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Advance Publication

Environ Health Perspect; DOI:10.1289/ehp.1307491

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

Qian Liang,1,2 Xiaoqian Gao,2 Yamei Chen,2 Kui Hong,1 and Hong-Sheng Wang
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1Department of Cardiology, Second Affiliated Hospital of Nanchang University, Nanchang, China; 2Department of Pharmacology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
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This EHP Advance Publication article has been peer-reviewed, revised, and accepted for publication. EHP Advance Publication articles are completely citable using the DOI number assigned to the article. This document will be replaced with the copyedited and formatted version as soon as it is available. Through the DOI number used in the citation, you will be able to access this document at each stage of the publication process.

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;

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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