Impaired energy expenditure following exposure to either DDT or DDE in mice may be mediated by DNA methylation changes in brown adipose

The insecticide dichlorodiphenyltrichloroethane (DDT) and its persistent metabolite, dichlorodiphenyldichloroethylene (DDE), have been associated with increased adiposity and obesity in multiple generations of rodents and humans. These lipophilic pollutants accumulate in adipose tissue and appear to decrease energy expenditure through the impairment of thermogenesis in brown adipose tissue. We hypothesized that impaired thermogenesis is due to persistent epigenetic modifications of brown adipose tissue. To address this, we exposed C57BL/6J mice to DDT or DDE from gestational day 11.5 to postnatal day 5, evaluated longitudinal body temperature, and performed reduced representation bisulfite sequencing and RNA-sequencing of brown adipose tissue from infant and adult offspring. Exposure to DDT or DDE reduced core body temperature in adult mice, and differential methylation at the pathway- and gene-level was persistent from infancy to adulthood. Furthermore, thermogenesis and biological pathways essential for thermogenic function, such as oxidative phosphorylation and mTOR signaling, were enriched with differential methylation and RNA transcription in adult mice exposed to DDT or DDE. PAZ6 human brown preadipocytes were differentiated in the presence of DDT or DDE to understand the brown adipocyte-autonomous effect of these pollutants. In vitro exposure led to limited changes in RNA expression; however mitochondrial membrane potential was decreased in vitro with 0.1 µM and 1 µM doses of DDT or DDE. These results demonstrate that concentrations of DDT and DDE relevant to human exposure have a significant effect on thermogenesis, the transcriptome, and DNA methylome of mouse brown adipose tissue, and the mitochondrial function of human brown adipocytes.