Key Characteristics of Cardiovascular Toxicants
2021; National Institute of Environmental Health Sciences; Volume: 129; Issue: 9 Linguagem: Inglês
10.1289/ehp9321
ISSN1552-9924
AutoresLars Lind, Jesús A. Araujo, Aaron Barchowsky, Scott M. Belcher, Brian R. Berridge, Nipavan Chiamvimonvat, Weihsueh A. Chiu, Vincent James Cogliano, Sarah E. Elmore, Aimen K. Farraj, Aldrin V. Gomes, Cliona M. McHale, Kathleen B. Meyer-Tamaki, Nikki Gillum Posnack, Hugo M. Vargas, Xi Yang, Lauren Zeise, Changcheng Zhou, Martyn T. Smith,
Tópico(s)Toxic Organic Pollutants Impact
ResumoVol. 129, No. 9 CommentaryOpen AccessKey Characteristics of Cardiovascular Toxicantsis companion ofLinking Pollutants and Therapeutics to Heart Health: Key Characteristics of Cardiovascular Toxicants Lars Lind, Jesus A. Araujo, Aaron Barchowsky, Scott Belcher, Brian R. Berridge, Nipavan Chiamvimonvat, Weihsueh A. Chiu, Vincent J. Cogliano, Sarah Elmore, Aimen K. Farraj, Aldrin V. Gomes, Cliona M. McHale, Kathleen B. Meyer-Tamaki, Nikki Gillum Posnack, Hugo M. Vargas, Xi Yang, Lauren Zeise, Changcheng Zhou, and Martyn T. Smith Lars Lind Department of Medical Sciences, Clinical Epidemiology, University of Uppsala, Sweden , Jesus A. Araujo Division of Cardiology, David Geffen School of Medicine at University of California Los Angeles (UCLA), UCLA, Los Angeles, California, USA Department of Environmental Health Sciences, Fielding School of Public Health and Molecular Biology Institute, UCLA, Los Angeles, California, USA , Aaron Barchowsky Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pennsylvania, USA , Scott Belcher Department of Biological Sciences, North Carolina State University, North Carolina, USA , Brian R. Berridge Division of the National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA , Nipavan Chiamvimonvat Department of Internal Medicine, University of California, Davis, Davis, California, USA , Weihsueh A. Chiu College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USA , Vincent J. Cogliano Office of Environmental Health Hazard Assessment, California Environmental Protection Agency (EPA), Oakland, California, USA , Sarah Elmore Office of Environmental Health Hazard Assessment, California Environmental Protection Agency (EPA), Oakland, California, USA , Aimen K. Farraj Public Health and Integrated Toxicology Division, Center for Public Health and Environmental Assessment, U.S. EPA, Research Triangle Park, North Carolina, USA , Aldrin V. Gomes Department of Neurobiology, Physiology and Behavior, College of Biological Sciences, University of California, Davis, Davis, California, USA , Cliona M. McHale Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, California, USA , Kathleen B. Meyer-Tamaki Sangamo Therapeutics, Brisbane, California, USA , Nikki Gillum Posnack Children's National Heart Institute and the Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Hospital, Washington, DC, USA , Hugo M. Vargas Translational Safety & Bioanalytical Sciences, Amgen, Inc., Thousand Oaks, California, USA , Xi Yang Division of Pharmacology and Toxicology, Office of Cardiology, Hematology, Endocrinology, and Nephrology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA , Lauren Zeise Office of Environmental Health Hazard Assessment, California Environmental Protection Agency (EPA), Oakland, California, USA , Changcheng Zhou Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, California, USA , and Martyn T. Smith Address correspondence to Martyn T. Smith, Division of Environmental Health Sciences, School of Public Health, 5123 Berkeley Way West, University of California, Berkeley, Berkeley, CA 94720-7356 USA. Telephone: (510) 642-8770. Email: E-mail Address: [email protected] Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, California, USA Published:24 September 2021CID: 095001https://doi.org/10.1289/EHP9321Cited by:1AboutSectionsPDF ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InRedditEmail AbstractBackground:The concept of chemical agents having properties that confer potential hazard called key characteristics (KCs) was first developed to identify carcinogenic hazards. Identification of KCs of cardiovascular (CV) toxicants could facilitate the systematic assessment of CV hazards and understanding of assay and data gaps