Cellular Mechanism of the Nonmonotonic Dose Response of Bisphenol A in Rat Cardiac Myocytes

BACKGROUND: The need for mechanistic understanding of nonmonotonic dose responses has been identified as one of the major data gaps in the study of bisphenol A (BPA). Previously we reported that acute exposure to BPA promotes arrhythmogenesis in female hearts through alteration of myocyte Ca(2+) handling, and that the dose response of BPA was inverted U-shaped. OBJECTIVE: We sought to define the cellular mechanism underlying the nonmonotonic dose response of BPA in the heart. METHODS: We examined rapid effects of BPA in female rat ventricular myocytes using video-edge detection, confocal and conventional fluorescence imaging, and patch clamp. RESULTS: The rapid effects of BPA in cardiac myocytes, as measured by multiple end points, including development of arrhythmic activities, myocyte mechanics, and Ca(2+) transient, were characterized by nonmonotonic dose responses. Interestingly, the effects of BPA on individual processes of myocyte Ca(2+) handling were monotonic. Over the concentration range of 10(-12) to 10(-6) M, BPA progressively increased sarcoplasmic reticulum (SR) Ca(2+) release and Ca(2+) reuptake and inhibited the L-type Ca(2+) current (I(CaL)). These effects on myocyte Ca(2+) handling were mediated by estrogen receptor (ER) β signaling. The nonmonotonic dose responses of BPA can be accounted for by the combined effects of progressively increased SR Ca(2+) reuptake/release and decreased Ca(2+) influx through I(CaL). CONCLUSION: The rapid effects of BPA on female rat cardiac myocytes are characterized by nonmonotonic dose responses as measured by multiple end points. The nonmonotonic dose response was produced by ERβ-mediated monotonic effects on multiple cellular Ca(2+) handling processes. This represents a distinct mechanism underlying the nonmonotonicity of BPA's actions.