title: Organophosphate Flame Retardants Act as Endocrine-Disrupting Chemicals in MA-10 Mouse Tumor Leydig Cells.
abstract: The organophosphate flame retardants (OPFRs) have emerged as alternatives to banned brominated flame retardants but little is known about their possible activity as endocrine disruptors. Our goal was to compare the effects of 7 commonly used OPFRsin vitroon MA-10 mouse Leydig tumor cells to those of a major brominated flame retardant, 2,2',4,4'-tetrabromodiphenyl ether (BDE-47). The effects of OPFRs and BDE-47 on mitochondrial activity, cell counts, oxidative stress, steroid secretion and gene expression were investigated. BDE-47 and all 7 OPFRs tested significantly reduced MA-10 cell mitochondrial activity (concentrations ≥50 μM) and cell number (concentrations ≥10 μM). All of the OPFRs significantly increased (10 μM, 1.7-4.4-fold) superoxide production whereas BDE-47 had no significant effect. Basal progesterone production was significantly increased (10 μM, 1.5 to 3-fold) by 2-ethylhexyl diphenyl phosphate, isodecyl diphenyl phosphate, isopropylated triphenyl phosphate, tert-butylphenyl diphenyl phosphate, and tricresyl phosphate, while BDE-47, triphenyl phosphate and tri-o-cresyl phosphate had no effect. Interestingly, isopropylated triphenyl phosphate enhanced dbcAMP-stimulated steroid production (∼2-fold), while tri-o-cresyl phosphate decreased (∼2/3) LH-stimulated steroid production. Several OPFRs affected the expression of genes involved in the biosynthesis of progesterone. In conclusion, all the OPFRs tested affected mitochondrial activity, cell survival, and superoxide production. Basal or stimulated steroid secretion was affected by all of the OPFRs except triphenyl phosphate; BDE-47 had no effect. Hence, the OPFRs currently used as alternatives affect Leydig cells to a greater extent than the brominated flame retardants that they have replaced.
authors.affiliation: *Department of Pharmacology and Therapeutics and.
authors.forename: Gauthier
authors.initials: G
authors.lastname: Schang
authors.affiliation: *Department of Pharmacology and Therapeutics and Department of Obstetrics and Gynecology, McGill University, Montreal, Quebec H3G 1Y6, Canada bernard.robaire@mcgill.ca.
authors.forename: Bernard
authors.initials: B
authors.lastname: Robaire
authors.affiliation: *Department of Pharmacology and Therapeutics and.
authors.forename: Barbara F
authors.initials: BF
authors.lastname: Hales
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D052244:Endocrine Disruptors / Q000737:chemistry / Q000633:toxicity*; D005411:Flame Retardants / Q000633:toxicity*; D007985:Leydig Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010755:Organophosphates / Q000737:chemistry / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D011374:Progesterone / Q000096:biosynthesis; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D052244:Endocrine Disruptors; D005411:Flame Retardants; D010755:Organophosphates; D011374:Progesterone; D013482:Superoxide Dismutase
keywords: BFRs.; flame retardants; oxidative stress; replacement chemicals; steroidogenesis