associated with current approaches.Objectives:We sought to develop a consensus-based synthesis of scientific evidence on the KCs of chemical and nonchemical agents known to cause CV toxicity along with methods to measure them.Methods:An expert working group was convened to discuss mechanisms associated with CV toxicity.Results:The group identified 12 KCs of CV toxicants, defined as exogenous agents that adversely interfere with function of the CV system. The KCs were organized into those primarily affecting cardiac tissue (numbers 1–4 below), the vascular system (5–7), or both (8–12), as follows: 1) impairs regulation of cardiac excitability, 2) impairs cardiac contractility and relaxation, 3) induces cardiomyocyte injury and death, 4) induces proliferation of valve stroma, 5) impacts endothelial and vascular function, 6) alters hemostasis, 7) causes dyslipidemia, 8) impairs mitochondrial function, 9) modifies autonomic nervous system activity, 10) induces oxidative stress, 11) causes inflammation, and 12) alters hormone signaling.Discussion:These 12 KCs can be used to help identify pharmaceuticals and environmental pollutants as CV toxicants, as well as to better understand the mechanistic underpinnings of their toxicity. For example, evidence exists that fine particulate matter [PM ≤2.5μm in aerodynamic diameter (PM2.5)] air pollution, arsenic, anthracycline drugs, and other exogenous chemicals possess one or more of the described KCs. In conclusion, the KCs could be used to identify potential CV toxicants and to define a set of test methods to evaluate CV toxicity in a more comprehensive and standardized manner than current approaches. https://doi.org/10.1289/EHP9321IntroductionAccording to the World Health Organization, cardiovascular disease (CVD) is the leading cause of death worldwide, taking 1.7 million lives annually (WHO 2017). Four of five of those deaths are due to myocardial infarction or stroke. Certain environmental pollutants, such as fine particulate matter [PM≤2.5μm in aerodynamic diameter (PM2.5)] (Brook et al. 2010, 2016), arsenic (States et al. 2009) and tobacco smoke (Gallucci et al. 2020), are well known to be associated with CVD, but other environmental contaminants, as well as natural toxins, viruses, and other agents, may also be cardiovascular (CV) toxicants.A systematic approach to identifying chemical hazards was recently developed for carcinogens (Smith et al. 2016), endocrine-disrupting chemicals (La Merrill et al. 2020), and reproductive toxicants (Arzuaga et al. 2019; Luderer et al. 2019) based on the established properties of chemicals known to cause cancer, endocrine disruption, and reproductive toxicity, respectively. These properties, called key characteristics (KCs), have quickly proved useful for the systematic evaluation of the literature on mechanisms by which chemicals induce these toxic effects (Guyton et al. 2018a, 2018b). The KCs are now widely used by various authoritative bodies and regulatory agencies and form the basis for the evaluation of mechanistic data at the International Agency for Research on Cancer (IARC 2019; Samet et al. 2020). Scientists in the pharmaceutical industry have also recognized that the KCs are likely to be useful in the design of a comprehensive set of tests to evaluate the potential hazards of novel drug candidates (Fielden et al. 2018; Smith et al. 2020).Our goal was to develop a consensus on the KCs of chemical and nonchemical agents known to cause CV toxicity and to provide a comprehensive list of tests to be used to evaluate chemicals and other environmental pollutants for CV toxicity. Given that many pharmaceutical drugs have adverse effects on the CV system and because those mechanisms are generally better understood than those of environmental pollutants, we included data from pharmaceuticals in the development of the KCs of CV toxicants. As outlined in Figure 1, we believe there are multiple ways in which these KCs of CV toxicants could be used to enhance current approaches in the clinic and in pharmaceutical development, environmental research, and hazard assessment.Figure 1. Utility of the key characteristics (KCs) of cardiovascular toxicants in research, drug discovery, hazard assessment, and clinical practice. An illustration of