Association of Arsenic Exposure With Cardiac Geometry and Left Ventricular Function in Young Adults

Pichler, Gernot; Grau-Pérez, María; Téllez-Plaza, María; Umans, Jason G.; Best, Lyle G.; Cole, Shelley A.; Goessler, Walter; Francesconi, Kevin A.; Newman, Jonathan; Redón, Josep; Devereux, Richard B.; Navas‐Acien, Ana

doi:10.1161/circimaging.119.009018

Cited by 40 publications

(21 citation statements)

References 66 publications

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“…7). Establishing this causal mechanism clarifies observational associations of iAS exposure and cardiac remodeling in humans independent of hypertension, and it stimulates further investigations not only upstream of NFAT activation, but also in the context of other environmental exposures and CVD endpoints (11).…”

Section: Discussionmentioning

confidence: 65%

“…Recent findings from a multistate cohort study in an American population with a low burden of CVD risk factors show that individuals exposed to iAS exhibit altered left ventricular geometry (11). Although these results highlighted stronger associations among participants with preexisting hypertension, the association was also present without hypertension, suggesting that iAS exposure may directly promote cardiac remodeling (11). Previously, our laboratory reported that a 4-wk exposure to 1,000 μg/L iAS may impart sex-disparate effects on the heart (12).…”

Section: Introductionmentioning

confidence: 99%

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Inorganic arsenic induces sex-dependent pathological hypertrophy in the heart

Kabir

Sinha

Mishra

et al. 2021

American Journal of Physiology-Heart and Circulatory Physiology

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Arsenic exposure through drinking water is widespread and well-associated with adverse cardiovascular outcomes, yet the pathophysiological mechanisms by which inorganic arsenic (iAS) induces these effects are largely unknown. Recently, an epidemiological study in an American population with a low burden of cardiovascular risk factors found that iAS exposure was associated with altered left ventricular geometry. Considering the possibility that iAS directly induces cardiac remodeling independent of hypertension, we investigated the impact of an environmentally relevant iAS exposure on the structure and function of male and female hearts. Adult male and female C56BL/6J mice were exposed to 615 μg/L iAS for eight weeks. Males exhibited increased systolic blood pressure via tail cuff photoplethysmography, left ventricular wall thickening via transthoracic echocardiography, and increased plasma atrial natriuretic peptide via enzyme immunoassay. RT-qPCR revealed increased myocardial RNA transcripts of Acta1, Myh7, and Nppa, and decreased Myh6, providing evidence of pathological hypertrophy in the male heart. Similar changes were not detected in females, and nitric oxide dependent mechanisms of cardioprotection in the heart appeared to remain intact. Further investigation found that Rcan1 was upregulated in male hearts and that iAS activated NFAT in HEK293 cells via luciferase assay. Interestingly, iAS induced similar hypertrophic gene expression changes in neonatal rat ventricular myocytes, which were blocked by calcineurin inhibition, suggesting that iAS may induce pathological cardiac hypertrophy in part by targeting the calcineurin-NFAT pathway. As such, these results highlight iAS exposure as an independent cardiovascular risk factor and provide biological impetus for its removal from human consumption.

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Section: Discussionmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Inorganic arsenic induces sex-dependent pathological hypertrophy in the heart

Kabir

Sinha

Mishra

et al. 2021

American Journal of Physiology-Heart and Circulatory Physiology

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“…Epidemiological studies have proved that long‐term exposure to As via contaminated drinking water, diet, or air can cause a variety of adverse health effects in humans. Apart from typical dermal changes, 2 multiorgan system damages, such as respiratory, 3 digestive, 4 urinary, 5 cardiovascular, 6 immune systems 7 and many other harmful effects also have been demonstrated. Among them, the liver, as the primarily metabolic and detoxifying organ, is already confirmed as a susceptible toxicity target to arsenic 8 .…”

Section: Introductionmentioning

confidence: 99%

Imbalanced inflammatory response in subchronic arsenic‐induced liver injury and the protective effects of Ginkgo biloba extract in rats: Potential role of cytokines mediated cell–cell interactions

Dong

Liu

Wang

et al. 2021

Environmental Toxicology

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Arsenic is a well‐known environmental toxicant and carcinogen, which has been epidemiologically proved related to the increased hepatic disorders. Researches have shown that aseptic inflammation and abnormal immune response are associated with arsenic‐induced liver injury. However, the immunotoxic effects of liver have not been extensively characterized. Ginkgo biloba extract (GBE), a natural products of G. biloba leaves with proven anti‐inflammatory and potential immunoregulatory activities, was used as intervention agent to explore its protective effects on arsenic‐induced hepatotoxicity. Thus, the underlying mechanism of the immunotoxic effects on arsenic‐induced liver injury were investigated in 2.5, 5.0, and 10.0 mg/kg NaAsO2 of Wistar rats for 16 weeks. Subsequently, GBE was used as intervention agent in 50 mg/kg for 6 weeks after cessation of arsenic exposure. The ratio of Th17 to Treg cells in peripheral blood as well as the secretion of inflammatory cytokines IL‐17A, IL‐6, TGF‐β1, and IL‐10 in serum and liver were detected. Meanwhile, the notable activation of aseptic inflammation‐related molecule TLR4 and its downstream targets MyD88 and NF‐κB in the liver were observed. In this work, we confirmed that subchronic exposed to arsenic triggered the infiltration of inflammatory cells in rat liver, coupled with obvious histopathological changes and aberrant hepatic serum biochemical parameters. Meanwhile, imbalanced immune response was verified by the notable abnormal ratio of Th17 to Treg cells in peripheral blood as well as the secretion of inflammatory cytokines IL‐17A, IL‐6, TGF‐β1, and IL‐10 in serum and liver of arsenic exposed rats. Further, the level of TLR4, MyD88, and NF‐κB in liver both transcription and translation activity were raised. Subsequently, GBE markedly mitigated arsenic‐induced liver injury, most impressively, post treatment with GBE prominently suppressed the overactivated inflammatory‐related TLR4‐MyD88‐NF‐κB pathway and evidently decreased the secretion of inflammation cytokines. Meanwhile, the disturbance of pro‐ and anti‐inflammatory response was reversed. We concluded that the disruption of pro‐ and anti‐inflammatory T‐cells balance caused by cytokines mediated cell–cell interactions may be one of the mechanisms underlying arsenic‐induced liver injury and that GBE intervention exerts an evidence protective effects, which might be closely associated with the suppression of inflammatory‐related TLR4 pathway.

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“…2016 ). Chronic exposure from contaminated drinking water was linked to ventricular wall thickness and hypertrophy in young adults ( Pichler et al. 2019 ).…”

Section: Examples Of How the Kcs May Produce CV Dysfunction And Diseasementioning

confidence: 99%

Key Characteristics of Cardiovascular Toxicants

Lind¹,

Araujo

Barchowsky

et al. 2021

Environ Health Perspect

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Background: 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 in aerodynamic diameter ( )] 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/EHP9321

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Association of Arsenic Exposure With Cardiac Geometry and Left Ventricular Function in Young Adults

Cited by 40 publications

References 66 publications

Inorganic arsenic induces sex-dependent pathological hypertrophy in the heart

Inorganic arsenic induces sex-dependent pathological hypertrophy in the heart

Imbalanced inflammatory response in subchronic arsenic‐induced liver injury and the protective effects of Ginkgo biloba extract in rats: Potential role of cytokines mediated cell–cell interactions

Key Characteristics of Cardiovascular Toxicants

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