Abstract
BackgroundThere is wide-spread human exposure to bisphenol A (BPA), a ubiquitous estrogenic endocrine disruptor that has been implicated as having potentially harmful effects on human heart health. Higher urine BPA concentrations have been shown to be associated with cardiovascular diseases in humans. However, neither the nature nor the mechanism(s) of BPA action on the heart are understood.Methodology/Principal FindingsThe rapid (<7 min) effects of BPA and 17β-estradiol (E2) in the heart and ventricular myocytes from rodents were investigated in the present study. In isolated ventricular myocytes from young adult females, but not males, physiological concentrations of BPA or E2 (10−9 M) rapidly induced arrhythmogenic triggered activities. The effects of BPA were particularly pronounced when combined with estradiol. Under conditions of catecholamine stimulation, E2 and BPA promoted ventricular arrhythmias in female, but not male, hearts. The cellular mechanism of the female-specific pro-arrhythmic effects of BPA and E2 were investigated. Exposure to E2 and/or BPA rapidly altered myocyte Ca2+ handling; in particular, estrogens markedly increased sarcoplasmic reticulum (SR) Ca2+ leak, and increased SR Ca2+ load. Ryanodine (10−7 M) inhibition of SR Ca2+ leak suppressed estrogen-induced triggered activities. The rapid response of female myocytes to estrogens was abolished in an estrogen receptor (ER) β knockout mouse model.Conclusions/SignificancePhysiologically-relevant concentrations of BPA and E2 promote arrhythmias in a female-specific manner in rat hearts; the pro-arrhythmic actions of estrogens are mediated by ERβ-signaling through alterations of myocyte Ca2+ handling, particularly increases in SR Ca2+ leak. Our study provides the first experimental evidence suggesting that exposure to estrogenic endocrine disrupting chemicals and the unique sensitivity of female hearts to estrogens may play a role in arrhythmogenesis in the female heart.
Highlights
Estrogenic endocrine disrupting chemicals (EDCs) are a structurally diverse group of compounds that mimic, or antagonize the effects of endogenous estrogens
Endogenous estrogens are well recognized to play important roles in the regulation and maintenance of sex-specific differences in cardiac physiology and pathophysiology; little is known about the cardiac effects of environmental estrogenic EDCs, such as the ubiquitous bisphenol A (BPA), and their interactions with endogenous estrogens
We show that physiologically-relevant concentrations of BPA and E2 have female-specific pro-arrhythmic effects in rodent cardiac myocytes and whole hearts
Summary
Estrogenic endocrine disrupting chemicals (EDCs) are a structurally diverse group of compounds that mimic, or antagonize the effects of endogenous estrogens. A significant example of estrogenic EDCs to human health is the nearly ubiquitous xenoestrogen bisphenol A (BPA). BPA is structurally similar to the potent non-steroidal synthetic estrogen diethylstilbestrol. As one of the highest produced synthetic chemicals worldwide, BPA is used extensively in the production of polycarbonate plastic and epoxy resins that are found in a wide range of consumer products such as food containers, food cans, water bottles, baby bottles, dental sealants and water pipes. Bioactive BPA is released from epoxy resins and polycarbonate food and beverage containers, especially after exposure to elevated temperatures [1]. There is wide-spread human exposure to bisphenol A (BPA), a ubiquitous estrogenic endocrine disruptor that has been implicated as having potentially harmful effects on human heart health. Higher urine BPA concentrations have been shown to be associated with cardiovascular diseases in humans. Neither the nature nor the mechanism(s) of BPA action on the heart are understood
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