how the KCs could be used in different areas and how translation of the resulting information could lead to accelerated research, inform better regulatory decisions, improve clinical practice, and ultimately prevent CVD. Note: CV, cardiovascular; CVD, cardiovascular disease; NAM, novel assessment methodologies.Descriptions of the KCs of CV ToxicantsExperts from various fields related to CV toxicity and chemical regulation convened and identified 12 KCs of CV toxicants using current scientific evidence, such as the earlier work of Laverty et al. (2011), expert knowledge, known examples of CV toxicants, and extensive debate. We acknowledge that these will likely evolve with new scientific discoveries. In considering the differences between acute and chronic effects, as well as between high- and low-dose effects, we concluded that these KCs cover temporal and dose-dependent cardiotoxic mechanisms. We did, however, restrict our task to adult CVD, excluding possible teratogenic effects of environmental pollutants on the developing CV system.We also identified representative biomarkers, assays, and end points that are most useful for testing each KC using experimental in vitro/ex vivo studies and in vivo animal models, as well as clinical or epidemiological findings in humans (Table 1). Further, we identified classic examples of CV toxicants for each KC (Table 1) and illustrated how some CV toxicants exhibit multiple KCs, whereas other toxicants may exhibit only one (Tables 2 and 3). We have divided the KCs into those primarily affecting cardiac tissue (numbered 1–4), vascular tissues (5–7), and those which could affect both the heart and vasculature (8–12).Table 1 Key characteristics (KCs) of cardiovascular (CV) toxicants: relevant assays and biomarkers and representative agents.Table 1 has four main columns, namely, Key Characteristic, In vitro or ex vivo; Relevant assays and biomarkers, and Representative chemical and other agents. The Relevant assays and biomarkers column is subdivided into two columns, namely, Animal and Human. The Representative chemical and other agents column is subdivided into two columns, namely, Pharmaceutical and Environmental.KCIn vitro/ex vivoRelevant assays and biomarkersRepresentative chemical and other agentsAnimalHumanPharmaceuticalEnvironmentalMainly cardiac1. Impairs regulation of cardiac excitabilityPatch-clamp recordings in heterologous expression systems, isolated myocytes, or human induced pluripotent stem cell-derived cardiomyocytes (blockade of Na or K ion currents, enhancement of late Na ion current); microelectrode array recordings or optical mapping in ex vivo heart preparation or monolayers of stem cell-derived cardiomyocytes (action potential duration and heterogeneity, conduction velocity), intracellular calcium imaging/measurements.ECG recordings (QRS duration, QTc intervals), electrophysiologic studies (HV intervals, effective refractory period, and cardiac arrhythmia inducibility), ambulatory ECG recordings (occurrences of torsade de pointes ventricular arrhythmias and sudden cardiac death).ECG recordings (QRS duration, QTc intervals), electrophysiologic studies (HV intervals, effective refractory period, and cardiac arrhythmia inducibility), cardiac implantable electronic device interrogation (occurrences of ventricular arrhythmias), development of torsade de pointes ventricular arrhythmias, and sudden cardiac death.Anti-arrhythmic drugs (sotalol, dofetilide, ibutilide, quinidine, procainamide, disopyramide); anti-malarial drug (chloroquine); antibiotics (clarithromycin, erythromycin, azithromycin); tyrosine kinase inhibitors (nilotinib, dasatinib, and sunitinib); antipsychotics (thioridazine, haloperidol); antidepressants (amitriptyline, imiprmaine, fluoxetine, desipramine, paroxetine); anticonvulsants (felbamate and fosphenytoin); gastric motility drug (cisapride).Tetrodotoxin, saxitoxin, batrachotoxin, and conotoxin (naturally occurring toxins); lead, alcohol, BPA.2. Impairs cardiac contractility and relaxationContractile measurements via edge detection or sarcomere detection, impedance-based contractility, force transducer, pressure–volume catheter or balloon catheter.Measure the above in isolated cardiomyocytes, stem cell-derived cardiomyocytes, isolated muscle