
Epigenomics
Genome-Wide Association Study
Humans

Substances

Endocrine Disruptors