Cardiac Consequences of Xenoestrogen Exposure: Interaction between Bisphenol Chemicals and the Myocardium
Open AccessCardiovascular disease is the leading cause of death in the United States for both men and women, and environmental contaminants and endocrine-disrupting chemicals are often overlooked risk factors. One such chemical, bisphenol A (BPA), is used to manufacture polycarbonate plastics – and human exposure to BPA can occur daily, with biomonitoring studies detecting BPA in >90% of the general population. Of concern, BPA was recently associated with a 46% increased risk of cardiovascular mortality. In response, a few structurally similar bisphenol chemicals have been introduced as replacements, including bisphenol s (BPS) and bisphenol f (BPF). However, it remains unclear how these estrogenic chemicals exert adverse effects on cardiac electrophysiology, and to what extent the outcomes of exposure are modulated by intrinsic cardiac differences. This dissertation aims to elucidate the interaction between baseline cardiac physiology and the effect of xenoestrogen exposures on cardiac function. The presented research is focused on two specific aims: 1) investigating the cardiotoxicity of environmental xenoestrogens (i.e., bisphenols) and comparing their potency to estradiol in vitro, and 2) evaluating the impact of bisphenols using an integrative whole heart model ex vivo. In Aim 1, we utilized whole-cell voltage clamp recordings and human induced pluripotent stem cell-derived cardiomyocytes to identify mechanistic explanations for bisphenol-induced cardiotoxicity. In Aim 2, we utilized intact rat and guinea pig hearts to ascertain effects on electrophysiology in 3D tissue, while also examining the influence of intrinsic demographic (i.e., sex and age) differences. Collectively, this dissertation work suggests that BPA inhibits key cardiac ion channels and impairs cardiac excitability similarly to supraphysiological estrogen in human cardiomyocytes, albeit likely through a distinct mechanism. The cardiotoxicity profile of BPA is dependent on baseline characteristics and experimental model type. Notably, BPA exerts concentration-dependent effects on cardiac electrophysiology (largely at micromolar doses), but BPS did not affect any tested parameter – indicating it may be a safer alternative. Accordingly, we propose additional considerations for future work to comprehensively address the additive cardiotoxicity of bisphenol chemicals. This research underscores the sensitivity of translational models and adds to the growing body of evidence informing regulatory considerations in medical device and plastic manufacturing.
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