fibers, intact heart preparations.Pressure–volume catheter; ejection fraction on echocardiography.Ejection fraction on echocardiography, cardiac CT and MRI; blood pressure and cardiac catheterization.Glycosides (e.g., digoxin); beta-adrenergic antagonists (e.g., metoprolol, atenolol, carvedilol); calcium sensitizer (e.g., levosimendan); adrenergic agonists (e.g., dobutamine, isoproterenol); haloanesthetics (e.g., halothane, isoflurane); chemotherapeutics (e.g., arsenic trioxide).Metals (e.g., barium, cadmium, cobalt, lead, nickel); ethanol; BPA.3. Induces cardiomyocyte injury and deathCytotoxicity (troponin release, ATP production, nuclear integrity, mitochondrial integrity) in isolated or induced pluripotent stem cell-derived cardiomyocytes; cytochrome complex release, loss of mitochondrial membrane potential.Cardiac biomarkers (e.g., troponin).Histopathological evaluation (hypertrophy, hyalinization, necrosis, vacuolation, fibrosis).Cardiac biomarkers (e.g., troponin).Histopathological evaluation (hypertrophy, hyalinization, necrosis, vacuolation, fibrosis).Anthracyclines (e.g., doxorubicin); sympathomimetics (e.g., isoproterenol); cardiac calcitropes (e.g., milrinone); imatinib mesylate; trastuzumab.Ethanol, air pollution; diethanolamine; ephedrine; methyl bromide; monochloroacetic acid; 3,3′,4′,4′,5 pentachlorobiphenyl (PCB 126); 2,3′,7,8-tetrachlorodibenzo-p-dioxin; urethane, cadmium.4. Induces proliferation of valve stromaIn vitro activation of 5HT2B receptors; DNA synthesis induction in cultured interstitial cells from human cardiac values via 5-HT2B activation; 5-HT2B receptor activation and/or in silico screening incorporated to de-select compounds during drug development.Valve leaflet fibroplasia and thickening in mice and rats; increased 5-HT levels in whole blood; echocardiogram assessment showing cardiac valve regurgitation.Valve leaflet fibroplasia and thickening; echocardiogram assessment showing cardiac valve regurgitation.Fenfluramine, pergolide, cabergoline, ergotamines, MDMA.None identified.Mainly vascular5. Impacts endothelial and vascular functionMeasurement of binding affinity, functional potency, or expression of vascular receptors and enzymes.Functional effects in isolated vascular tissue preparations segments (human and animal); enzymatic or biochemical effects in endothelial cell culture (e.g., nitric oxide synthase activity, endothelin).Intracellular calcium imaging/measurements.Blood pressure; regional blood flow measurement (Doppler, ultrasonic transit time, microspheres); vascular resistance determinations.Blood pressure; cutaneous blood flow assessment (laser Doppler); brachial flow-mediated dilation; arterial stiffness (pulse wave velocity).Phenylephrine, sunitinib, sodium nitroprusside, prazosin, minoxidil; calcium channel blockers (e.g., verapamil, nifedipine, diltiazem).PCBs, BPA, malathion, DDT, air pollution, cigarette smoke, arsenic, cadmium, lead.6. Alters hemostasisPlatelet aggregation; platelet activation and function (e.g., surface and cytoplasmic markers and EVs by flow cytometry).Altered coagulation and fibrinolysis (e.g., ACT, PT, APTT; assays of global coagulation; levels of coagulation factors).Endothelial cell anti-aggregation and coagulation function.Blood cell and platelet counts, MPV; platelet aggregation; platelet activation and function, tail vein bleeding time.Serum antibodies (e.g., anti-PF4 in HIT, lupus anticoagulants).Altered coagulation and fibrinolysis (e.g., ACT, PT, APTT; coagulation component levels; thrombus formation in blood vessels, tissue ischemia).Blood cell and platelet count, MPV; platelet activation and function.Serum antibodies (e.g., anti-PF4 in HIT, lupus anticoagulants).Altered coagulation and fibrinolysis (e.g., ACT, PT, APTT; assays of global coagulation).Vitamin K and vitamin K epoxide levels in serum or plasma (warfarin).Ibuprofen, quinine, oxaliplatin (immune-mediated thrombocytopenia); heparin (HIT); warfarin (interferes with fibrin clot formation by vitamin K deficiency); procainamide, chlorpromazine, and hydralazine (may induce lupus anticoagulants.Air pollution (PM2.5), arsenic, cadmium.7. Causes dyslipidemiaAltered gene expression of lipid-related genes and altered synthesis and secretion of VLDL in cultured hepatocytes.Altered