Bisphenol S rapidly depresses heart function through estrogen receptor-β and decreases phospholamban phosphorylation in a sex-dependent manner

Abstract

The health effects of the endocrine disruptor Bisphenol A (BPA) led to its partial replacement with Bisphenol S (BPS) in several products including food containers, toys, and thermal paper receipts. The acute effects of BPS on myocardial contractility are unknown. We perfused mouse hearts from both sexes for 15 min with physiologically relevant doses of BPS or BPA. In females BPS (1 nM) decreased left ventricular systolic pressure by 5 min, whereas BPA (1 nM) effects were delayed to 10 min. BPS effects in male mice were attenuated. In both sexes ER-β antagonism abolished the effects of BPS. Cardiac myofilament function was not impacted by BPS or BPA in either sex, although there were sex-dependent differences in troponin I phosphorylation. BPS increased phospholamban phosphorylation at S16 only in female hearts, whereas BPA reduced phosphorylation in both sexes. BPA decreased phospholamban phosphorylation at T17 in both sexes while BPS caused dephosphorylation only in females. This is the first study to compare sex differences in the acute myocardial response to physiologically relevant levels of BPS and BPA, and demonstrates a rapid ability of both to depress heart function. This study raises concerns about the safety of BPS as a replacement for BPA.

Bisphenol-S and Bisphenol-F alter mouse pancreatic β-cell ion channel expression and activity and insulin release through an estrogen receptor ERβ mediated pathway

“…Acute 219 treatment with BPS induced a rapid increase in heart rate in response to catecholamines (Gao et 220 al., 2015). BPS also rapidly depressed left ventricular contraction and myocyte contractility 221 (Ferguson et al, 2019). In both cases, the ERβ antagonist PHTPP abolished BPS actions, 222…”

Bisphenols and phthalates: Plastic chemical exposures can contribute to adverse cardiovascular health outcomes

“…Future areas of interest include: (a) epidemiological or clinical research with additional cardiovascular endpoints—including electrocardiogram or echocardiogram measurements; (b) clinical and experimental work that focuses on vulnerable patient populations—including those with congenital heart defects, cardiomyopathies, or cardiac arrhythmias, as chemical exposures may contribute to cardiovascular dysfunction; (c) clinical and experimental work focused on neonatal, infant and pediatric populations—as cardiac, autonomic and metabolic systems continue to develop and mature after birth; (d) use of (nonrodent) experimental models that better replicate human electrophysiology; (e) studies that explore the effects of bisphenol and phthalate mixtures (or studies that take into account a pediatric patient's “exposome”); and finally, (f) comparative studies that examine the cardiac safety profile of alternative chemicals. The latter is particularly important as we move toward adopting BPA and DEHP substitutes, without a thorough understanding of their safety or impact on cardiovascular health (M. Ferguson, Lorenzen‐Schmidt, & Pyle, 2019; Gao, Ma, Chen, & Wang, 2015; Lozano & Cid, 2013; Trasande, 2017; van der Meer et al, 2014). Through comprehensive examination of bisphenol and phthalate toxicity in vulnerable populations, protective measures or mitigation strategies may be revealed and implemented.…”

Bisphenol S and bisphenol F are less disruptive to cardiac electrophysiology and potentially safer for use in medical products, as compared to bisphenol A

“…Notably, the same group has reported nearly identical effects with BPA-treatment, which suggest that the two chemicals may act via a common mechanism (Yan et al 2011). In a separate study by Ferguson, et al, BPS or BPA-treatment rapidly reduced mechanical function in heart preparations, but slightly different post-translational modifications were observed in myofilament proteins (Ferguson et al 2019). Investigations into the cardiac effects of BPF are even more limited, with a single report noting a decrease in the heart rate of zebrafish following BPF-exposure (Mu et al 2019).…”

“…Unfortunately, many of these alternative chemicals are considered ‘regrettable substitutions’, as BPS and BPF may exert biological effects that are similar to BPA (Kojima et al 2019; Moon 2019; Trasande 2017). To date, it is unclear whether BPA alternatives offer a superior cardiac safety profile, as recent work suggests that BPS and BPF may also impair cardiac function (Ferguson et al 2019; Gao et al 2015; Mu et al 2019). Recent biomonitoring studies have observed an uptick in BPS and BPF exposure in the general population as BPA is phased out and replaced (Lehmler et al 2018), which highlights the urgent need to investigate the impact of BPA analogues on cardiac health.…”