Analysis of genomic dose‐response information on arsenic to inform key events in a mode of action for carcinogenicity

Abstract

A comprehensive literature search was conducted to identify information on gene expression changes following exposures to inorganic arsenic compounds. This information was organized by compound, exposure, dose/concentration, species, tissue, and cell type. A concentration-related hierarchy of responses was observed, beginning with changes in gene/protein expression associated with adaptive responses (e.g., preinflammatory responses, delay of apoptosis). Between 0.1 and 10 microM, additional gene/protein expression changes related to oxidative stress, proteotoxicity, inflammation, and proliferative signaling occur along with those related to DNA repair, cell cycle G2/M checkpoint control, and induction of apoptosis. At higher concentrations (10-100 microM), changes in apoptotic genes dominate. Comparisons of primary cell results with those obtained from immortalized or tumor-derived cell lines were also evaluated to determine the extent to which similar responses are observed across cell lines. Although immortalized cells appear to respond similarly to primary cells, caution must be exercised in using gene expression data from tumor-derived cell lines, where inactivation or overexpression of key genes (e.g., p53, Bcl-2) may lead to altered genomic responses. Data from acute in vivo exposures are of limited value for evaluating the dose-response for gene expression, because of the transient, variable, and uncertain nature of tissue exposure in these studies. The available in vitro gene expression data, together with information on the metabolism and protein binding of arsenic compounds, provide evidence of a mode of action for inorganic arsenic carcinogenicity involving interactions with critical proteins, such as those involved in DNA repair, overlaid against a background of chemical stress, including proteotoxicity and depletion of nonprotein sulfhydryls. The inhibition of DNA repair under conditions of toxicity and proliferative pressure may compromise the ability of cells to maintain the integrity of their DNA.

Evaluation of gene expression changes in human primary uroepithelial cells following 24‐Hr exposures to inorganic arsenic and its methylated metabolites

“…However, cells in vivo would be expected to be exposed to a mixture of inorganic arsenic and methylated metabolites, making direct comparisons difficult. The mouse study does provide additional evidence for a transition in gene expression comparable to that noted in the review of the in vitro data in primary cells [Gentry et al, 2010], with a transition or threshold concentration on the order of 0.1 lM.…”

“…The changes in gene expression were bimodal in nature, with significant changes in expression following exposure to the lowest concentration (0.5 mg As/L) and the two highest concentrations (10 and 50 mg As/L), but no significant changes observed following exposure to 2 mg As/L. Based on the arsenite measured in the urine of the treated mice ( 0.05 to 16 lg/L), the bladder cells in vivo would be expected to be exposed to similar concentrations in vivo as those evaluated in vitro (0.01-10 lM) by Gentry et al [2010]. However, cells in vivo would be expected to be exposed to a mixture of inorganic arsenic and methylated metabolites, making direct comparisons difficult.…”

Arsenite Effects on Mitochondrial Bioenergetics in Human and Mouse Primary Hepatocytes Follow a Nonlinear Dose Response

“…Previous studies in transformed cell lines have suggested reversal in the direction of gene expression change between low and high arsenite concentrations [42]. These changes appear to involve oxidative stress response, proteotoxicity, and proliferative signaling at low doses and predominantly apoptotic genes at high doses [42].…”

An updated inhalation unit risk factor for arsenic and inorganic arsenic compounds based on a combined analysis of epidemiology studies

“…Lately, there has been a surge of interest to use state-of-the art molecular techniques to obtain mechanistic data to decipher the molecular mechanisms of the arsenic carcinogenic MOA and to quantify actual risks at environmentally relevant concentrations (Chilakapati et al, 2010;Suzuki et al, 2009;Gentry et al, 2010). However, in vitro studies are limited in that it is very hard to estimate the threshold dose where toxicity occurs based on in vitro dose response data and these types of studies are hard to replicate using in vivo models (Snow et al, 2005).…”