title: Tetrabromobisphenol A (TBBPA), induces cell death in TM4 Sertoli cells by modulating Ca2+ transport proteins and causing dysregulation of Ca2+ homeostasis.
abstract: Tetrabromobisphenol A (TBBPA) is a commonly used brominated flame retardant (BFR) utilized to reduce the flammability of a variety of products. Studies have indicated that a number of BFRs are becoming widely distributed within the environment and are bio-accumulating within organisms. There has been much speculation that a variety of phenolic pollutants (including compounds chemically related to TBBPA, such as bisphenol A) may cause endocrine disruption and Ca2+ dysregulation in cells involved in spermatogenesis. In this study we therefore investigate the effects of TBBPA on mouse TM4 Sertoli cells (essential for sperm development). Results show that TBBPA increases Ca2+ within these cells in the 5-60 microM concentration range (EC50, 21 microM). TBBPA also causes cell death (LC50, 18 microM) partly via apoptosis, involving Ca2+-dependent mitochondrial depolarisation. Studies on intracellular Ca2+ transporters shows that TBBPA can inhibit sarcoplasmic/endoplasmic reticulum Ca2+-ATPases (SERCA) at low concentrations (IC50, 0.4 to 1.2 microM) and also activate the Ryanodine receptor Ca2+ channel within the 0.4-4 microM concentration range. Therefore these studies suggest that the cytotoxic effects of TBBPA on cells is partly due to dysregulation of Ca2+ signalling, by directly affecting Ca2+ transport proteins.
authors.affiliation: School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: Oluseye A
authors.initials: OA
authors.lastname: Ogunbayo
authors.forename: Pei F
authors.initials: PF
authors.lastname: Lai
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Connolly
authors.forename: Francesco
authors.initials: F
authors.lastname: Michelangeli
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005411:Flame Retardants / Q000008:administration & dosage / Q000633:toxicity*; D006706:Homeostasis / Q000187:drug effects; D007928:Lethal Dose 50; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D011075:Polybrominated Biphenyls / Q000008:administration & dosage / Q000633:toxicity*; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects* / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors*; D012708:Sertoli Cells / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D005411:Flame Retardants; D011075:Polybrominated Biphenyls; D019837:Ryanodine Receptor Calcium Release Channel; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C020806:tetrabromobisphenol A; D002118:Calcium