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Elucidating the Effects of the Environmental Pollutant Benzo[a]pyrene [BaP] on Cardiac Arrhythmogenicity

ABSTRACT: Benzo[a]pyrene (BaP) is a product of combustion and is an abundant constituent of wildfire derived smoke and particulate matter 2.5 (PM2.5). Although arrythmias are associated with wildfire, the mechanism remains unclear. We hypothesized that BaP might predispose individuals to arrhythmias and possibly sudden cardiac death. Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from healthy donors (n=3) were used to investigate the cardiovascular toxicity of BaP. Across a broad concentration range, BaP did not affect iPSC-CM viability, and a 4-day exposure of BaP at 50 M did not affect contractility. After exposure to BaP at 50 M for 5 days, iPSC-CMs were subjected to bulk RNA sequencing, and analysis revealed markers of inflammation were upregulated, and ion channel expression was modulated. Because inflammation is associated with reactive oxygen species (ROS) production, iPSC-CMs exposed to BaP had a concentration-dependent increase in ROS production. Mitotracker fluorescent imaging revealed decreased mitochondrial membrane potentials after iPSC-CMs treatment with 50 μM BaP. Seahorse assays revealed that BaP exposure decreased oxygen consumption rate, basal respiration, and maximal respiration in a dose-dependent manner. Using multiple electrode array (MEA) assays, iPSC-CMs exposed to 50 M BaP for 3 days, had prolonged field potential duration (FPD) and increased beat period (BP). However, co-treatment with N-acetyl cysteine (NAC), a nucleophile that scavenges ROS and preserves glutathione, attenuated the effect of BaP on FPD and BP (p<0.001). In summary, BaP exposure upregulated inflammatory cytokines and increased ROS production by impairing mitochondrial function. BaP had proarrhythmic effects of increased BP and FPD and was abrogated by NAC. Thus, BaP inhalation from wildfire smoke may predispose individuals to QT prolongation, arrhythmia, and sudden cardiac death.

ORGANISM(S): Homo sapiens

PROVIDER: GSE244567 | GEO | 2024/08/25

REPOSITORIES: GEO

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Project description:Many oncology drugs have been found to induce cardiotoxicity in a subset of patients, which significantly limits their clinical use and impedes the benefit of lifesaving anti-cancer treatments. Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) carry donor-specific genetic information and have been proposed for explore the inter-individual difference in oncology drug-induced cardiotoxicity. Herein, we evaluated the inter- and intra- individual variability of iPSC-CM-related assays and presented a practical approach for using donor-specific iPSC-CMs to predict personalized doxorubicin (DOX)-induced cardiotoxicity (DIC) prior to chemotherapy. Our findings demonstrated that donor-specific iPSC-CMs exhibited greater line-to-line variability than the intra-individual variability in impedance cytotoxicity and transcriptome assays. The variable and dose-dependent cytotoxic responses of iPSC-CMs resembled those observed in clinical practice, and largely replicated the reported mechanisms of DIC. By categorizing iPSC-CMs into DOX-resistant and DOX-sensitive cell lines based on their phenotypic reactions to DOX, we found that the sensitivity of donor-specific iPSC-CMs to DOX may predict in vivo DIC risk. Furthermore, we assessed the limitations of the model for identification of potential genetic/molecular biomarker and pinpointed a differentially expressed gene, DND microRNA-mediated repression inhibitor 1 (DND1), between the DOX-resistant and DOX-sensitive iPSC-CMs. We also discussed the selection of DOX dose and exposure duration for inter-individual variability of DIC assessment. Our results support the utility of donor-specific iPSC-CMs in assessing inter-individual difference and enabling personalized cardiotoxicity prediction. Further studies will encompass a large panel of donor-specific iPSC-CMs to investigate the role of the DND1 and known DIC genetic variants, and to identify potential novel molecular and genetic biomarkers for predicting DOX and other oncology drug-induced cardiotoxicity.

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Elucidating the Effects of the Environmental Pollutant Benzo[a]pyrene [BaP] on Cardiac Arrhythmogenicity

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