Divergent Mechanisms Leading to Signaling Dysfunction in Embryonic Muscle by Bisphenol A and Tetrabromobisphenol A

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 (V_m). 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 caused V_m depolarization. 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-induced V_m hyperpolarization. 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.