Evaluation of tetrabromobisphenol A effects on human glucocorticoid and androgen receptors: A comparison of results from human- with yeast-based in vitro assays.
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.
Swiss Center for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, Pharmacenter, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
Katharina R
KR
Beck
Swiss Center for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, Pharmacenter, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
Tanja J
TJ
Sommer
Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), Computer Aided Molecular Design Group, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
Daniela
D
Schuster
Swiss Center for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, Pharmacenter, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: alex.odermatt@unibas.ch.
Alex
A
Odermatt
D059002:Androgen Receptor Antagonists / Q000633:toxicity*; D052244:Endocrine Disruptors / Q000633:toxicity; D005411:Flame Retardants / Q000633:toxicity*; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D011075:Polybrominated Biphenyls / Q000633:toxicity*; D011487:Protein Conformation; D011944:Receptors, Androgen / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014158:Transcription, Genetic; D015003:Yeasts / Q000187:drug effects
D059002:Androgen Receptor Antagonists; D052244:Endocrine Disruptors; D005411:Flame Retardants; D011075:Polybrominated Biphenyls; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; C020806:tetrabromobisphenol A
Androgen receptor; Endocrine disrupting chemical; Glucocorticoid receptor; In vitro assay; Tetrabromobisphenol A; Toxicity
Toxicol In Vitro. 2001 Aug-Oct;15(4-5):413-9
11566572
Environ Health Perspect. 2001 Mar;109(3):245-51
11333185
Environ Health Perspect. 1999 Jul;107(7):593-7
10379007
Regul Toxicol Pharmacol. 2016 Jun;77:143-59
26828025
J Toxicol Environ Health A. 2009;72(21-22):1431-8
20077215
Basic Clin Pharmacol Toxicol. 2005 Apr;96(4):309-15
15755314
Toxicol Pathol. 2015 Jun;43(4):464-73
25476797
Lancet Oncol. 2016 Apr;17(4):419-420
26928709
Environ Health Perspect. 1985 Feb;59:31-6
3921360
Environ Res. 1999 Aug;81(2):108-16
10433842
Brain Res Dev Brain Res. 2004 Jul 19;151(1-2):1-12
15246687
Mol Biol Cell. 1992 Nov;3(11):1245-57
1457829
J Chem Inf Model. 2005 Jan-Feb;45(1):160-9
15667141
J Immunotoxicol. 2009 Dec;6(4):285-92
19908946
N Engl J Med. 2006 Nov 23;355(21):2226-35
17124020
Toxicol Appl Pharmacol. 1997 Mar;143(1):205-12
9073609
J Mol Biol. 1997 Apr 4;267(3):727-48
9126849
Arch Toxicol. 2016 Jul;90(7):1695-707
26302867
Cell Biol Toxicol. 2014 Dec;30(6):345-60
25341744
EFSA J. 2024 Jul 15;22(7):e8859
39010865
Arch Toxicol. 2014 Mar;88(3):553-73
24352537
Chemosphere. 2006 Jun;64(2):187-208
16434081
Toxicol Sci. 2013 Dec;136(2):382-91
24014645
Environ Sci Technol. 2014;48(15):8706-16
24960280
Food Chem Toxicol. 2015 Jun;80:206-214
25818463
Environ Health Perspect. 1985 May;60:225-32
2992922
J Invest Dermatol. 2013 Feb;133(2):361-70
22951731
Environ Health Perspect. 1998 Dec;106(12):769-72
9831536
Toxicol Sci. 2007 Apr;96(2):237-45
17234645
J Mol Biol. 2010 Jan 22;395(3):568-77
19913032
PLoS One. 2008;3(10):e3545
18958157
EMBO J. 2003 Mar 3;22(5):1158-67
12606580
Toxicol Sci. 2006 Jul;92(1):157-73
16601080
Chemosphere. 2002 Feb;46(5):709-16
11999794
Crit Rev Toxicol. 2015 Mar;45(3):245-72
25629923
Ann Nutr Metab. 2015;66 Suppl 1:8-16
25925336
Toxicol Sci. 2006 May;91(1):49-58
16481339
Toxicol Sci. 2007 Apr;96(2):268-78
17205976
J Appl Toxicol. 2014 May;34(5):498-505
23765520
Proc Natl Acad Sci U S A. 1995 May 9;92(10):4701-5
7753868
Mol Endocrinol. 2004 Jul;18(7):1620-30
15071092
Toxicology. 2015 Mar 2;329:10-20
25576683
Sci Rep. 2012;2:937
23226835
Biochem Pharmacol. 2008 Nov 15;76(10):1184-93
18765234
Gene. 1990 Feb 14;86(2):257-61
2108906
J Steroid Biochem Mol Biol. 2006 Dec;102(1-5):222-31
17045799
Toxicol Sci. 2005 Jan;83(1):89-100
15456914
Environ Health. 2012 Nov 14;11:86
23151181
J Clin Endocrinol Metab. 2002 Mar;87(3):1142-50
11889178
Environ Health Perspect. 2013 Oct;121(10):1194-9
23959441
PLoS One. 2012;7(10):e46958
23056542
J Steroid Biochem Mol Biol. 2010 May 31;120(2-3):69-75
20346397
J Biol Chem. 1994 Oct 7;269(40):24983-8
7929182
Mol Endocrinol. 2013 Mar;27(3):394-406
23340252
Environ Sci Technol. 2014 Nov 4;48(21):12902-11
25269596