OR23-2 Increased Exposure to Brominated Flame Retardant Associates with Differences in DNA Methylation Similar to Natural Estrogen

Abstract

In 1973, approximately 6.5 million Michigan residents were exposed to an industrial mixture of polybrominated biphenyl (PBB), an endocrine-disrupting compound, when it was added to farm animal feed during a factory accident. Highly exposed individuals and their children have numerous endocrine-related health problems, including genitourinary conditions, spontaneous abortions, and early puberty, though the underlying mechanism behind these health problems remains unknown. Other endocrine-disrupting compounds have been linked to epigenetic differences, but no epigenetic studies have been done for PBB. In this study, DNA from the blood of individuals with PBB exposure was interrogated with the MethylationEPIC BeadChip (N = 658). Associations between each of the ~850,000 CpG sites and current, serum PBB levels were tested with a linear regression that controlled for age, sex, lipid levels, and cell type proportions. After multiple test correction (FDR <0.05), 1890 CpG sites associated with total PBB levels. These CpGs were not enriched in any particular biological pathway, but were enriched in enhancer and insulator regions, and depleted in regions near the transcription start site or in CpG islands (p < 0.05). In order to better understand the function of the enhancers that were enriched, PBB-associated CpGs were also interrogated for transcription factor binding sites, correlations with hormones, and links to gene expression. They were also more likely to be in ARNT and ESR2 transcription factor binding sites (p = 3.27e-23 and p = 1.62e-6, respectively), and there was significant overlap between CpGs associated with PBB and CpGs associated with estrogen (p <2.2e-16). PBB-associated CpGs were also enriched for CpGs known to be associated with gene expression in blood (eQTMs) (p <0.05). These eQTMs were associated with the expression of genes that were enriched for pathways related to endocrine-related autoimmune disease (FDR <0.05). Taken together, these results indicate that exposure to PBB is associated with differences in epigenetic marks that suggest that it is acting similarly to estrogen and is associated with endocrine-related autoimmune pathways.