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Environ Health Perspect. 2014 Jun;122(6):601-8. doi: 10.1289/ehp.1307491. Epub 2014 Feb 25.

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

Author information

1
Department of Cardiology, Second Affiliated Hospital of Nanchang University, Nanchang, China.

Abstract

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.

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(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).

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.

PMID:
24569941
PMCID:
PMC4050515
DOI:
10.1289/ehp.1307491
[Indexed for MEDLINE]
Free PMC Article

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