Abstract
Chronic arsenic exposure results in higher risk of skin, lung, and bladder cancer, as well as cardiovascular disease and diabetes. The purpose of this study was to investigate the effects on expression of selected genes in the blood lymphocytes from 159 people exposed chronically to arsenic in their drinking water using a novel RT-PCR TaqMan low-density array (TLDA). We found that expression of tumor necrosis factor-α (TNF-α), which activates both inflammation and NF-κB-dependent survival pathways, was strongly associated with water and urinary arsenic levels. Expression of KCNA5, which encodes a potassium ion channel protein, was positively associated with water and toe nail arsenic levels. Expression of 2 and 11 genes were positively associated with nail and urinary arsenic, respectively. Because arsenic exposure has been reported to be associated with long QT intervals and vascular disease in humans, we also used this TLDA for analysis of gene expression in human cardiomyocytes exposed to arsenic in vitro. Expression of the ion-channel genes CACNA1, KCNH2, KCNQ1 and KCNE1 were down-regulated by 1-μM arsenic. Alteration of some common pathways, including those involved in oxidative stress, inflammatory signaling, and ion-channel function, may underlay the seemingly disparate array of arsenic-associated diseases, such as cancer, cardiovascular disease, and diabetes.
Highlights
Extensive epidemiological studies have demonstrated that environmental exposure to arsenic causes cancer of the skin, lung, and bladder [1,2,3] and is a co-carcinogen in combination with UV light for skin cancer [4]
We investigated the molecular responses to arsenic exposure in humans and cultured cardiomyocytes using a novel TaqMan low-density array (TLDA) in order to better understand the mode of action of arsenic
Considering all the exposure estimates, expression of tumor necrosis factor-α (TNF-α) was associated with both water and urinary concentrations of arsenic, that of POLB was associated with nail and urinary levels, and that of KCNA5 was associated with water and nail levels
Summary
Extensive epidemiological studies have demonstrated that environmental exposure to arsenic causes cancer of the skin, lung, and bladder [1,2,3] and is a co-carcinogen in combination with UV light for skin cancer [4]. Exposure to arsenic either chronically through the drinking water [5] or acutely through medical therapy for acute promyelocytic leukemia or poisoning [6,7] is associated with cardiovascular abnormalities [8,9]. This is frequently manifest as a prolongation of the QT (time between initial deflection of QRS complex to the end of T wave) interval as measured on an electrocardiogram, resulting in life-threatening malignant ventricular arrhythmias [7]. No studies have implicated a role for arsenic on cardiomyocytes per se; to our knowledge, no in vitro exposures of such cells to arsenic have been performed
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