Academic journal article Environmental Health Perspectives

Prenatal Exposure to Mercury: Associations with Global DNA Methylation and Hydroxymethylation in Cord Blood and in Childhood

Academic journal article Environmental Health Perspectives

Prenatal Exposure to Mercury: Associations with Global DNA Methylation and Hydroxymethylation in Cord Blood and in Childhood

Article excerpt

Introduction

Mercury is a global contaminant that bioaccumulates in the environment. Coal-burning emissions and industrial waste are among the major anthropogenic sources of mercury, and ocean mercury levels have tripled since the industrial revolution (Lamborg et al. 2014). Nonoccupational human exposures predominately occur through the consumption of fish and other seafood contaminated with methylmercury that has been biomagnified up the food chain (Driscoll et al. 2013). Methylmercury readily crosses the placenta and blood-brain barrier, exposing the fetus during critical windows of development (Stern and Smith 2003). Prenatal exposure to mercury, typical of regular fish consumption with elevated mercury content, has been associated with lower cognitive test scores and may also hinder infant growth in the first few years of life (Karagas et al. 2012). The specific mechanism of mercury toxicity remains poorly characterized, but several mechanisms, including oxidative stress, disruption of calcium homeostasis, and alterations of neurotransmitters, among others, are hypothesized to be involved (Castoldi et al. 2003). Recently, epidemiological studies have shown that prenatal mercury exposure is associated with DNA methylation at specific genomic regions (Bakulski et al. 2015; Cardenas et al. 2015) that could serve as a mechanism linking exposure and infant neurobehavioral outcomes (Maccani et al. 2015).

Epigenetic modifications during fetal development play a critical role during embryogenesis regulating cell lineage commitment, chromosome silencing, retrotransposon repression, and genetic imprinting (Cheng et al. 2015). One of the most widely studied epigenetic modifications is DNA methylation at the 5' position of cytosine (C) nucleotides, also referred to as 5-methylcytosine (5mC) (Relton et al. 2015). More recently, it has been demonstrated that 5mC can undergo oxidation by the ten-eleven translocation (TET) family of enzymes to form 5-hydroxymethyl-cytosine (5hmC) (Dao et al. 2014). Regulation of gene expression by 5hmC has been shown to be independent of 5mC and plays a crucial role during embryogenesis, particularly in neurogenesis (Etchegaray et al. 2015; Hahn et al. 2013). Similar to 5mC, genomic 5hmC is cell type-specific, and it is most abundant in neurons, embryonic stem cells, and pluripotent cells (Ruzov et al. 2011). While there is emerging literature on mercury exposure with DNA methylation and its potential role in neurodevelopment and fetal programming, we are not aware of any studies that have examined associations with 5hmC genomic content. Epigenetic measurements associated with prenatal mercury exposure might help elucidate mechanisms associated with toxicity, particularly for exposures occurring in the developing fetus during critical periods of epigenomic remodeling (Waterland and Michels 2007). Alternatively, unique epigenetic signatures could serve as biomarkers of exposure and be used as biosensors even years after the exposure window (Ladd-Acosta 2015). Identifying if epigenomic changes at birth and sustained throughout childhood are associated with prenatal exposure to mercury will help elucidate their potential role as biomarkers of exposure or disease susceptibility.

In the present analysis, we examined the association of prenatal maternal second trimester mercury exposure with global DNA 5hmC and 5mC content in cord blood. We tested for persistence of the association among blood DNA samples collected from children during early and midchildhood. We hypothesized that prenatal maternal mercury concentration would be associated with both global DNA methylation and hydroxymethylation, and the observed association would persist into early and midchildhood, reflecting persistent epigenetic reprogramming events occurring in utero.

Methods

Study Population

Mother-child pairs were participants in Project Viva, a prospective prebirth cohort study (Oken et al. …

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