Sex-Specific Programming of Cardiac DNA Methylation by Developmental Phthalate Exposure
Svoboda, LK; Wang, K; Cavalcante, RG; Neier, K; Colacino, JA; Sartor, MA; Dolinoy, DC
| HERO ID | 9415261 |
|---|---|
| In Press | No |
| Year | 2020 |
| Title | Sex-Specific Programming of Cardiac DNA Methylation by Developmental Phthalate Exposure |
| Authors | Svoboda, LK; Wang, K; Cavalcante, RG; Neier, K; Colacino, JA; Sartor, MA; Dolinoy, DC |
| Volume | 13 |
| Page Numbers | 2516865720939971 |
| Abstract | Phthalate plasticizers are ubiquitous chemicals linked to several cardiovascular diseases in animal models and humans. Despite 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. |
| Doi | 10.1177/2516865720939971 |
| Pmid | 32864567 |
| Url | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85089159570&doi=10.1177%2f2516865720939971&partnerID=40&md5=b4066d5dcc5bce99d7e5d665e9fc6ef1 |
| Is Certified Translation | No |
| Dupe Override | No |
| Comments | Journal: Epigenetics insights ISSN: 2516-8657 |
| Is Public | Yes |
| Language Text | English |
| Keyword | Developmental origins of health and disease (DOHaD); DNA methylation; heart; phthalate; sex differences; toxicoepigenetics; bone morphogenetic protein 6; cytosine; DNA methyltransferase 3A; endothelin converting enzyme; netrin 1; phosphatidylinositol 4,5 bisphosphate 3 kinase; phthalic acid; phthalic acid bis(2 ethylhexyl) ester; protein tyrosine phosphatase; retinal specific ATP binding cassette transporter; Smad7 protein; zinc finger protein GLI2; adult; animal experiment; animal model; animal tissue; Article; bioinformatics; bisulfite sequencing; controlled study; CpG island; death; DNA extraction; DNA methylation; enhanced reduced representation bisulfate sequencing; female; gene expression; gene mapping; heart disease; heart failure; heart muscle fibrosis; high throughput sequencing; histone methylation; insulin signaling; male; nonhuman; nuclear reprogramming; perinatal drug exposure; phenotype; quality control; sex difference |