Translational toxicoepigenetic Meta-Analyses identify homologous gene DNA methylation reprogramming following developmental phthalate and lead exposure in mouse and human offspring

Rebekah L Petroff; Dana C Dolinoy; Kai Wang; Luke Montrose; Vasantha Padmanabhan; Karen E Peterson; Douglas M Ruden; Maureen A Sartor; Laurie K Svoboda; Martha M Téllez-Rojo; Jaclyn M Goodrich

doi:10.1016/j.envint.2024.108575

Translational toxicoepigenetic Meta-Analyses identify homologous gene DNA methylation reprogramming following developmental phthalate and lead exposure in mouse and human offspring

Environ Int. 2024 Apr:186:108575. doi: 10.1016/j.envint.2024.108575. Epub 2024 Mar 11.

Authors

Affiliations

¹ Environmental Health Sciences, University of Michigan, Ann Arbor, MI, USA.
² Environmental Health Sciences, University of Michigan, Ann Arbor, MI, USA; Nutritional Sciences, University of Michigan, Ann Arbor, MI, USA.
³ Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA.
⁴ Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA.
⁵ Environmental Health Sciences, University of Michigan, Ann Arbor, MI, USA; Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA; Obstetrics and Gynecology, University of Michigan Medical School, Ann Arbor, MI, USA.
⁶ Obstetrics and Gynecology, Wayne State University, Detroit, MI, USA.
⁷ Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA; Biostatistics, University of Michigan, Ann Arbor, MI, USA.
⁸ Environmental Health Sciences, University of Michigan, Ann Arbor, MI, USA; Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA.
⁹ Center for Research on Nutrition and Health, National Institute of Public Health, Cuernavaca, Mexico.
¹⁰ Environmental Health Sciences, University of Michigan, Ann Arbor, MI, USA. Electronic address: gaydojac@umich.edu.

Abstract

Although toxicology uses animal models to represent real-world human health scenarios, a critical translational gap between laboratory-based studies and epidemiology remains. In this study, we aimed to understand the toxicoepigenetic effects on DNA methylation after developmental exposure to two common toxicants, the phthalate di(2-ethylhexyl) phthalate (DEHP) and the metal lead (Pb), using a translational paradigm that selected candidate genes from a mouse study and assessed them in four human birth cohorts. Data from mouse offspring developmentally exposed to DEHP, Pb, or control were used to identify genes with sex-specific sites with differential DNA methylation at postnatal day 21. Associations of human infant DNA methylation in homologous mouse genes with prenatal DEHP or Pb were examined with a meta-analysis. Differential methylation was observed on 6 cytosines (adjusted-p < 0.05) and 90 regions (adjusted-p < 0.001). This translational approach offers a unique method that can detect conserved epigenetic differences that are developmentally susceptible to environmental toxicants.

Keywords: DEHP; DNA methylation; Developmental exposures; Epigenetics; Lead (Pb); Translational toxicology.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
DNA Methylation* / drug effects
Diethylhexyl Phthalate / toxicity
Environmental Pollutants / toxicity
Epigenesis, Genetic* / drug effects
Female
Humans
Infant
Lead* / toxicity
Male
Mice
Phthalic Acids* / toxicity
Pregnancy
Prenatal Exposure Delayed Effects* / chemically induced
Prenatal Exposure Delayed Effects* / genetics

Substances

Diethylhexyl Phthalate
Environmental Pollutants
Lead
Phthalic Acids

Abstract

Publication types

MeSH terms

Substances

Grants and funding