Cellular mechanism of the nonmonotonic dose response of bisphenol a in rat cardiac myocytes

INTRODUCTION Bisphenol A (BPA; CAS 80-05-7) is one of the highest production volume chemicals worldwide, with annual production exceeding 3 million metric tons. BPA is used in the production of [...]
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.sup.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.sup.2+] transient, were characterized by nonmonotonic dose responses. Interestingly, the effects of BPA on individual processes of myocyte [Ca.sup.2+] handling were monotonic. Over the concentration range of [10.sup.-12] to [10.sup.-6] M, BPA progressively increased sarcoplasmic reticulum (SR) [Ca.sup.2+] release and [Ca.sup.2+] reuptake and inhibited the L-type [Ca.sup.2+] current ([I.sub.CaL]). These effects on myocyte [Ca.sup.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.sup.2+] reuptake/release and decreased [Ca.sup.2+] influx through [I.sub.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.sup.2+] handling processes. This represents a distinct mechanism underlying the nonmonotonicity of BPA's actions. http://dx.doi.org/10.1289/ehp.1307491