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. 2022 Nov 1:454:116247.
doi: 10.1016/j.taap.2022.116247. Epub 2022 Sep 17.

Overview of the cardiovascular effects of environmental metals: New preclinical and clinical insights

Jiapeng Huang  1 , Karim El-Kersh  2 , Koren K Mann  3 , Katherine A James  4 , Lu Cai  5
Affiliations

Overview of the cardiovascular effects of environmental metals: New preclinical and clinical insights

Jiapeng Huang et al. Toxicol Appl Pharmacol. .

Abstract

Environmental causes of cardiovascular diseases (CVDs) are global health issues. In particular, an association between metal exposure and CVDs has become evident but causal evidence still lacks. Therefore, this symposium at the Society of Toxicology 2022 annual meeting addressed epidemiological, clinical, pre-clinical animal model-derived and mechanism-based evidence by five presentations: 1) An epidemiologic study on potential CVD risks of individuals exposed occupationally and environmentally to heavy metals; 2) Both presentations of the second and third were clinical studies focusing on the potential link between heavy metals and pulmonary arterial hypertension (PAH), by presenting altered blood metal concentrations of both non-essential and essential metals in the patients with PAH and potential therapeutic approaches; 3) Arsenic-induced atherosclerosis via inflammatory cells in mouse model; 4) Pathogenic effects on the heart by adult chronic exposure to very low-dose cadmium via epigenetic mechanisms and whole life exposure to low dose cadmium via exacerbating high-fat-diet-lipotoxicity. This symposium has brought epidemiologists, therapeutic industry, physicians, and translational scientists together to discuss the health risks of occupational and environmental exposure to heavy metals through direct cardiotoxicity and indirect disruption of homeostatic mechanisms regulating essential metals, as well as lipid levels. The data summarized by the presenters infers a potential causal link between multiple metals and CVDs and defines differences and commonalities. Therefore, summary of these presentations may accelerate the development of efficient preventive and therapeutic strategies by facilitating collaborations among multidisciplinary investigators.

Keywords: Cardiovascular diseases; Epidemiological evidence; Metal toxicities; Pulmonary hypertension, arsenics, cadmium.

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Conflict of interest statement

Declaration of Competing Interest No conflict interest needs to be claimed.

Figures

Fig. 1.
Fig. 1.. Proposed mechanism of antimony (Sb) adverse effects in pulmonary arterial hypertension (PAH).
Environmental antimony exposure can potentially increase oxidative stress resulting in redox imbalance, contribute to disturbance of right ventricular (RV) calcium homeostasis, and increase RV endoplasmic reticulum stress which can result in worsening RV dysfunction and maladaptive RV response in PAH. (Created with BioRender.com).
Fig. 2.
Fig. 2.. Arsenic causes different pro-atherogenic changes depending on the type of macrophages.
In vitro, macrophages polarized with either IFNγ or IL-4 for 48 h in the presence or absence of arsenic were analyzed by bulk RNA sequencing. Arsenic induced different gene expression changes depending on the polarization. For example, arsenic decreased liver X receptor signaling in IFNγ-stimulated macrophages, but not in IL-4-stimulated macrophages. Arsenic decreased MHC II and CCL17/22 in IL-4-stimulated macrophages, but not IFNγ. In vivo, cells from the atherosclerotic plaques of ApoE−/− mice (tap water versus 200 ppb arsenic for 13 weeks) were isolated and analyzed by single cell RNA sequencing (scRNASeq). Foam cell macrophages in control animals (green cluster 2) increased heterogeneity (to red cluster 3 and light blue cluster 8). Resident-like macrophages changed from yellow cluster 10 (control) to purple cluster 4 (arsenic). However, these changes were distinct and dependent upon the original cluster from which they were derived. (Figure created with Biorender).
Fig. 3.
Fig. 3.. Cardiac effects of low-dose Cd exposure with and without the second stress, HFD or Western diet.
The experimental designs were briefly described for a few studies, for which mice and rats were chronically exposed to low-dose Cd (blue bar) either intraperitoneally or in the drinking water at different stages of life for various durations. In panel A: a, starting at 6 week (wks) old and continuing for 4 wks only, followed by abstaining Cd for 56 wks (white box); b, starting at 8 wks old and continuing for 12 wks; c, starting at 8 wks old and continuing for 10 wks, followed by abstaining Cd for 4 wks; d, whole-life Cd exposure until sacrifice. All four strategies caused only mild cardiac pathogenesis without significant cardiac dysfunction. In Panel B: the exacerbated effects of whole-life exposure to low-dose Cd in the drinking water (blue bar) on post-weaning HFD- or Western diet (yellow bar)-induced cardiac remodeling and dysfunction. This illustration was made based on the experimental models and outcomes by Turdi et al. (Panel A-a), Turkcan et al. (Panel A-b), Das et al. (Panel A-c), Liang et al. (Panel A-d, Panel B, Western diet), and Zhou et al. (Panel A-d, Panel B, HFD).
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