Obesity has been classically linked to poor diet/excessive calorie intake and insufficient physical activity. However, it has recently been discovered that environmental components may contribute significantly to the widespread obesity epidemic. The rapidly increasing obese populations in industrialized, developed and even undeveloped countries cannot be strictly accounted for by poor diet and physical inactivity. Environmental chemicals, termed ?obesogens? are endocrine disruptors, that can trigger adipogenesis (fat cell formation). However, their mechanism(s) of action remain unknown. Tetrabromobisphenol-A (TBBPA) and tributylin (TBT) are known obesogenic chemicals. We hypothesize that TBBPA and TBT promote adipogenesis by decreasing levels of THY1 (CD90), a cell surface protein present on pre-adipocytes, certain fibroblasts, and stem cells, (e.g. human mesenchymal stem cells (hMSCs)). Our lab previously discovered fibroblasts are heterogeneous for THY1 expression, where only THY1-/low fibroblasts differentiate into adipocytes, which identified THY1?s crucial role during adipogenesis and cell fate determination. Using a well-established mouse pre-adipocyte cell line (3T3-L1), I show that TBBPA reduces THY1 mRNA and protein and promotes adipogenesis. However, whether this occurs in human stem cells, such as hMSCs and induced pluripotent stem cells (iPSCs) is unknown. Obesity and adipogenesis are also subject to epigenetic and post- translational changes, which include increases in both global DNA methylation and the abundance of specific regulatory microRNAs (miRNA). My supporting data in hMSCs shows obesogens increase certain miRNAs that are predicted to bind THY1 mRNA. Gene expression can also be regulated by DNA methylation. My supporting data shows that TBBPA increases methylation on the THY1 promoter in hMSCs. Therefore, I hypothesize that obesogens, such as TBBPA, alter post-transcriptional regulation of THY1 to decrease its expression, thereby priming precursor cells to become adipocytes. Therefore, I will determine the in vitro effects and underlying molecular mechanisms of obesogens on THY1 expression in human stem cells.
(AIM 1). I will also determine the environmental obesogen effects on THY1 expression in vivo (AIM 2). The results from this project will help determine the obesogenic effects on stem cell function and will offer insight on as to how post-translational changes alter stem cell fate and lineage. Studies of environmental obesogens should be made a priority, since they likely overwhelmingly contribute to the growing worldwide obesity epidemic.
Research Narrative This research project will fill important gaps in our knowledge of how environmental chemicals termed ?obesogens? promote adipogenesis (fat cell formation) by targeting a cell surface protein, called Thy1 (CD90) on stem cells. This project seeks to determine the molecular mechanism that facilitates obesogen effects on human stem cells and on in vivo exposure using a mouse model. Knowledge gained from these studies have the potential to lead to new understanding of the potential harmful effects of obesogens and hopefully lead to change in our current science policy to reduce human exposure.
|Woeller, Collynn F; Flores, E'Lissa; Pollock, Stephen J et al. (2017) Editor's Highlight: Thy1 (CD90) Expression is Reduced by the Environmental Chemical Tetrabromobisphenol-A to Promote Adipogenesis Through Induction of microRNA-103. Toxicol Sci 157:305-319|