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.

KEYWORDS:

• Toxicoepigenetics
• DNA methylation
• Developmental origins of health and disease (DOHaD)
• surrogate tissue
• sex differences
• environmental epigenomics

Author Contributions

All authors provided critical feedback and helped shape the research, analysis and manuscript. KN, CAR, TRJ, CL performed experiments. LKS, RC, CAR, ZT, SL, JMG, JAC, MAS, DCD analyzed data. LKS wrote manuscript in consultation with DCD, JAC, MAS, and JMG.

Disclosure statement

The authors declare no conflict of interest.

Data Availability

ERRBS sequencing data have been uploaded to GEO (accession number GSE150670). RNA-seq data are available from the TaRGET II Consortium: https://targetepigenomics.org/.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

This work was supported by the National Institute of Environmental Health Sciences [P01 ES022844/RD83543601]; National Institute of Environmental Health Sciences [ES026697]; National Institute of Environmental Health Sciences [ES028802]; National Institute of Environmental Health Sciences [T32 ES007062]; National Institute of Environmental Health Sciences [P30 ES017885].