Bisphenol A and 17β-Estradiol Promote Arrhythmia in the Female Heart via Alteration of Calcium Handling

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.

Rapid Estrogen Receptor-Mediated Mechanisms Determine the Sexually Dimorphic Sensitivity of Ventricular Myocytes to 17β-Estradiol and the Environmental Endocrine Disruptor Bisphenol A

“…However, the effect of BPA on the heart, an estrogen-sensitive system, remained unknown until recently. We have demonstrated that exposure to nanomolar BPA and/or E 2 rapidly induced arrhythmogenic triggered activities and promoted the development of ventricular arrhythmias in female rat hearts (11). The proarrhythmic effect of BPA was more pronounced in the presence of physiological concentrations of E 2 and was augmented by ␤-adrenergic stress.…”

“…Gonadectomy surgery was performed by the vendor, and gonadectomized rats were received from the vendor and used 2 wk after surgery. Animals were housed as previously described (11). Sani-chip bedding (Irradiated Aspen Sani-chip; P.J.…”

Low dose effects of bisphenol A

“…[60][61][62] Overall, these in vitro studies have examined a large number of cell types and biological endpoints that may be relevant to cellular function in vivo. The low dose cut-off of 1 × 10 -7 M has been debated and it may be reasonable to shift the low dose cut-off for in vitro studies to 10 One final study deserves attention due to its use of Organization for Economic Cooperation and Development (OECD) guidelines to test the effects of BPA on histopathological changes in the ovary.…”

Need for Regulatory Policies in India, on the Use of Bisphenol a in Food Contact Plastic Containers

“…The potential endocrine disrupting effects of BPA was first recognized in 1997 (refs 15-17). Thereafter, several studies also provided evidence on the endocrine disrupting action of BPA [18][19][20][21][22][23][24][25][26][27][28] . BPA is similar in function to the natural hormone 17-estradiol and binds mainly to the estrogen receptor (ER) to exhibit estrogenic activities 29,30 .…”