Proarrhythmic toxicity of low dose bisphenol A and its analogs in human iPSC-derived cardiomyocytes and human cardiac organoids through delay of cardiac repolarization

Ma, Jianyong; Wang, Nathan Y; Jagani, Ravikumar; Wang, Hongsheng

doi:10.1016/j.chemosphere.2023.138562

Cited by 16 publications

(6 citation statements)

References 83 publications

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“…Although the reported potency of BPA on L-type calcium channels does vary across models, ranging from ~16.5% at 1 nM BPA in hiPSC-CM, ~12% at 10 nM in rat ventricular cardiomyocytes, and ~10% at 5 μM BPA in transfected cell lines (Liang et al 2014;Ma et al 2023b;Prudencio et al 2021). As expected with calcium channel inhibitors, we found that both BPA and E2 hasten repolarization by shortening the APD and FPD in hiPSC-CM in a dose-dependent manner, which aligns with previous work (Hyun et al 2021;Jiang et al 1992;Prudencio et al 2021).…”

Section: Discussionmentioning

confidence: 99%

“…Potential mechanisms underlying the effects on calcium handling and contractility include the phosphorylation of key calcium handling proteins (Gao et al 2013; Liang et al 2014), and/or the inhibition of inward calcium current (Deutschmann et al 2013; Hyun et al 2021; Jiang et al 1992; Liang et al 2014; Meyer et al 1998; Prudencio et al 2021). Although the reported potency of BPA on L-type calcium channels does vary across models, ranging from ∼16.5% at 1 nM BPA in hiPSC-CM, ∼12% at 10 nM in rat ventricular cardiomyocytes, and ∼10% at 5 μM BPA in transfected cell lines (Liang et al 2014; Ma et al 2023b; Prudencio et al 2021). As expected with calcium channel inhibitors, we found that both BPA and E2 hasten repolarization by shortening the APD and FPD in hiPSC-CM in a dose-dependent manner, which aligns with previous work (Hyun et al 2021; Jiang et al 1992; Prudencio et al 2021).…”

Section: Discussionmentioning

confidence: 99%

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Comparative cardiotoxicity assessment of bisphenol chemicals and estradiol using human induced pluripotent stem cell-derived cardiomyocytes

Cooper,

Salameh,

Posnack

2023

Preprint

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Background: Bisphenol A (BPA) is commonly used to manufacture consumer and medical grade plastics. Due to health concerns, BPA substitutes are being incorporated, including bisphenol S (BPS) and bisphenol F (BPF), without a comprehensive understanding of their toxicological profile. Objective: Previous studies suggest that bisphenol chemicals perturb cardiac electrophysiology in a manner that is similar to beta estradiol (E2). We aimed to compare the effects of E2 with BPA, BPF, and BPS using human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM). Methods: Cardiac parameters were evaluated using microelectrode array (MEA) technology and live cell fluorescent imaging at baseline and in response to chemical exposure (0.001-100 uM). Results: Cardiac metrics remained relatively stable after exposure to nanomolar concentrations (1-1,000 nM) of E2, BPA, BPF, or BPS. At higher micromolar concentrations, chemical exposures resulted in a decrease in the depolarizing spike amplitude, shorter field potential and action potential duration, shorter calcium transient duration, and decrease in hiPSC-CM contractility (E2 > BPA > BPF >> BPS). Cardiomyocyte physiology was largely undisturbed by BPS exposure. BPA induced effects were exaggerated when co-administered with an L-type calcium channel antagonist (verapamil) or E2, and reduced when co-administered with an L type calcium channel agonist (Bay K8644) or an estrogen receptor alpha antagonist (MPP). E2 induced effects generally mirrored those of BPA, but were not exaggerated by coadministration with an L-type calcium channel antagonist. Discussion: Collectively across multiple cardiac endpoints, E2 was the most potent and BPS was the least potent disruptor of hiPSC-CM function. Although the observed cardiac effects of E2 and BPA were similar, a few distinct differences suggest that these chemicals may act (in part) through different mechanisms. hiPSC-CM are a useful model for screening cardiotoxic chemicals, nevertheless, the described in vitro findings should be validated using a more complex ex vivo and/or in vivo model.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Comparative cardiotoxicity assessment of bisphenol chemicals and estradiol using human induced pluripotent stem cell-derived cardiomyocytes

Cooper,

Salameh,

Posnack

2023

Preprint

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“…This innovative approach minimized cardiotoxicity in both hiPSC-CMs and cardiac spheroids while preserving doxorubicin’s anti-cancer effect. In addition to investigating the cardiotoxic effects induced by anti-cancer drugs, cardiac organoids have also recently become a vital tool in exploring the cardiotoxicity arising from environmental pollutants [ 127 ], [ 128 ], [ 129 ]. Following exposure to polystyrene microplastics with a dose equivalent to the exposure level in humans, cardiac organoids exhibited increased oxidative stress, inflammatory response, apoptosis, and collagen accumulation which were consistent with an in vivo study [ 128 ].…”

