Cellular Mechanism of the Nonmonotonic Dose Response of Bisphenol A in Rat Cardiac Myocytes
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Citation: Liang Q, Gao X, Chen Y, Hong K, Wang HS. Cellular Mechanism of the Nonmonotonic Dose Response of Bisphenol A in Rat Cardiac Myocytes. Environ Health Perspect; http://dx.doi.org/10.1289/ehp.1307491.
Received: 9 August 2013
Accepted: 21 February 2014
Advance Publication: 25 February 2014
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Background: The need for mechanistic understanding of non-monotonic dose responses was 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: To define the cellular mechanism underlying the non-monotonic dose response of BPA in the heart.
Methods: Rapid effects of BPA in female rat ventricular myocytes were examined 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 endpoints including development of arrhythmic activities, myocyte mechanics and Ca2+ transient, were characterized by non-monotonic 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 non-monotonic 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: BPA’s rapid effects on female rat cardiac myocytes are characterized by non-monotonic dose responses as measured by multiple endpoints. The non-monotonic dose response is produced by ERβ-mediated monotonic effects on multiple cellular Ca2+ handling processes. This represents a distinct mechanism underlying the non-monotonicity of BPA’s actions.
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