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.
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.
Methods
We examined rapid effects of BPA in female rat ventricular myocytes using video-edge detection, confocal and conventional fluorescence imaging, and patch clamp.
Objective
We sought to define the cellular mechanism underlying the nonmonotonic dose response of BPA in the heart.
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).