Oncogene expression profiles in K6/ODC mouse skin and papillomas following a chronic exposure to monomethylarsonous acid

Delker, Don A.; Geter, David R.; Roop, Barbara C.; Ward, William O.; Ahlborn, Gene J.; Allen, James W.; Nelson, Garret B.; Ouyang, Ming; Welsh, William J.; Yan, Chen; O’Brien, Thomas G.; Kitchin, Kirk T.

doi:10.1002/jbt.20304

Cited by 9 publications

(6 citation statements)

References 60 publications

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“…They showed that the effects of methylated metabolites on F344 female rats resulted in pathological changes of the bladder which were attributed to MMA(III) following DMA(V) treatments in the diet. Other studies have also provided some evidence of the carcinogenicity of MMA(III) in rodent models (Delker et al, 2009; Krishnamohan et al, 2006). In an attempt to elicit some type of toxicological response, researchers had employed very high concentrations of MMA(III) in these studies, far beyond the relevant levels of exposures in human populations.…”

Section: Discussionmentioning

confidence: 99%

Global gene expression changes in human urothelial cells exposed to low-level monomethylarsonous acid

et al. 2012

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Bladder cancer has been associated with chronic arsenic exposure. Monomethylarsonous acid [MMA(III)] is a metabolite of inorganic arsenic and has been shown to transform an immortalized urothelial cell line (UROtsa) at concentrations 20-fold less than arsenite. MMA(III) was used as a model arsenical to examine the mechanisms of arsenical-induced transformation of urothelium. A microarray analysis was performed to assess the transcriptional changes in UROtsa during the critical window of chronic 50 nM MMA(III) exposure that leads to transformation at three months of exposure. The analysis revealed only minor changes in gene expression at one and two months of exposure, contrasting with substantial changes observed at three months of exposure. The gene expression changes at three months were analyzed showing distinct alterations in biological processes and pathways such as a response to oxidative stress, enhanced cell proliferation, anti-apoptosis, MAPK signaling, as well as inflammation. Twelve genes selected as markers of these particular biological processes were used to validate the microarray and these genes showed a time-dependent changes at one and two months of exposure, with the most substantial changes occurring at three months of exposure. These results indicate that there is a strong association between the acquired phenotypic changes that occur with chronic MMA(III) exposure and the observed gene expression patterns that are indicative of a malignant transformation. Although the substantial changes that occur at three months of exposure may be a consequence of transformation, there are common occurrences of altered biological processes between the first two months of exposure and the third, which may be pivotal in driving transformation.

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Section: Discussionmentioning

confidence: 99%

Global gene expression changes in human urothelial cells exposed to low-level monomethylarsonous acid

et al. 2012

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“…We identified 101 genes that were differentially expressed between genotypes basally (Figure 1A). Web-based DAVID gene function organizing tool (22) allowed grouping of most of these 101 genes into 45 overlapping biological process categories. Five categories from this list include response to hypoxia, cell proliferation, transcription, apoptosis and metabolism that account for two thirds of the identified genes (Figure 1B).…”

Section: Resultsmentioning

confidence: 99%

Ron receptor-dependent gene regulation in a mouse model of endotoxin-induced acute liver failure

Kulkarni

Kutcher

Stuart

et al. 2012

Hepatobiliary & Pancreatic Diseases International

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Background Prior experimentation has shown that loss of the tyrosine kinase (TK) signaling domain of the Ron receptor leads to marked hepatocyte protection in a model of lipopolysaccharide (LPS)-induced acute liver failure (ALF) in D-galactosamine (GalN)-sensitized mice. Methods To elucidate the role of Ron in the regulation of hepatic gene expression, microarray analyses were performed on liver RNA isolated temporally from wild type (WT) and TK−/− mice during the progression of ALF. Gene array data was validated using Western analyses and immunohistochemistry analyses as well as by ex vivo culture systems. Results At baseline, 101 genes were differentially expressed between WT and TK−/− livers, which regulated processes involved in hypoxia, proliferation, apoptosis and metabolism. One hour after ALF induction, WT livers exhibited increased cytokine expression compared to TK−/− livers and after 4 hours, an induction of suppressor of cytokine signaling (SOCS) genes as well as JAK-STAT pathway activation were prominent in TK−/− livers compared to controls. Conclusions In conclusion, our studies suggest a novel hepato-protective mechanism in the Ron TK−/− mice wherein increased and sustained SOCS production and JAK-STAT activation in the hepatocyte may inhibit the destructive proinflammatory milieu and promote survival factors which blunt hepatic death and ensuing development of ALF.

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“…The mechanism of MMA (III) in triggering malignant urothelial transformation during bladder cancer has been well studied (Medeiros et al, 2012;Wang et al, 2007;Wnek et al, 2010). There is limited data showing how MMA (III) potentiates skin cancer (Chen et al, 2008;Delker et al, 2009), or the role of MMA (III) in other arsenic induced diseases. One report on nanomolar levels of MMA (III) impairing vascular smooth muscle contractility in mice suggests that MMA (III) contributes to arsenicassociated cardiovascular diseases more potently than arsenite FIG.…”

Section: Discussionmentioning

confidence: 99%

Cardiac Epithelial-Mesenchymal Transition Is Blocked by Monomethylarsonous Acid (III)

Huang

Barnett

2014

Toxicological Sciences

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Arsenic exposure during embryonic development can cause ischemic heart pathologies later in adulthood which may originate from impairment in proper blood vessel formation. The arsenic-associated detrimental effects are mediated by arsenite (iAs(III)) and its most toxic metabolite, monomethylarsonous acid [MMA (III)]. The impact of MMA (III) on coronary artery development has not yet been studied. The key cellular process that regulates coronary vessel development is the epithelial-mesenchymal transition (EMT). During cardiac EMT, activated epicardial progenitor cells transform to mesenchymal cells to form the cellular components of coronary vessels. Smad2/3 mediated TGFβ2 signaling, the key regulator of cardiac EMT, is disrupted by arsenite exposure. In this study, we compared the cardiac toxicity of MMA (III) with arsenite. Epicardial progenitor cells are 15 times more sensitive to MMA (III) cytotoxicity when compared with arsenite. MMA (III) caused a significant blockage in epicardial cellular transformation and invasion at doses 10 times lower than arsenite. Key EMT genes including TGFβ ligands, TβRIII, Has2, CD44, Snail1, TBX18, and MMP2 were down regulated by MMA (III) exposure. MMA (III) disrupted Smad2/3 activation at a dose 20 times lower than arsenite. Both arsenite and MMA (III) significantly inhibited Erk1/2 and Erk5 phosphorylation. Nuclear translocation of Smad2/3 and Erk5 was also blocked by arsenical exposure. However, p38 activation, as well as smooth muscle differentiation, was refractory to the inhibition by the arsenicals. Collectively, these findings revealed that MMA (III) is a selective disruptor of cardiac EMT and as such may predispose to arsenic-associated cardiovascular disorders.

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Oncogene expression profiles in K6/ODC mouse skin and papillomas following a chronic exposure to monomethylarsonous acid

Cited by 9 publications

References 60 publications

Global gene expression changes in human urothelial cells exposed to low-level monomethylarsonous acid

Global gene expression changes in human urothelial cells exposed to low-level monomethylarsonous acid

Ron receptor-dependent gene regulation in a mouse model of endotoxin-induced acute liver failure

Cardiac Epithelial-Mesenchymal Transition Is Blocked by Monomethylarsonous Acid (III)

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