Tissue and sex-specific programming of DNA methylation by perinatal lead exposure: implications for environmental epigenetics studies

Abstract

Early developmental environment can influence long-term health through reprogramming of the epigenome. Human environmental epigenetics studies rely on surrogate tissues, such as blood, to assess the effects of environment on disease-relevant but inaccessible target tissues. However, the extent to which environment-induced epigenetic changes are conserved between these tissues is unclear. A better understanding of this conservation is imperative for effective design and interpretation of human environmental epigenetics studies. The Toxicant Exposures and Responses by Genomic and Epigenomic Regulators of Transcription (TaRGET II) consortium was established by the National Institute of Environmental Health Sciences to address the utility of surrogate tissues as proxies for toxicant-induced epigenetic changes in target tissues. We and others have recently reported that perinatal exposure to lead (Pb) is associated with adverse metabolic outcomes. Here, we investigated the sex-specific effects of perinatal exposure to a human environmentally relevant level of Pb on DNA methylation in paired liver and blood samples from adult mice using enhanced reduced-representation bisulphite sequencing. Although Pb exposure ceased at 3 weeks of age, we observed thousands of sex-specific differentially methylated cytosines in the blood and liver of Pb-exposed animals at 5 months of age, including 44 genomically imprinted loci. We observed significant tissue overlap in the genes mapping to differentially methylated cytosines. A small but significant subset of Pb-altered genes exhibit basal sex differences in gene expression in the mouse liver. Collectively, these data identify potential molecular targets for Pb-induced metabolic diseases, and inform the design of more robust human environmental epigenomics studies.

Perinatal DEHP exposure induces sex- and tissue-specific DNA methylation changes in both juvenile and adult mice

“…The only gene showing prior correlation with DEHP exposure from CTD was a glycine transporter gene Slc6a9 , and it was found with hypomethylation on exon 15 in both male blood and liver at 5 months. These findings overall represent a low level of consistency in DEHP-induced differential methylation between liver and blood, and a similar dearth of overlap between blood and liver was reported in our lead exposure study ( 54 ).…”

“…As an important component in G protein-coupled receptors, GNAS plays a role in development of obesity and regulation of energy balance ( 61 ). Notably, GNAS was previously found to have differential methylation in response to many types of environmental exposures, including bisphenol A ( 62 ), lead ( 54 ), folic acid depletion ( 63 ), gases/fumes ( 64 ), and prenatal maternal stress ( 65 ), suggesting the GNAS imprinted cluster may be an especially labile region, sensitive to many environmental exposures. Although there was prior evidence from CTD showing the impact of DEHP on DNA methylation levels of imprinted genes Igf2r , Peg3, and H19 in mouse oocytes ( 18 ), we did not observe any significant changes in DNA methylation at these genes in either blood or liver.…”

Toxicoepigenetics and Environmental Health: Challenges and Opportunities

“…156−161 We recently demonstrated that a comparison of DNA methylation changes between liver and blood in mice perinatally exposed to lead showed few overlaps between blood and liver, and the overlaps identified were sex-specific. 156 Similar sex differences in blood DNA methylation have also been identified in human populations. 162,163 These findings have important implications for environmental epidemiology studies that seek to find epigenomic markers of exposures and disease in surrogate samples such as blood, hair, and saliva.…”

“…Consideration of sex will be imperative in toxicoepigenetics studies aimed at identifying epigenetic mechanisms and biomarkers linking environmental exposures and disease. Indeed, work from our lab and others has identified sex-specific effects of environmental exposures on DNA methylation and histone marks. − We recently demonstrated that a comparison of DNA methylation changes between liver and blood in mice perinatally exposed to lead showed few overlaps between blood and liver, and the overlaps identified were sex-specific . Similar sex differences in blood DNA methylation have also been identified in human populations. , These findings have important implications for environmental epidemiology studies that seek to find epigenomic markers of exposures and disease in surrogate samples such as blood, hair, and saliva.…”

“…Our recent work in TaRGET II demonstrates that changes in DNA methylation after perinatal exposure to lead or the plasticizer di-2-ethylhexyl phthalate are highly tissue- and sex-dependent, with little concordance between liver and blood. ,, Our findings are in keeping with recent work in human subjects, which found correlation in DNA methylation between blood and the liver at only a minority of CpG sites within 35 hemostatic genes . Additional studies have demonstrated limited correlation in DNA methylation between human blood and other tissues. − These findings have important implications for environmental epidemiology studies and suggest that the most meaningful biomarkers may be restricted to a subset of genes that are correlated across tissue, sex, and age.…”