Early-Life Lead Exposure Results in Dose- and Sex-Specific Effects on Weight and Epigenetic Gene Regulation in Weanling Mice

Abstract

Aims: Epidemiological and animal data suggest that the development of adult chronic conditions is influenced by early-life exposure-induced changes to the epigenome. This study investigates the effects of perinatal lead (Pb) exposure on DNA methylation and bodyweight in weanling mice. Materials & methods: Viable yellow agouti (A^vy) mouse dams were exposed to 0, 2.1, 16 and 32 ppm Pb acetate before conception through weaning. Epigenetic effects were evaluated by scoring coat color of A^vy/a offspring and quantitative bisulfite sequencing of two retrotransposon-driven (A^vy and CDK5 activator-binding protein intracisternal A particle element) and two imprinted (Igf2 and Igf2r) loci in tail DNA. Results: Maternal blood Pb levels were below the limit of detection in controls, and 4.1, 25.1 and 32.1 µg/dl for each dose, respectively. Pb exposure was associated with a trend of increased wean bodyweight in males (p = 0.03) and altered coat color in A^vy/a offspring. DNA methylation at A^vy and the CDK5 activator-binding protein intracisternal A-particle element was significantly different from controls following a cubic trend (p = 0.04; p = 0.01), with male-specific effects at the A^vy locus. Imprinted genes did not shift in methylation across exposures. Conclusion: Dose- and sex-specific responses in bodyweight and DNA methylation indicate that Pb acts on the epigenome in a locus-specific fashion, dependent on the genomic feature hosting the CpG site of interest, and that sex is a factor in epigenetic response.

KEYWORDS::

• developmental origins of health and disease
• DNA methylation
• environmental epigenomics
• epigenetics
• lead
• metastable epiallele
• plasticity
• viable yellow agouti

Acknowledgements

The authors would like to thank BN Sanchez, Z Zhang and KE Peterson for their technical and intellectual assistance with this project.

Financial & competing interests disclosure

This work was supported by the University of Michigan (UM) NIEHS/EPA Children‘s Environmental Health Formative Center (P20 ES018171/RD834800), as well as the UM NIEHS Core Center (P30 ES017885). C Faulk was supported by the UM NIEHS Core Center (T32 ES007062). JM Goodrich was supported by the UM NIH National Center for Advancing Translational Sciences grant (2UL1TR000433). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This work was supported by the University of Michigan (UM) NIEHS/EPA Children‘s Environmental Health Formative Center (P20 ES018171/RD834800), as well as the UM NIEHS Core Center (P30 ES017885). C Faulk was supported by the UM NIEHS Core Center (T32 ES007062). JM Goodrich was supported by the UM NIH National Center for Advancing Translational Sciences grant (2UL1TR000433). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.