Evaluation of tetrabromobisphenol A effects on human glucocorticoid and androgen receptors: A comparison of results from human- with yeast-based in vitro assays

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• 作者：Katharina R. Beck^a ; Tanja J. Sommer^a ; Daniela Schuster^b ; Alex Odermatt^a ; ^{alex.odermatt@unibas.ch" class="auth_mail" title="E-mail the corresponding author}
• 关键词：AR ; androgen receptor ; EDCs ; endocrine disrupting chemicals ; EDSP ; Endocrine Disruptor Screening Program ; ER ; estrogen receptor ; GR ; glucocorticoid receptor ; HSP ; heat shock protein ; IARC ; International Agency for Research on Cancer ; LOD ; limit of detection ; MAPK ; mitogen activated protein kinase ; NCoR ; nuclear receptor corepressor ; NK cell ; natural killer cell ; NTP ; U. S. National Toxicology Program ; PCBs ; polychlorinated biphenyls ; PDB ; Protein Data Bank ; P-gp ; P-glycoprotein ; PR ; progesterone
• 刊名：Toxicology
• 出版年：2016
• 出版时间：31 August 2016
• 年：2016
• 卷：370
• 期：Complete
• 页码：70-77
• 全文大小：1245 K

文摘

The incidence of immune-related diseases increased over the last years in industrialized countries, suggesting a contribution of environmental factors. Impaired glucocorticoid action has been associated with immune disorders. Thus, there is an increasing interest to identify chemicals disrupting glucocorticoid action. The widely used flame retardant tetrabromobisphenol A (TBBPA) was reported earlier to potently inhibit glucocorticoid receptor (GR) and moderately androgen receptor (AR) activity in yeast-based reporter gene assays. To further characterize possible GR disrupting effects of TBBPA, transactivation experiments using a human HEK-293 cell-based reporter gene assay and cell-free receptor binding experiments were performed in the present study. Both, transactivation and GR binding experiments failed to detect any activity of TBBPA on GR function. Molecular docking calculations supported this observation. Additionally, the current study could confirm the antiandrogenic activity of TBBPA seen in the yeast assay, although the effect was an order of magnitude less pronounced in the HEK-293 cell-based system. In conclusion, TBBPA does not directly affect GR function and, considering its rapid metabolism and low concentrations found in humans, it is unlikely to cause adverse effects by acting through AR. This study emphasizes the use of cell-free assays in combination with cell-based assays for the in vitro evaluation of endocrine disrupting chemicals.