Lead Exposure during Early Human Development and DNA Methylation of Imprinted Gene Regulatory Elements in Adulthood

Abstract

Background:Lead exposure during early development causes neurodevelopmental disorders by unknown mechanisms. Epidemiologic studies have focused recently on determining associations between lead exposure and global DNA methylation; however, such approaches preclude the identification of loci that may alter human disease risk.Objectives:The objective of this study was to determine whether maternal, postnatal, and early childhood lead exposure can alter the differentially methylated regions (DMRs) that control the monoallelic expression of imprinted genes involved in metabolism, growth, and development.Methods:Questionnaire data and serial blood lead levels were obtained from 105 participants (64 females, 41 males) of the Cincinnati Lead Study from birth to 78 months. When participants were adults, we used Sequenom EpiTYPER assays to test peripheral blood DNA to quantify CpG methylation in peripheral blood leukocytes at DMRs of 22 human imprinted genes. Statistical analyses were conducted using linear regression.Results:Mean blood lead concentration from birth to 78 months was associated with a significant decrease in PEG3 DMR methylation (β = –0.0014; 95% CI: –0.0023, –0.0005, p = 0.002), stronger in males (β = –0.0024; 95% CI: –0.0038, –0.0009, p = 0.003) than in females (β = –0.0009; 95% CI: –0.0020, 0.0003, p = 0.1). Elevated mean childhood blood lead concentration was also associated with a significant decrease in IGF2/H19 (β = –0.0013; 95% CI: –0.0023, –0.0003, p = 0.01) DMR methylation, but primarily in females, (β = –0.0017; 95% CI: –0.0029, –0.0006, p = 0.005) rather than in males, (β = –0.0004; 95% CI: –0.0023, 0.0015, p = 0.7). Elevated blood lead concentration during the neonatal period was associated with higher PLAGL1/HYMAI DMR methylation regardless of sex (β = 0.0075; 95% CI: 0.0018, 0.0132, p = 0.01). The magnitude of associations between cumulative lead exposure and CpG methylation remained unaltered from 30 to 78 months.Conclusions:Our findings provide evidence that early childhood lead exposure results in sex-dependent and gene-specific DNA methylation differences in the DMRs of PEG3, IGF2/H19, and PLAGL1/HYMAI in adulthood.Citation:Li Y, Xie C, Murphy SK, Skaar D, Nye M, Vidal AC, Cecil KM, Dietrich KN, Puga A, Jirtle RL, Hoyo C. 2016. Lead exposure during early human development and DNA methylation of imprinted gene regulatory elements in adulthood. Environ Health Perspect 124:666–673; http://dx.doi.org/10.1289/ehp.1408577

Sex- and brain region- specific effects of prenatal stress and lead exposure on permissive and repressive post-translational histone modifications from embryonic development through adulthood

“…Adverse neurodevelopmental effects of Pb, PS and the combination, as demonstrated in human studies and paralleled in animal models, can be persistent (Anderson et al, 2016; Brubaker et al, 2010; Canfield et al, 2003; Cecil et al, 2008; Cohn et al, 1993; Jett et al, 1997; Lanphear et al, 2005; Li et al, 2016). Findings from this study confirm long-lasting changes in PTHM levels in response to these exposures, as evidenced in FC and HIPP at PND60 with Pb exposure having been discontinued at PND21, with effects differing by sex and by brain region.…”

Maternal blood lead concentrations, DNA methylation of MEG3 DMR regulating the DLK1/MEG3 imprinted domain and early growth in a multiethnic cohort

“…Although our data were too limited for sex-specific analyses, we previously reported female-specific associations between Pb exposure and lower methylation of regulatory sequencing of IGF2/H19 imprinted domains (Li, Xie et al 2015). In animal models, Faulk et.…”

“…Covariates evaluated for potential confounding were selected based on previous studies, and included cigarette smoking, categorized as never smoked, smoked during pregnancy, or quit smoking before pregnancy (Murphy, Adigun et al 2012), antibiotic use (during pregnancy or not), (Vidal, Murphy et al 2013), physical activity dichotomized as ever or never (Vidal, Murphy et al 2013), socioeconomic status estimated by maternal years of schooling, and race/ethnicity defined as self-reported non-Hispanic Black, Hispanic, and non-Hispanic Other vs. non-Hispanic Whites (King, Murphy et al 2015), and pre-pregnancy BMI (Vidal, Murtha et al 2013). We also included maternal age and sex as animal and human studies suggest that the effects of environmental Pb exposure may be sex-specific (Faulk, Barks et al 2014; Li, Xie et al 2015). We used SAS V9.03 for data analysis (SAS Institute Inc.) and the R package.…”

“…A growing body of in vitro and in vivo evidence supports that environmental exposure to toxic metals, including Pb, can alter DNA methylation (Takiguchi, Achanzar et al 2003; Reichard, Schnekenburger et al 2007; Jiang, Xu et al 2008; Pilsner, Hu et al 2009; Bailey and Fry 2014; Faulk, Liu et al 2014; Li, Xie et al 2015; Nye, Hoyo et al 2015). However, epigenetic targets are still not known.…”

“…These genes are functionally haploid and controlled by parental allele-specific differentially methylated regions (DMRs) established in gametes during early development and this methylation pattern is largely maintained in somatic tissues. Here we investigated the effects of maternal blood Pb levels on the DMRs of four imprinted genes (two maternally methylated: PEG3 and PLAGL1, and two paternally methylated: H19 and MEG3) three of which previously have been found to be associated with birth weight (Hoyo, Daltveit et al 2014) and early life Pb exposure (Li, Xie et al 2015). …”