title: Structural bisphenol analogues differentially target steroidogenesis in murine MA-10 Leydig cells as well as the glucocorticoid receptor.
abstract: Although much information on the endocrine activity of bisphenol A (BPA) is available, a proper human hazard assessment of analogues that are believed to have a less harmful toxicity profile is lacking. Here the possible effects of BPA, bisphenol F (BPF), bisphenol S (BPS), as well as the brominated structural analogue and widely used flame retardant tetrabromobisphenol A (TBBPA) on human glucocorticoid and androgen receptor (GR and AR) activation were assessed. BPA, BPF, and TBBPA showed clear GR and AR antagonism with IC50 values of 67 μM, 60 μM, and 22 nM for GR, and 39 μM, 20 μM, and 982 nM for AR, respectively, whereas BPS did not affect receptor activity. In addition, murine MA-10 Leydig cells exposed to the bisphenol analogues were assessed for changes in secreted steroid hormone levels. Testicular steroidogenesis was altered by all bisphenol analogues tested. TBBPA effects were more directed towards the male end products and induced testosterone synthesis, while BPF and BPS predominantly increased the levels of progestagens that are formed in the beginning of the steroidogenic pathway. The MA-10 Leydig cell assay shows added value over the widely used H295R steroidogenesis assay because of its fetal-like characteristics and specificity for the physiologically more relevant testicular Δ4 steroidogenic pathway. Therefore, adding an in vitro assay covering fetal testicular steroidogenesis, such as the MA-10 cell line, to the panel of tests used to screen potential endocrine disruptors, is highly recommendable.
authors.affiliation: Endocrine Toxicology Research Group, Institute for Risk Assessment Sciences (IRAS), Utrecht University, P.O. Box 80.177, NL-3508 TD Utrecht, The Netherlands; Center for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven, The Netherlands. Electronic address: m.j.e.roelofs@uu.nl.
authors.forename: Maarke J E
authors.initials: MJ
authors.lastname: Roelofs
authors.affiliation: Endocrine Toxicology Research Group, Institute for Risk Assessment Sciences (IRAS), Utrecht University, P.O. Box 80.177, NL-3508 TD Utrecht, The Netherlands.
authors.forename: Martin
authors.initials: M
authors.lastname: van den Berg
authors.affiliation: RIKILT-Institute of Food Safety, Wageningen University and Research Centre, Akkermaalsbos 2, 6708 WB Wageningen, The Netherlands.
authors.forename: Toine F H
authors.initials: TF
authors.lastname: Bovee
authors.affiliation: Center for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven, The Netherlands; Endocrine Toxicology Research Group, Institute for Risk Assessment Sciences (IRAS), Utrecht University, P.O. Box 80.177, NL-3508 TD Utrecht, The Netherlands.
authors.forename: Aldert H
authors.initials: AH
authors.lastname: Piersma
authors.affiliation: Endocrine Toxicology Research Group, Institute for Risk Assessment Sciences (IRAS), Utrecht University, P.O. Box 80.177, NL-3508 TD Utrecht, The Netherlands.
authors.forename: Majorie B M
authors.initials: MB
authors.lastname: van Duursen
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000633:toxicity*; D001681:Biological Assay; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D052244:Endocrine Disruptors / Q000633:toxicity; D015870:Gene Expression; D007985:Leydig Cells / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D010636:Phenols / Q000633:toxicity*; D011075:Polybrominated Biphenyls / Q000633:toxicity; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D013450:Sulfones / Q000633:toxicity; D013737:Testis / Q000187:drug effects / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism; D015003:Yeasts / Q000378:metabolism; D000098831:Bisphenol S Compounds; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D052244:Endocrine Disruptors; D010636:Phenols; D011075:Polybrominated Biphenyls; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D013450:Sulfones; D013739:Testosterone; C543008:bisphenol S; D000098831:Bisphenol S Compounds; C020806:tetrabromobisphenol A; C006780:bisphenol A; D000098826:Bisphenol A Compounds
keywords: (Fetal-like) steroidogenesis; (Structural) bisphenol analogues (TBBPA, BPA, BPF, BPS); Androgen receptor (AR); Glucocorticoid receptor (GR); Murine MA-10 Leydig cells; Testosterone (T)