Exposure to DDX in Mice Reveals Impaired Energy Expenditure May be Mediated by DNA Methylation Changes

Abstract

ID 29773 Poster Board 262Persistent pollutants dichlorodiphenyltrichloroethane (DDT) and dichlorodiphenyldichloroethylene (DDE) have been associated with obesity across human and rodent studies. Current research suggests the impairment of thermogenesis in brown adipose tissue plays a significant role in the decreased energy expenditure and increased adiposity of exposed individuals. We hypothesized that mice perinatally exposed to DDT or DDE would exhibit impaired thermogenesis mediated by changes in DNA methylation. At 9 weeks, exposed offspring exhibited a lower rectal temperature than age-matched controls (DDE p< 0.05, DDT p<0.01), which continued into adulthood (DDT p<.001). Brown adipose tissue was isolated from mice at postnatal day 12 and 20 weeks for reduced representation bisulfite sequencing and RNA sequencing. 49 KEGG pathways were differentially methylated following DDT or DDE exposure (p<0.05). Of the 11 pathways enriched across more than one treatment, age, or nucleic acid; most notable were ovarian steroidogenesis, oxidative phosphorylation, mTOR signaling, and thermogenesis. Brown adipocytes were exposed to DDT or DDE over early differentiation and used to validate in vivo results. Preliminary results show increased expression of ribosomal subunit 18s in adipocytes exposed to DDE (p<0.05), suggesting a dysregulation of protein synthesis. Adipocytes exposed to DDE also exhibited a trend in decreased mitochondrial DNA copy number and increased expression of ATPase subunit g, Atp5mg, (p<0.05) consistent with the enrichment direction in the oxidative phosphorylation pathway for both DNA methylation and RNA expression. These preliminary data are consistent with published findings describing impaired mitochondrial function following DDE exposure and may provide insight into the mechanisms behind thermogenic impairment.