plasma levels of lipids in rodents; altered gene expression of lipid- related genes in liver specimens.Altered plasma levels of lipids in occupational and epidemiological studies.Human immunodeficiency virus protease inhibitors; antipsychotic drugs.PCBs, PFAS, BPA, phthalates, cadmium and lead.Both cardiac and vascular8. Impairs mitochondrial functionMitochondrial oxygen consumption determination; mitochondrial ROS measurement; mitochondrial Ca2+ imaging; mitochondrial biogenesis, and mitochondrial content determination; mitochondrial membrane polarization measurements; mitochondrial DNA oxidation measurements; ultrastructure imaging.Measurement of the above in isolated cardiomyocytes; submitochondrial preparations; intact heart preparations; human induced pluripotent stem cell-derived cardiomyocytes.8-OHdG adducts of mitochondrial DNA; mitochondrial oxidative damage (e.g., protein carbonyls and malondialdehyde); histopathological, immunohistochemical, and mitochondrial ultrastructure examination; cardiac contractility–ejection fraction, diastolic relaxation, instrumented LV pressures, QA interval.Blood mitochondrial DNA methylation; cardiac magnetic resonance.Chemotherapeutics (e.g., anthracyclines, cisplatin, arsenic trioxide); antiviral compounds (e.g., azidothymidine); anti-diabetics (e.g., rosiglitazone).Air pollution; metals (e.g., arsenic, mercury, cadmium and lead); diphenylmethane derivatives (e.g., BPA); ethanol, chlorinated hydrocarbons (e.g., PCBs).9. Modifies autonomic nervous system activityMeasurement of binding affinity or functional potency at autonomic receptors (e.g., alpha and beta-adrenergic; muscarinic subtypes) and transporters (e.g., norepinephrine).Assessment of sympathetic/parasympathetic receptor-mediated function (e.g., cAMP levels, protein phosphorylation) in isolated tissues (heart or vascular tissues).Assess membrane currents/action potentials in isolated neurons/nerves that control CV function.Measure electrical and mechanical activity in co-cultures of cardiomyocytes with para/sympathetic neurons.Direct measures of sympathetic nerve activity using electrodes or implantable telemetry (membrane currents, action potentials); heart rate variability, baroreflex sensitivity chemoreceptor sensitivity, with linkage to functional and biochemical measures of CV function (e.g., echocardiography, blood pressure and ECG telemetry, pressure–volume catheter, plasma and urinary catecholamines) in rodents and/or dogs.Heart rate variability, baroreflex sensitivity, chemoreceptor sensitivity, Valsalva maneuver, isometric handgrip test, deep breathing test, cold pressor test, mental arithmetic, orthostatic test, head-up tilt test, plasma and urinary catecholamines, noradrenaline spillover rate, microneurography (e.g., muscle sympathetic nerve activity), sudomotor function (responses of sweat glands to stimuli), and linkage to measures of CV function (e.g., echocardiography, ECG, blood pressure, and plasma and urinary catecholamines).Beta-adrenergic agonists (e.g., dobutamine), beta-adrenergic antagonists (atenolol and esmolol), alpha-adrenergic agonists (e.g., clonidine), alpha-adrenergic antagonists (prazosin), muscarinic antagonists (atropine).Ambient particulate matter air pollution, heavy metals (lead, mercury), cigarette smoke, BPA.10. Induces oxidative stressIncreased ROS generation in macrophages, endothelial cells, cardiomyocytes, fibroblasts, human induced pluripotent stem cell-derived cardiomyocytes; increased lipid peroxidation in liposomes.Increased lipid peroxidation in rats and mice (e.g., malondialdehyde, 8-isoprostanes, hydroxyeicosatetraenoates, hydroxyoctadecadienoates); decreased paraoxonase 1 activity in mice and glutathione peroxidase in rats; oxidative changes in plasma lipoproteins of hyperlipidemic mice resulting in proatherogenic LDL and dysfunctional pro-inflammatory high-density lipoprotein.Increased lipid peroxidation and decreased paraoxonase 1 activity in plasma; decreased glutathione peroxidase, decreased superoxide dismutase in blood; Increased NOX in blood.Anthracyclines.Air pollution, (PM2.5, ultrafine particles); diesel exhaust; gasoline exhaust; PAHs; arsenic; cadmium; lead; mercury; pesticides (organophosphates); insecticides (carbamates, fenitrothion), tobacco