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The brominated flame retardant tetrabromobisphenol‐A increases DNA methylation at the THY1 (CD90) locus to promote adipogenesis

Obesity has been classically linked to poor diet/excessive calorie intake and insufficient physical activity. However, an emerging concept is that environmental pollutants may be driving the global obesity epidemic. The rapid increase in the prevalence of obesity in industrialized, developed and even undeveloped countries cannot be strictly accounted for by poor diet and physical inactivity. Environmental chemicals, termed “obesogens” can promote adipogenesis (fat cell formation). Tetrabromobisphenol‐A (TBBPA), a brominated flame retardant found in infant mattresses and electronics such as cell phones, is an obesogens. However, its mechanism of action remains unknown. We hypothesize that TBBPA promotes adipogenesis by decreasing levels of THY1 (CD90), a cell surface protein present on pre‐adipocytes, certain fibroblasts, and stem cells. We previously determined that fibroblasts are heterogeneous for THY1 expression, where only THY1‐/low fibroblasts differentiate into adipocytes, pointing to THY1's crucial role during adipogenesis and cell fate. Using the well‐established mouse pre‐adipocyte cell line (3T3‐L1), we determined that TBBPA reduces THY1 mRNA and protein levels, promoting adipogenesis. Epigenetic changes, such as increases in global DNA methylation are known to occur during adipogenesis and obesity. DNA hypermethylation typically silences gene expression. Therefore, we hypothesized that obesogens, such as TBBPA, alter epigenetic regulation of THY1 to decrease its expression, thereby priming precursor cells to become adipocytes. Using pyrosequencing, we found that CG rich regions on THY1 are hypermethylated during adipogenesis, resulting in decreased THY1 expression and cell differentiation to adipocytes. Using the methylation inhibitor, 5‐aza‐dC, we determined that the adipogenic effects of TBBPA are blunted when methylation is impeded, which results in increased THY1 levels. Our results confirm THY1 plays a critical role in adipogenesis and that its expression is regulated by increases in DNA methylation. Furthermore, TBBPA, a widely‐used flame retardant, increases DNA methylation at the Thy1 locus to promote adipogenesis. Environmental obesogens contribute to the worldwide obesity epidemic and their further study is critical to combating this epidemic.