Impact of bisphenol structural analogues on cardiac electrophysiology and intracellular calcium handling
Authors: Cooper Blake , Salameh Shatha , Guerrelli Devon , Posnack Nikki 
Published: May 2023

Bisphenol A (BPA) is widely used to manufacture polycarbonate plastics and epoxy resins – and detected in greater than 90% of the US general population. Of concern, higher urinary BPA levels have been associated with a 46% higher cardiovascular mortality. There is sufficient evidence that BPA inhibits voltage-gated calcium channels, yet its estrogenic chemical structure points to more diverse endocrine disrupting properties. Manufacturers have shifted to replacement chemicals, such as bisphenol F (BPF) and bisphenol S (BPS), but these analogues may have comparable deleterious effects. This study aimed to investigate the underlying mechanisms of BPA’s impact on cardiac electrophysiology, using human cardiomyocytes exposed to pharmacological agents alone or in combination with BPA. We hypothesized that BPA exposure can alter the cardiac action potential and disrupt intracellular calcium handling more severely than BPF or BPS.Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) were cultured on a microelectrode array (MEA) system for electrical recordings. Separately, hiPSC-CM were loaded with potentiometric dye (FluoVolt) or calcium indicator dye (Fluo 4-AM) for assessment of optical action potentials and intracellular calcium cycling. Parameters were recorded at baseline and after acute (<20 min) treatment with chemical-supplemented media (10nM-100μM), in response to external pacing.Field potential duration (FPD), an analog for the QT interval, was significantly shorter after exposure to 30μM BPA (335 vs. 383 ms), BPF (344 vs. 395 ms), and estradiol (314 vs. 379 ms), as compared to vehicle control. Action potential duration (APD) and calcium transient duration (CaD) shortening was also observed for 30μM BPA, BPF, and estradiol, as compared to pre-treatment values. No change in FPD, APD, or CaD was observed for BPS. Pretreatment with a general estrogen receptor antagonist (ICI 182,780) exacerbated FPD shortening (278 ms) compared with BPA alone (299 ms), while treatment with an estrogen receptor β-specific agonist (diarylpropionitrile) resulted in a modest recovery of FPD (340 ms) compared with BPA alone (302 ms). Pre-treatment with an L-type calcium channel agonist (Bay K8644) fully recovered FPD to baseline levels (405 ms) compared with BPA alone (307 ms).Dose-dependent impairment of electrophysiology and calcium handling was observed in hiPSC-CM after exposure to BPA, aligning with previous findings that BPA exerts an inhibitory effect on the L-type calcium channel current. BPA shortened FPD and APD more severely than either BPF or BPS, but to a lesser extent than estradiol. This study characterized the effects of bisphenols on cardiac electrophysiology and expanded mechanistic insights using a clinically relevant model. These findings can inform regulatory decisions on the use of replacement chemicals and provide a detailed assessment of how bisphenol exposure may precipitate adverse cardiovascular outcomes. R01HD108839 to NGP, F31HL162549 to BC This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.