Table 2.

Key characteristics (KCs) of cardiovascular toxicants applied to three established environmental contaminants that are cardiotoxic.

KC	Evidence for each KC for ${\mathrm{PM}}_{2.5}$ 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 cardiac
1. 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 vascular
5. Impacts endothelial and vascular function	Altered 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 hemostasis	Altered 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 dyslipidemia	Induced 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 vascular
8. Impairs mitochondrial function	—	—	—
9. Modifies autonomic nervous system activity	Altered 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 stress	Induced 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 inflammation	Induced 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 inflammation, such as ICAM-1 and VCAM-1, in humans (Kumar et al. 2014a). Elevated blood levels and hepatic expression of IL-6 and $\text{TNF}\mathrm{\alpha }$ in rats and mice after exposure to a PCB mixture (Wahlang et al. 2014; Xu et al. 2019a). In vitro exposure of human monocytes and vascular ECs to PCB 126 induced expression of inflammatory cytokines, including $\text{TNF}\mathrm{\alpha }$, monocyte/macrophage chemokine 1f and $\text{IL-}1\mathrm{\beta }$ in the monocytes and up-regulated inflammatory genes, such as IL-6, CRP, ICAM-1, and VCAM-1 in the EC (Milner 1989).	BPA exposure is associated with increased inflammatory makers (Song et al. 2017) and atherosclerosis or coronary artery disease in epidemiological studies (Lind and Lind 2011; Melzer et al. 2012a, 2012b). In utero BPA exposure increases cardiac fibrosis and inflammation in offspring (Belcher et al. 2015; Gear et al. 2017; Rasdi et al. 2020) and impedes recovery after myocardial infarction in adult animals (Patel et al. 2015; Shang et al. 2019). Notably, the effects of BPA on cardiac remodeling and inflammation are significantly attenuated in estrogen $\text{receptor-}\mathrm{\beta }$ knockout mice, which further suggests a mechanistic link to BPA’s estrogenic activity (Kasneci et al. 2017).
12. Alters hormone signaling	Altered hypothalamus–pituitary–adrenal axis-related stress hormones (Niu et al. 2018), altered thyroid hormone levels during pregnancy (Zhao et al. 2019), and altered insulin and glucose homeostasis (Brook et al. 2016; Zheng et al. 2013), in epidemiological studies. Altered hypothalamus–pituitary–adrenal axis-related stress hormones (Liu et al. 2020), altered renin–angiotensin system signaling (Ghelfi et al. 2010), altered insulin and glucose homeostasis (Xu et al. 2011), altered testosterone synthesis (Yang et al. 2019), and altered $\text{PPAR}\mathrm{\gamma }$ signaling (Zheng et al. 2013), in experimental in vivo studies.	Altered circulating thyroid hormone levels in humans, rats, and fish (sea bass) (Collins et al. 1977; Meeker et al. 2007; Schnitzler et al. 2011; Takser et al. 2005). In young non-pregnant women, a clinical indicator of ovarian responsiveness, the FSH:LH ratio, was associated with PCBs (Gallo et al. 2018). In rats, the pituitary content of FSH and LH was increased by PCB-126 exposure (Desaulniers et al. 1999), and rats exposed to a PCB mixture showed increases in uterine weights and uterine ${}^3\mathrm{H}$-thymidine labeling (Jansen et al. 1993). In vitro effects on the estrogen receptor have also been observed (Gjernes et al. 2012; Tavolari et al. 2006).	Disruption of intracellular calcium homeostasis is likely mediated through estrogenic effects of BPA, which results in posttranslational modifications of key calcium-handling proteins (Belcher et al. 2012; Gao et al. 2013; Liang et al. 2014).

Note: Details are provided for those KCs that we for cancer treatments and cardiovascular toxicity of the European Society of Cardiology considered to have the strongest evidence for each agent (e.g., a combination of data from human epidemiological/clinical studies and in vivo animal studies, as well as in vitro studies). —, Other KCs; BPA, Bisphenol A; CRP, C-reactive protein; ECs, endothelial cells; FSH, follicle-stimulating hormone; ICAM-1, intracellular adhesion molecule 1; $\text{IL-}1\mathrm{\beta }$, interleukin 1 beta; IL-6, interleukin 6; LH, luteinizing hormone; PCBs, polychlorinated biphenyls; ${\mathrm{PM}}_{2.5}$, particulate matter $\le 2.5\mathrm{\mu }\mathrm{m}$ in aerodynamic diameter (fine particulate matter); $\text{PPAR}\mathrm{\gamma }$, peroxisome proliferator-activated receptor gamma; ROS, reactive oxygen species; $\text{TNF}\mathrm{\alpha }$, tumor necrosis factor alpha; VCAM-1, vascular cell adhesion molecule 1.