Effect of prenatal bisphenol A exposure on child obesity through epigenetic influence on the insulin-like growth factor 2 receptor(IGF2R)gene

Abstract

BACKGROUND: Epigenetic mechanisms have been suggested to play a role in the link between in utero exposure to bisphenol A (BPA) and pediatric obesity; however, there is little evidence regarding this in humans. OBJECTIVES: We identified differentially methylated CpG sites among 594-targeted obesity-related CpG sites (reported from previous epigenome-wide association studies) in children aged 2 and 6 years, depending on prenatal BPA exposure at second trimester. We then evaluated the relationship between the CpG methylation status and body mass index (BMI) in a prospective children’s cohort at ages 2, 4, 6, and 8 years. METHODS: Longitudinal blood samples of 59 children, aged 2 and 6 years, from the Environment and Development in Children cohort were used for methylation analysis using the Infinium Human Methylation BeadChip 450K, and compared between low and high prenatal BPA exposure groups based on the 80th percentile of maternal BPA levels. RESULTS: The unimodal CpG site, cg19196862(IGF2R), and bimodal CpG sites, cg09196346 and cg27596172, at the age of 2 years were significantly different depending on prenatal BPA exposure. There was significant increase in the methylation levels of cg19196862(IGF2R) in the high BPA group at age 2 years (p = 0.00030, false discovery rate corrected p < 0.05) but not at 6 years. With one standard deviation increase of methylation at cg19196862(IGF2R) at age 2 years, the BMI Z-score at ages 2, 4, 6, and 8 years increased significantly by 0.25 (95% confidence interval (CI); 0.05, 0.46), 0.240 (95% CI; 0.03, 0.45), 0.23 (95% CI; 0.02, 0.44), and 0.31 (95% CI; 0.02, 0.60), respectively. When stratified by sex, this positive association was significant in girls, but not in boys. CONCLUSION: Prenatal exposure to BPA may influence differential methylation of IGF2R at age 2 years, which could persistently affect the BMI Z-scores in early childhood.