Exposure to aflatoxin B1 in utero is associated with DNA methylation in white blood cells of infants in The Gambia.

Hector Hernandez-Vargas,Michael N Routledge,Jovita Castelino,Matt J Silver,Sophie E Moore,Florence Le Calvez-Kelm,Branwen J Hennig,Andrew M Prentice,Zdenko Herceg,Christopher P Wild,Yun Yun Gong,Geoffroy Durand,Marie-Pierre Cros,Paula Dominguez-Salas

doi:10.1093/ije/dyv027

Abstract

Exposure to environmental toxins during embryonic development may lead to epigenetic changes that influence disease risk in later life. Aflatoxin is a contaminant of staple foods in sub-Saharan Africa, is a known human liver carcinogen and has been associated with stunting in infants. We have measured aflatoxin exposure in 115 pregnant women in The Gambia and examined the DNA methylation status of white blood cells from their infants at 2-8 months old (mean 3.6 ± 0.9). Aflatoxin exposure in women was assessed using an ELISA method to measure aflatoxin albumin (AF-alb) adducts in plasma taken at 1-16 weeks of pregnancy. Genome-wide DNA methylation of infant white blood cells was measured using the Illumina Infinium HumanMethylation450beadchip. AF-alb levels ranged from 3.9 to 458.4 pg/mg albumin. We found that aflatoxin exposure in the mothers was associated to DNA methylation in their infants for 71 CpG sites (false discovery rate < 0.05), with an average effect size of 1.7% change in methylation. Aflatoxin-associated differential methylation was observed in growth factor genes such as FGF12 and IGF1, and immune-related genes such as CCL28, TLR2 and TGFBI. Moreover, one aflatoxin-associated methylation region (corresponding to the miR-4520b locus) was identified. This study shows that maternal exposure to aflatoxin during the early stages of pregnancy is associated with differential DNA methylation patterns of infants, including in genes related to growth and immune function. This reinforces the need for interventions to reduce aflatoxin exposure, especially during critical periods of fetal and infant development.

Highlights

It has been proposed that changes to the epigenome during fetal development can contribute to disease susceptibility in adulthood.[1,2] Critical developmental periods exist during which the fetus is sensitive to the environment and adapts to prepare for survival following birth.[3]
A description of the infant samples and covariates is presented in Table 1, together with aflatoxin-albumin (AFalb) adduct levels in maternal blood obtained during the first trimester of pregnancy (Figure 1a)
We have shown for the first time that dietary exposure of pregnant women to aflatoxin is associated with genome-wide DNA methylation in the white blood cells (WBC) of their infants

Summary

Introduction

It has been proposed that changes to the epigenome during fetal development can contribute to disease susceptibility in adulthood.[1,2] Critical developmental periods exist during which the fetus is sensitive to the environment and adapts to prepare for survival following birth.[3] the earliest point of embryogenesis is a time of marked epigenetic change wherein genome-wide demethylation of the oocyte and sperm genomes occurs, followed by de novo genome-wide and tissue-specific methylation.[4] During this period, environmental exposures and stresses can influence the developing epigenome, causing life-long phenotypic alterations and potentially resulting in increased susceptibility to adult disease. We studied the consequences of early-life exposure to aflatoxin at the DNA methylation level, using a hypothesis-free genome-wide approach. The methylomewide analysis of infants’ DNA from a Gambian cohort reveals non-random differences in methylation related to early-life aflatoxin exposure

Methods

Results

Discussion