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

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  • معلومة اضافية
    • نبذة مختصرة :
      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. BOJECTIVE: 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. 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 [ABSTRACT FROM AUTHOR]