title: Divergent Mechanisms Leading to Signaling Dysfunction in Embryonic Muscle by Bisphenol A and Tetrabromobisphenol A.
abstract: Bisphenol A (BPA) and its brominated derivative tetrabromobisphenol A (TBBPA) are high production volume chemicals used in the manufacture of various consumer products. Although regarded as endocrine disruptors, these chemicals are suspected to exert nongenomic actions on muscle function that are not well understood. Using skeletal muscle microsomes, we examined the effects of BPA and TBBPA on ryanodine receptor type 1 (RyR1), dihydropyridine receptor (DHPR), and sarcoplasmic/endoplasmic reticulum Ca2+ATPase (SERCA). We assessed the impact of these chemicals on Ca2+dynamics and signaling in embryonic skeletal myotubes through fluorescent Ca2+imaging and measurement of resting membrane potential (Vm). TBBPA activated RyR1 and inhibited DHPR and SERCA, inducing a net efflux of Ca2+from loaded microsomes, whereas BPA exhibited little or no activity at these targets. Regardless, both compounds disrupted the function of intact myotubes. TBBPA diminished and eventually abrogated Ca2+transients, altered intracellular Ca2+equilibrium, and causedVmdepolarization. For some cells, BPA caused rapid Ca2+transient loss without marked changes in cytosolic and sarcoplasmic reticulum Ca2+levels, likely owing to altered cellular excitability as a result of BPA-inducedVmhyperpolarization. BPA and TBBPA both interfere with skeletal muscle function through divergent mechanisms that impair excitation-contraction coupling and may be exemplary of their adverse outcomes in other muscle types.
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis (R.Z., I.N.P.), and The Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, Sacramento (I.N.P.), California ruizhang@ucdavis.edu.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis (R.Z., I.N.P.), and The Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, Sacramento (I.N.P.), California.
authors.forename: Isaac N
authors.initials: IN
authors.lastname: Pessah
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D056966:Excitation Contraction Coupling / Q000187:drug effects; D005453:Fluorescence; D006706:Homeostasis / Q000187:drug effects; D008297:Male; D051379:Mice; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism*; D010636:Phenols / Q000494:pharmacology*; D011075:Polybrominated Biphenyls / Q000494:pharmacology*; D011817:Rabbits; D011869:Radioligand Assay; D012433:Ryanodine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014260:Triclosan / Q000494:pharmacology; D014316:Tritium; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D002118:Calcium; D010636:Phenols; D011075:Polybrominated Biphenyls; D012433:Ryanodine; D014260:Triclosan; D014316:Tritium; C020806:tetrabromobisphenol A; C006780:bisphenol A; D000098826:Bisphenol A Compounds