摘要：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 Ca2+ 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 Ca2+ transient, were characterized by nonmonotonic dose responses. Interestingly, the effects of BPA on individual processes of myocyte Ca2+ handling were monotonic. Over the concentration range of 10–12 to 10–6 M, BPA progressively increased sarcoplasmic reticulum (SR) Ca2+ release and Ca2+ reuptake and inhibited the L-type Ca2+ current (ICaL). These effects on myocyte Ca2+ 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 Ca2+ reuptake/release and decreased Ca2+ influx through ICaL. 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 Ca2+ handling processes. This represents a distinct mechanism underlying the nonmonotonicity of BPA’s actions. Citation: Liang Q, Gao X, Chen Y, Hong K, Wang HS. 2014. Cellular mechanism of the nonmonotonic dose response of bisphenol A in rat cardiac myocytes. Environ Health Perspect 122:601–608; http://dx.doi.org/10.1289/ehp.1307491
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