Altered Gene Expression by Low-Dose Arsenic Exposure in Humans and Cultured Cardiomyocytes: Assessment by Real-Time PCR Arrays

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.

Monomethylarsonous acid, but not inorganic arsenic, is a mitochondria-specific toxicant in vascular smooth muscle cells

“…It has been suggested that arsenic alters common pathways such as those involved in oxidative stress and inflammatory signaling, which underlie a variety of arsenic-associated diseases (States et al 2009, Straif et al 2009, Mo et al 2011, Kim et al 2015). The generation of ROS in particular is a major pathological mechanism induced by arsenic and is involved in the pathogenesis of cancer (Shi et al 2004), insulin resistance (Padmaja Divya et al 2015), metabolic syndrome (Ando et al 2009), and cardiovascular disease (States et al 2009).…”

Combined effects of DNA methyltransferase 1 and 3A polymorphisms and urinary total arsenic levels on the risk for clear cell renal cell carcinoma

“…Mo et al found that DNMT1 expression was upregulated by low-dose arsenic exposure in a human cardiomyocyte cell line (Mo et al, 2011). Cui et al reported that exposure to low levels of arsenic reduced DNMT1 expression and inhibited DNMT activity in human liver cancer cells (Cui et al, 2006).…”

“…In a human cardiomyocyte cell line, exposure to low-dose arsenic induced changes in DNA methyltransferase 1 (DNMT1) gene expression (Mo et al, 2011). Long-term exposure to low-dose arsenic altered mRNA and protein levels of DNMT1 and DNMT3A in human urothelial cells compared with the levels in human urothelial cells that were not exposed to arsenic .…”

Inhibition of nucleotide excision repair by arsenic

“…A follow-up study [46] further demonstrated that expression of ERCC1 was decreased at both the mRNA and protein levels. A dosedependent decrease in the mRNA expression of ERCC1 was also found in human cardiomyocytes exposed to arsenite for 72 h [47]. However, elevated ERCC1 gene expression has The cells were lysed and DNA extracted for analysis of the BPDE-DNA adducts.…”