An in vitro approach for prioritization and evaluation of chemical effects on glucocorticoid receptor mediated adipogenesis
| Autor: | Gina Song, Briana Foley, Tyler Beames, Daniel Doheny, Jessica K. Hartman, Patrick D. McMullen, Bethany Parks, Miyoung Yoon, Chad Deisenroth, Rebecca A. Clewell, Alina Efremenko |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cell Survival Cellular differentiation Gene Expression Biology Pharmacology Fatty Acid-Binding Proteins Toxicology Dexamethasone 03 medical and health sciences chemistry.chemical_compound Receptors Glucocorticoid Glucocorticoid receptor Adipokines Adipocyte Adipocytes medicine Humans Progenitor cell Cells Cultured Adipogenesis L-Lactate Dehydrogenase Stem Cells Cell Differentiation Lipid Metabolism 030104 developmental biology chemistry Stem cell Obesogen Glucocorticoid medicine.drug |
| Zdroj: | Toxicology and Applied Pharmacology. 355:112-126 |
| ISSN: | 0041-008X |
| DOI: | 10.1016/j.taap.2018.05.016 |
| Popis: | Rising obesity rates worldwide have socio-economic ramifications. While genetics, diet, and lack of exercise are major contributors to obesity, environmental factors may enhance susceptibility through disruption of hormone homeostasis and metabolic processes. The obesogen hypothesis contends that chemical exposure early in development may enhance adipocyte differentiation, thereby increasing the number of adipocytes and predisposing for obesity and metabolic disease. We previously developed a primary human adipose stem cell (hASC) assay to evaluate the effect of environmental chemicals on PPARG-dependent adipogenesis. Here, the assay was modified to determine the effects of chemicals on the glucocorticoid receptor (GR) pathway. In differentiation cocktail lacking the glucocorticoid agonist dexamethasone (DEX), hASCs do not differentiate into adipocytes. In the presence of GR agonists, adipocyte maturation was observed using phenotypic makers for lipid accumulation, adipokine secretion, and expression of key genes. To evaluate the role of environmental compounds on adipocyte differentiation, progenitor cells were treated with 19 prioritized compounds previously identified by ToxPi as having GR-dependent bioactivity, and multiplexed assays were used to confirm a GR-dependent mode of action. Five chemicals were found to be strong agonists. The assay was also modified to evaluate GR-antagonists, and 8/10 of the hypothesized antagonists inhibited adipogenesis. The in vitro bioactivity data was put into context with extrapolated human steady state concentrations (Css) and clinical exposure data (Cmax). These data support using a human adipose-derived stem cell differentiation assay to test the potential of chemicals to alter human GR-dependent adipogenesis. |
| Databáze: | OpenAIRE |
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