cigarette.11. Causes inflammationAnalysis of pro-inflammatory gene expression; measurement of cytokine secretion by immune cells (e.g., macrophages); flow cytometry analysis of immune cells; immunofluorescent staining of inflammatory markers; characterization of macrophage polarization; analysis of endothelial cell function.Analysis of circulating cytokine levels (e.g., IL-1β, IL-6); flow cytometry analysis of immune cell population in blood and tissues; analysis of inflammatory gene expression in various tissues including aorta; immunostaining of key inflammatory markers in tissues; characterization of macrophage phenotypes within atherosclerotic plaques; calculation of atherosclerotic plaque stability.Measurement of circulation inflammatory markers (e.g., IL-6, CRP); analysis of immune cells by flow cytometry or other standard methods.Procainamide (antiarrhythmic); hydralazine (vasodilator); doxorubicin (anthracycline).PCBs, BPA, arsenic, cadmium, lead, and air pollution (PM2.5).12. Alters hormone signalingAltered contractility in isolated cardiomyocytes or intact heart preparations; whole-heart ECG; modifications of intracellular calcium imaging; changes in vascular contractility; changes in SR protein expression, or posttranslational modifications, signal transduction; pharmacological agonist/antagonist studies; adrenal-derived cell lines, increased expression of vascular endothelial growth factor and endothelial nitric oxide synthase in human primary endothelial cells.Multiple end points in numerous experimental species (including rodents, canine, porcine, primates): ECG recordings, heart rate variability, baroreflex sensitivity, increased blood pressure, in hormone-receptor knockout rodent models; altered responses to ischemia, cardiac transcriptome; changes in fibrosis and extracellular matrix composition.Multiple end points in epidemiological studies: modifications in blood pressure, hemostasis and vascular resistance; sex-specific lipid profiles, arrhythmia risk, increased hypertrophy, heart failure and dilated cardiomyopathy; altered ECG; increased risk for coronary and peripheral artery disease and atherosclerosis, atrial fibrillation, disturbances in cardiac output and contractility; atherogenic lipid profiles.Amiodarone; rosiglitazone; testosterone; androgens and anabolic steroids; adrenergic agonists and antagonists; selective estrogen receptor modulators and anti-estrogens; glucocorticoids.BPA, PCBs, arsenic, cadmium, and lead.Note: 5-HT, 5-hydroxytryptamine (serotonin); 5-HT2B, 5-HT subtype 2B; ACT, activated clotting time; APTT, activated partial thromboplastin time; ATP, adenosine triphosphate; BPA, bisphenol A; cAMP, cyclic adenosine monophosphate; CRP, C-reactive protein; CT, computed tomography; DDT, dichlorodiphenyltrichloroethane; ECG, electrocardiogram; EV, extracellular vesicle; HIT, heparin-induced thrombocytopenia; HV interval, conduction time through the distal His- Purkinje tissue measured from the onset of the His-bundle deflection to the earliest ventricular activation; K+, potassium ion; LDL, low-density lipoprotein; LV, left ventricular; MDMA, 3,4-methylenedioxymethamphetamine; MPV, mean platelet volume; MRI, magnetic resonance imaging; Na+, sodium ion; NOX, nicotinamide adenine dinucleotide phosphate oxidase; PAH, polycyclic aromatic hydrocarbon; PCBs, polychlorinated biphenyls; PF4, platelet factor 4; PFAS, per- and poly-fluorinated substances; PM2.5, particulate matter in aerodynamic diameter (fine particulate matter); PT, prothrombin time; QTc, corrected QT interval; ROS, reactive oxygen species; SR, sarcoplasmic reticulum; VLDL, very-low-density lipoprotein.Table 2 Key characteristics (KCs) of cardiovascular toxicants applied to three established environmental contaminants that are cardiotoxic.Table 2 has four columns, namely, Key Characteristic, Evidence for each Key Characteristic for Fine Particulate Matter air pollution (Human-animal-in vitro), Evidence for each Key Characteristic for polychlorinated biphenyls (Human-animal-in vitro), and Evidence for each Key Characteristic for Bisphenol A (Human-animal-in vitro).KCEvidence for each KC for PM2.5 air pollution (human–animal–in vitro)Evidence for each KC for PCBs (human–animal–in vitro)Evidence for each KC for BPA (human–animal–in vitro)Mainly cardiac1. Impairs regulation of cardiac excitability——Disrupts intracellular calcium ion homeostasis in excised rat hearts and ventricular myocytes (Posnack et al. 2015; Ramadan et al. 2018; Yan et al. 2011). Directly inhibits multiple voltage-gated calcium channels human cells in vitro and ex vivo in rat aorta (Deutschmann et al. 2013; Feiteiro et al. 2018; Michaela et al. 2014), which are important for nodal cell depolarization, atrioventricular conduction, and the plateau phase of the cardiac action potential. Sinus bradycardia and slowed cardiac electrical conduction observed in experimental models in ex vivo and in vivo studies (Belcher et al. 2015; Patel et al. 2015; Posnack et al. 2014).2. Impairs cardiac contractility and relaxation———3. Induces cardiomyocyte injury and death———4. Induces proliferation of valve stroma———Mainly vascular5. Impacts endothelial and vascular functionAltered vasomotor tone in epidemiological (Dales et al. 2007; Krishnan et al. 2012; Zanobetti et al. 2014) and experimental in vivo (Hansen et al. 2007) and ex vivo (Hansen et al. 2007) studies.——6. Alters hemostasisAltered hemostasis in epidemiological (Hajat et al. 2015; Riediker et al. 2004; Viehmann et al. 2015; Zhang et al. 2018), and experimental in vivo studies (Liang et al. 2019; Sun et al. 2008).——7. Causes dyslipidemiaInduced dyslipidemia in epidemiological (Mathew et al. 2018; McGuinn et al. 2019), and experimental in vivo (Li et al. 2020; Xu et al. 2019b) studies.Dyslipidemia in humans resulting in increased serum levels of cholesterol and triglycerides (Chase et al. 1982; Penell et al. 2014; Tokunaga and Kataoka 2003).In rodents and zebrafish, PCBs most likely cause dyslipidemia in vivo by altering the regulation of genes related to lipogenesis and lipid catabolism in liver cells (Chapados and Boucher 2017; Li et al. 2019; Wahlang et al. 2013). In vitro, human and mouse hepatocytes exposed to PCBs in vitro have increased triglyceride and total cholesterol concentrations (Boucher et al. 2015; Chen et al. 2020a; Wu et al. 2017).—Both cardiac and vascular8. Impairs mitochondrial function———9. Modifies autonomic nervous system activityAltered autonomic nervous system activity in multiple epidemiological (Kirrane et al. 2019; Lee et al. 2014; Mordukhovich et al. 2015; Park et al. 2010; Peters et al. 2015; Pieters et al. 2012), experimental in vivo (Anselme et al. 2007; Bessac and Jordt 2008; Carll et al. 2013; Hazari et al. 2011; Widdicombe and Lee 2001), and in vitro (Deering-Rice et al. 2011) studies.—Differences in beta-adrenergic receptor expression have been observed in animal models (Belcher et al. 2015) and alterations in heart rate variability have been reported in human subjects (Bae et al. 2012).10. Induces oxidative stressInduced oxidative stress in epidemiological (Lee et al. 2014; Li et al. 2016; Weichenthal et al. 2016), experimental in vivo (Xu et al. 2019b; Yue et al. 2019), and in vitro lung epithelial (Niu et al. 2020) and dual lung and cardiomyocyte (Gorr et al. 2015) studies.Altered glutathione metabolism and lipid peroxidation in humans, and in vivo in rats, mice, and crabs (Deng et al. 2019; Feng et al. 2019; Kumar et al. 2014b; Shan et al. 2020; Tremblay-Laganière et al. 2019). Increased ROS production in vitro in human ECs and neutrophil granulocytes (Berntsen et al. 2016; Long et al. 2017; Tang et al. 2017), and in various tissues in pig, mice, hamster, and fish (scup) (Green et al. 2008; Han et al. 2012; Hennig et al. 2002; Long et al. 2020; Majkova et al. 2011; Murati et al. 2017; Schlezinger et al. 2006).Population-based epidemiological studies have noted associations between BPA exposure, inflammation, and oxidative stress (Kataria et al. 2017; Steffensen et al. 2020; Wang et al. 2019b; Yang et al. 2009).11. Causes inflammationInduced inflammation in epidemiological (Altuwayjiri et al. 2021; Liu et al. 2019; Pope et al. 2016; Riediker et al. 2004; Zhang et al. 2020a), experimental in vivo (Bai and Sun 2016; Hadei and Naddafi 2020; Tong 2016), and in vitro lung epithelial (Schwarze et al. 2007) macrophage (Zhao et al. 2016), and dual lung and cardiomyocyte (Gorr et al. 2015) studies.Increased biomarkers of inflammat
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