[OR33-3] Low-Dose Bisphenol-A Promotes Arrhythmogenesis in the Female Heart Via Alteration of Calcium Handling.

HS Wang, M Dong, Y Chen, SM Belcher, Pharmacology and Cell Biophys, Univ of Cincinnati, Cincinnati, OH

There is broad human exposure to the ubiquitous estrogenic pollutant bisphenol A (BPA). Despite increasing recognition that BPA can have harmful effects on the reproductive, nervous and immune systems, the effects of environmentally-relevant concentrations of BPA on the heart are unknown. Highlighting a critical need to understand the cardiac effects of BPA exposure, results of large-scale epidemiologic studies have recently demonstrated that higher urine BPA concentrations are associated with cardiovascular disease. Here we show that rapid exposure (5 min) to low-dose (10^-10 M) BPA or 17b-estradiol (E2) markedly increases the frequency of arrhythmogenic triggered activities in short-term cultured female rat ventricular myocytes. An inverted U-shaped dose response curve was observed for E2 and for BPA with each having maximal stimulatory effects at 10^-10 M. The effect of BPA on arrhythmogenesis was amplified in the presence of physiological levels of E2, strongly suggesting a synergistic pro-arrhythmic interaction between E2 and BPA. The effect of acute BPA exposure on whole heart was also examined using a work-performing model. In hearts from females, but not male rats, low-doses of BPA markedly increased the frequency of arrhythmia events. The cellular mechanism underlying the pro-arrhythmic effect of BPA was investigated using imaging techniques. BPA or E2 rapidly stimulated contractile properties and Ca transients in female, but not male myocytes, suggesting a sex-specific alteration of myocyte Ca handling. While sarcoplasmic reticulum (SR) Ca reuptake, SR Ca load, or Ca extrusion via the Na/Ca exchanger was not affected, BPA markedly increased the frequency of Ca sparks, indicating spontaneous Ca release from the SR. Such elevated spontaneous SR Ca release, or SR leak, plays an important role in arrhythmogenesis under various pathophysiological conditions. In conclusion, our results show that BPA exerts sex-specific, pro-arrhythmic effects on the female heart, and those effects are likely mediated by increases in the activity of the ryanodine receptors and Ca leak from the SR. These studies have identified new and important potential cardiac risks associated with BPA exposure, especially for women.

Supported by NIH grant awarded ES05145 to SMB and The UC Center for Environmental Genetics (P30-ES06096).

Date: Saturday, June 13, 2009
Session Info: ORAL SESSION: BASIC/TRANSLATIONAL - The Widespread Disruption of Endocrine Signaling (1:15 PM-2:30 PM)
Presentation Time: 1:15 PM
Room: 144A