DNA methylation at GRIN2B partially mediates the association between prenatal bisphenol F exposure and cognitive functions in 7-year-old children in the SELMA study.

Elin Engdahl,Ping-I Daniel Lin,Joëlle Rüegg,Katherine Svensson,Carl-Gustaf Bornehag,Ali Alavian-Ghavanini,Christian Lindh

doi:10.1016/j.envint.2021.106617

Abstract

Accumulating evidence suggests that prenatal chemical exposure triggers epigenetic modifications that could influence health outcomes later in life. In this study, we investigated whether DNA methylation (DNAm) levels at the glutamate ionotropic receptor NMDA type subunit 2B (GRIN2B) gene underlies the association between prenatal exposure to an endocrine disrupting chemical (EDC), bisphenol F (BPF), and lower cognitive functions in 7-year-old children. Data from 799 children participating in the Swedish Environmental Longitudinal Mother and child Asthma and allergy (SELMA) pregnancy cohort was analyzed. Prenatal BPF exposure was assessed by measuring BPF levels in maternal urine. At age 7, DNAm of three CpG sites in a regulatory region of the GRIN2B gene was analyzed from buccal swabs using bisulfite-Pyrosequencing. Cognitive functions, including full-scale IQ and four subscales, were evaluated using the Wechsler Intelligence Scale for Children (WISC-IV). Associations between prenatal BPF exposure and GRIN2B DNAm, as well as between GRIN2B DNAm and cognitive functions, were determined using regression models adjusted for potential confounders. Generalized structural equation models (gSEM) were used to evaluate if GRIN2B DNAm mediates the association between prenatal BPF exposure and cognitive functions at 7years of age. Prenatal BPF exposure was positively associated with GRIN2B DNAm levels at the third CpG site (CpG3), while CpG3 methylation was inversely associated with cognitive test scores. Mediation analyses showed that CpG3 methylation exerted 6-9% of the association between BPF exposure and full-scale IQ, as well as verbal comprehension and perceptual reasoning in boys, while not significant in girls. This study is the first to identify locus-specific DNAm as a mediating factor underlying an epidemiological association between prenatal EDC exposure and cognitive functions in childhood. It also confirms previous findings, that GRIN2B DNAm is responsive to environmental exposures.

Highlights

The developing brain is vitally dependent on proper hormonal signaling of, e.g., thyroid and sex steroid hormones (Miranda and Sousa, 2018)
It is of concern that human populations are constantly exposed to chemicals that interfere with hormonal signaling, so called endocrine disrupting chemicals (EDCs), even from the time in utero (Bergman et al, 2013)
We have recently demonstrated that prenatal exposure to bisphenol F (BPF), used as a substitute for Bisphenol A (BPA) in the production of polycarbonate plastics and epoxy resins (Chen et al, 2016), is associated with impaired cognition in children, primarily in boys, at 7 years of age (Bornehag et al, 2021; Tanner et al, 2020)

Summary

Introduction

The developing brain is vitally dependent on proper hormonal signaling of, e.g., thyroid and sex steroid hormones (Miranda and Sousa, 2018). We have recently demonstrated that prenatal exposure to bisphenol F (BPF), used as a substitute for BPA in the production of polycarbonate plastics and epoxy resins (Chen et al, 2016), is associated with impaired cognition in children, primarily in boys, at 7 years of age (Bornehag et al, 2021; Tanner et al, 2020) The mechanism underlying this association is not known, but other studies have shown that changes in DNA methylation (DNAm) patterns can mediate persistent effects of early-life events on human health later in life (Checknita et al, 2018; Fasanelli et al, 2015; Tobi et al, 2018; Wiklund et al, 2019). It confirms previous findings, that GRIN2B DNAm is responsive to environmental exposures

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