The U.S. population is exposed to a number of environmental chemicals termed endocrine disruptors that may be associated with the increasing incidence of metabolic disorders and obesity, particularly in children. A number of these chemicals are believed to act as peroxisome proliferator activated receptor (PPAR) agonists and affect homeostatic pathways associated with glucose metabolism, lipid metabolism and inflammatory responses. The health consequences of aberrant PPAR activation are potentially significant and include increased risk for obesity, type-2 diabetes, cardiovascular disease and chronic inflammatory diseases. Studies were conducted to establish a high throughput in vitro cell culture screening assay to identify gene expression changes in key biological pathways that occur from putative environmental PPAR agonists using a low-density focused array card followed by RNA silencing studies of the PPARa and PPARg genes using selected human cell lines including THP1 cells, a human monocyte cell line. In our hands we found this approach to lack high sensitivity due to the multiple cell manipulations required. However, some of the more potent responses associated with treatment with positive controls (fibrate and glitazone) and test chemicals (such as tributyltin chloride and perfluorooctanoate) indicated that PPARa, PPARg or both were associated with the regulation of genes associated with several pathways including cholesterol homeostasis and acute phase proteins. Our results should be helpful particularly in epidemiological studies of children exposed to environmental obesogens as it provides potentially biologically relevant markers that can be examined.
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