Background: Bisphenol S (BPS) has increasingly been used as a substitute for bisphenol A (BPA) in some “BPA-free” consumer goods and in thermal papers. Wide human exposure to BPS has been reported; however, the biological and potential toxic effects of BPS are poorly understood.

Objective: In this study, we sought to elucidate the sex-specific rapid effect of BPS in rat hearts and its underlying mechanism.

Methods: We examined the rapid effects of BPS in rat hearts using electrophysiology, confocal and conventional fluorescence imaging, and immunoblotting. Treatment was administered via acute perfusion of excised hearts or isolated cardiac myocytes.

Results: In female rat hearts acutely exposed to 10^–9 M BPS, the heart rate was increased; in the presence of catecholamine-induced stress, the frequency of ventricular arrhythmia events was markedly increased. BPS-exposed hearts showed increased incidence of arrhythmogenic-triggered activities in female ventricular myocytes and altered myocyte Ca²⁺ handling, particularly spontaneous Ca²⁺ release from the sarcoplasmic reticulum. The dose responses of BPS actions were inverted U-shaped. The impact of BPS on myocyte Ca²⁺ handling was mediated by estrogen receptor β signaling and by rapid increases in the phosphorylation of key Ca²⁺ handling proteins, including ryanodine receptor and phospholamban. The proarrhythmic effects of BPS were female specific; male rat hearts were not affected by BPS at the organ, myocyte, or protein levels.

Conclusion: Rapid exposure to low-dose BPS showed proarrhythmic impact on female rat hearts; these effects at the organ, cellular, and molecular levels are remarkably similar to those reported for BPA. Evaluation of the bioactivity and safety of BPS and other BPA analogs is necessary before they are used as BPA alternatives in consumer products.

Citation: Gao X, Ma J, Chen Y, Wang HS. 2015. Rapid responses and mechanism of action for low-dose bisphenol S on ex vivo rat hearts and isolated myocytes: evidence of female-specific proarrhythmic effects. Environ Health Perspect 123:571–578;  http://dx.doi.org/10.1289/ehp.1408679

Address correspondence to H.-S. Wang, Department of Pharmacology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0575 USA. Telephone: (513) 558-2379. E-mail: wanghs@uc.edu

This work was supported by the National Institutes of Health (grant R01-ES017262) and the University of Cincinnati Center for Environmental Genetics (grant P30-ES006096).

The authors declare they have no actual or potential competing financial interests.

Received: 12 May 2014 Accepted: 28 January 2015 Advance Publication: 26 February 2015 Final Publication: 1 June 2015