Section: Applications Of 3d Models In Cardiovascular Researchmentioning

confidence: 99%

The new era of cardiovascular research: revolutionizing cardiovascular research with 3D models in a dish

Yang,

Kiskin

et al. 2024

Medical Review

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Cardiovascular research has heavily relied on studies using patient samples and animal models. However, patient studies often miss the data from the crucial early stage of cardiovascular diseases, as obtaining primary tissues at this stage is impracticable. Transgenic animal models can offer some insights into disease mechanisms, although they usually do not fully recapitulate the phenotype of cardiovascular diseases and their progression. In recent years, a promising breakthrough has emerged in the form of in vitro three-dimensional (3D) cardiovascular models utilizing human pluripotent stem cells. These innovative models recreate the intricate 3D structure of the human heart and vessels within a controlled environment. This advancement is pivotal as it addresses the existing gaps in cardiovascular research, allowing scientists to study different stages of cardiovascular diseases and specific drug responses using human-origin models. In this review, we first outline various approaches employed to generate these models. We then comprehensively discuss their applications in studying cardiovascular diseases by providing insights into molecular and cellular changes associated with cardiovascular conditions. Moreover, we highlight the potential of these 3D models serving as a platform for drug testing to assess drug efficacy and safety. Despite their immense potential, challenges persist, particularly in maintaining the complex structure of 3D heart and vessel models and ensuring their function is comparable to real organs. However, overcoming these challenges could revolutionize cardiovascular research. It has the potential to offer comprehensive mechanistic insights into human-specific disease processes, ultimately expediting the development of personalized therapies.

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“…Lastly, isotretinoin (13-cis-retinoic acid, category X) showed similar effect to tretinoin, but abolished cardiac differentiation at lower concentrations. Ma et al (2023) studied the effects of bisphenol A (BPA), a common environmental chemical, and its analogues, in human iPSC-derived cardiac organoids by patch-clamp and confocal fluorescence imaging. Acute exposure to BPA led to a delayed repolarization and prolonged the duration of action potential, related to the inhibition of hERG K + channels.…”

Section: Ipscs and Cardiac Adrsmentioning

confidence: 99%

iPSCs as a groundbreaking tool for the study of adverse drug reactions: A new avenue for personalized therapy

Rispoli,

Scandiuzzi Piovesan,

Decorti

et al. 2023

WIREs Mechanisms of Disease

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Induced pluripotent stem cells (iPSCs), obtained by reprogramming different somatic cell types, represent a promising tool for the study of drug toxicities, especially in the context of personalized medicine. Indeed, these cells retain the same genetic heritage of the donor, allowing the development of personalized models. In addition, they represent a useful tool for the study of adverse drug reactions (ADRs) in special populations, such as pediatric patients, which are often poorly represented in clinical trials due to ethical issues. Particularly, iPSCs can be differentiated into any tissue of the human body, following several protocols which use different stimuli to induce specific differentiation processes. Differentiated cells also maintain the genetic heritage of the donor, and therefore are suitable for personalized pharmacological studies; moreover, iPSC‐derived differentiated cells are a valuable tool for the investigation of the mechanisms underlying the physiological differentiation processes. iPSCs‐derived organoids represent another important tool for the study of ADRs. Precisely, organoids are in vitro 3D models which better represent the native organ, both from a structural and a functional point of view. Moreover, in the same way as iPSC‐derived 2D models, iPSC‐derived organoids are appropriate personalized models since they retain the genetic heritage of the donor. In comparison to other in vitro models, iPSC‐derived organoids present advantages in terms of versatility, patient‐specificity, and ethical issues. This review aims to provide an updated report of the employment of iPSCs, and 2D and 3D models derived from these, for the study of ADRs.This article is categorized under: Cancer > Stem Cells and Development

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Proarrhythmic toxicity of low dose bisphenol A and its analogs in human iPSC-derived cardiomyocytes and human cardiac organoids through delay of cardiac repolarization

Cited by 16 publications

References 83 publications

Comparative cardiotoxicity assessment of bisphenol chemicals and estradiol using human induced pluripotent stem cell-derived cardiomyocytes

Comparative cardiotoxicity assessment of bisphenol chemicals and estradiol using human induced pluripotent stem cell-derived cardiomyocytes

The new era of cardiovascular research: revolutionizing cardiovascular research with 3D models in a dish

iPSCs as a groundbreaking tool for the study of adverse drug reactions: A new avenue for personalized therapy

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