Dataset Information

Developmental Dieldrin Exposure Alters DNA Methylation at Genes Related to Dopaminergic Neuron Development and Parkinson’s Disease in Mouse Midbrain

ABSTRACT: Human and animal studies have shown that exposure to the organochlorine pesticide dieldrin is associated with increased risk of Parkinson’s disease (PD). Despite previous work showing a link between developmental dieldrin exposure and increased neuronal susceptibility to MPTP toxicity in male C57BL/6 mice, the mechanism mediating this effect has not been identified. Here, we tested the hypothesis that developmental exposure to dieldrin increases neuronal susceptibility via genome-wide changes in DNA methylation. Starting at 8 weeks of age and prior to mating, female C57BL/6 mice were exposed to 0.3 mg/kg dieldrin by feeding (every 3 days) throughout breeding, gestation, and lactation. At 12 weeks of age, pups were sacrificed and midbrains were dissected. DNA was isolated and dieldrin-related changes in DNA methylation were assessed via reduced representation bisulfite sequencing (RRBS). We identified significant, sex-specific differentially methylated CpGs (DMCs) and regions (DMRs) by developmental dieldrin exposure (FDR<0.05), including DMCs at the Nr4a2 and Lmx1b genes, which are involved in dopaminergic neuron development and maintenance. Developmental dieldrin exposure had distinct effects on the male and female epigenome. Furthermore, a separate set of changes in DNA methylation was identified after adult exposure to dieldrin, suggesting that adult and developmental dieldrin toxicity may not act through a shared epigenetic mechanism. Together, our data suggest that developmental dieldrin exposure establishes sex-specific poised epigenetic states early in life. These poised epigenomes may mediate sensitivity to additional environmental stimuli and contribute to the development of late-life neurodegenerative disease, including PD.

ORGANISM(S): Mus musculus

PROVIDER: GSE134636 | GEO | 2019/07/23

REPOSITORIES: GEO

ACCESS DATA

Similar Datasets

Project description:DEHP study Phthalate plasticizers are ubiquitous chemicals linked to several cardiovascular diseases in animal models and in humans. In spite of this, the mechanisms by which phthalate exposures cause adverse cardiac health outcomes are unclear. In particular, whether phthalate exposures during pregnancy interfere with normal developmental programming of the cardiovascular system, and the resulting implications this may have for long-term disease risk, are unknown. Recent studies suggest that the effects of phthalates on metabolic and neurobehavioral outcomes are sex-specific. However, the influence of sex on cardiac susceptibility to phthalate exposures has not been investigated. One mechanism by which developmental exposures may influence long-term health is through altered programming of DNA methylation. In this work, we utilized an established mouse model of human-relevant perinatal exposure and enhanced reduced representation bisulfite sequencing to investigate the long-term effects of diethylhexyl phthalate (DEHP) exposure on DNA methylation in the hearts of adult male and female offspring at 5 months of age (n=5-7 mice per sex and exposure). Perinatal DEHP exposure led to hundreds of sex-specific, differentially methylated cytosines (DMCs) and differentially methylated regions (DMRs) in the heart. Pathway analysis of DMCs revealed enrichment for several pathways in females, including insulin signaling, regulation of histone methylation, and tyrosine phosphatase activity. In males, DMCs were enriched for glucose transport, energy generation, and developmental programs. Notably many sex-specific genes differentially methylated with DEHP exposure in our mouse model were also differentially methylated in published data of heart tissues collected from human heart failure patients. Together these data highlight the potential role for DNA methylation in DEHP-induced cardiac effects, and emphasize the importance of sex as a biological variable in environmental health studies. Lead study Environmental factors play an important role in the etiology of cardiovascular diseases. Cardiovascular diseases exhibit marked sexual dimorphism; however, the sex-specific effects of environmental exposures on cardiac health are incompletely understood. Perinatal and adult exposures to the metal lead (Pb) are linked to several adverse cardiovascular outcomes, but the sex-specific effects of this toxicant on the heart have received little attention. Perinatal environmental exposures can lead to disease through disruption of the normal epigenetic programming that occurs during early development. Using a mouse model of human-relevant perinatal environmental exposure, we investigated the effects of exposure to Pb during gestation and lactation on DNA methylation in the hearts of adult offspring mice (n=6 per sex). Two weeks prior to mating, dams were assigned to control or Pb acetate (32 ppm) water, and exposure continued until offspring were weaned at 3 weeks of age. Enhanced reduced-representation bisulfite sequencing was used to measure DNA methylation in the hearts of offspring at 5 months of age. Although Pb exposure stopped at 3 weeks of age, we discovered hundreds of differentially methylated cytosines (DMCs) and regions (DMRs) in males and females at 5 months of age. DMCs/DMRs and their associated genes were sex-specific, with a small, but statistically significant subset overlapping between sexes. Pathway analysis revealed altered methylation of genes important for cardiac and other tissue development in males, and histone demethylation in females. Together, these data demonstrate that perinatal exposure to Pb induces sex-specific changes in cardiac DNA methylation that are present long after cessation of exposure, and highlight the importance of considering sex in environmental epigenetics and mechanistic toxicology studies.

Dataset Information

Developmental Dieldrin Exposure Alters DNA Methylation at Genes Related to Dopaminergic Neuron Development and Parkinson’s Disease in Mouse Midbrain

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure