Identification of interspecies concordance of mechanisms of arsenic-induced bladder cancer

Sen, Banalata; Wolf, Douglas C.; Turpaz, Yaron; Bugrim, Andrej; Retief, Jacques D.; Hester, Susan

doi:10.1016/j.tiv.2007.06.021

Cited by 15 publications

(6 citation statements)

References 41 publications

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“…Rather, uroepithelial injury could be the consequence of the retention of high levels of inorganic arsenic in this tissue in an animal which neither efficiently methylates nor clears arsenic. Effects on the urothelium in the As3mt KO mice and in the wild type mice are consistent with previous studies using human urothelial cells (UROtsa) in vitro which also do not have As3mt activity (Styblo et al, 2002;Sen et al, 2007).…”

Section: Discussionsupporting

confidence: 91%

Severe systemic toxicity and urinary bladder cytotoxicity and regenerative hyperplasia induced by arsenite in arsenic (+3 oxidation state) methyltransferase knockout mice. A preliminary report

Yokohira

Arnold

Pennington

et al. 2010

Toxicology and Applied Pharmacology

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Arsenic (+3 oxidation state) methyltransferase (As3mt) catalyzes reactions which convert inorganic arsenic to methylated metabolites. This study determined whether the As3mt null genotype in the mouse modifies cytotoxic and proliferative effects seen in urinary bladders of wild type mice after exposure to inorganic arsenic. Female wild type C57BL/6 mice and As3mt KO mice were divided into 3 groups each (n=8) with free access to a diet containing 0, 100 or 150 ppm of arsenic as arsenite (As(III)). During the first week of As(III) exposure, As3mt KO mice exhibited severe and lethal systemic toxicity. At termination, urinary bladders of both As3mt KO and wild type mice showed hyperplasia by light microscopy. As expected, arsenic-containing granules were found in the superficial urothelial layer of wild type mice. In As3mt KO mice these granules were present in all layers of the bladder epithelium and were more abundant and larger than in wild type mice. Scanning electron microscopy of the bladder urothelium of As3mt KO mice treated with 100 ppm As(III) showed extensive superficial necrosis and hyperplastic changes. In As3mt KO mice, livers showed severe acute inflammatory changes and spleen size and lymphoid areas were decreased compared with wild type mice. Thus, diminished arsenic methylation in As3mt KO mice exacerbates systemic toxicity and the effects of As(III) on the bladder epithelium, showing that altered kinetic and dynamic behavior of arsenic can affect its toxicity.

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Section: Discussionsupporting

confidence: 91%

Severe systemic toxicity and urinary bladder cytotoxicity and regenerative hyperplasia induced by arsenite in arsenic (+3 oxidation state) methyltransferase knockout mice. A preliminary report

Yokohira

Arnold

Pennington

et al. 2010

Toxicology and Applied Pharmacology

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“…These apical endpoints included transitional cell death, proliferation, and hyperplasia. Experiments characterized the effects in the target cell using transcriptional profiling (Sen et al, 2005(Sen et al, , 2007. These studies were designed to identify key molecular changes associated with exposure to DMA and to better characterize the pathways or key events leading to the various apical outcomes.…”

Section: Placement Of the Effect Within A Biological System: Relevant...mentioning

confidence: 99%

“…These studies were designed to identify key molecular changes associated with exposure to DMA and to better characterize the pathways or key events leading to the various apical outcomes. In brief, the authors identified transcriptomic changes at doses below which one sees the apical adverse endpoint of transitional cell death in the target epithelium from exposed rats as well as in vitro (Sen et al, 2005(Sen et al, , 2007. The authors suggested that the toxicity observed at the higher doses may add to precursor effects present at the FIG.…”

Section: Placement Of the Effect Within A Biological System: Relevant...mentioning

confidence: 99%

Identification and Characterization of Adverse Effects in 21st Century Toxicology

Keller

Juberg²,

Catlin

et al. 2012

Toxicological Sciences

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The practice of toxicology is changing rapidly, as demonstrated by the response to the 2007 NRC report on "Toxicity Testing in the 21(st) Century." New assays are being developed to replace animal testing; yet the use of data from these assays in decision making is not clear. A Health and Environmental Sciences Institute committee held a May 2011 workshop to discuss approaches to identifying adverse effects in the context of the NRC report. Scientists from industry, government, academia, and NGOs discussed two case studies and explored how information from new, high data content assays developed for screening can be used to differentiate adverse effects from adaptive responses. The terms "adverse effect" and "adaptive response" were defined, as well as two new terms, the relevant pathways of toxicological concern (RPTCs) and relevant responses for regulation (RRRs). RPTCs are biochemical pathways associated with adverse events and need to be elucidated before they are used in regulatory decision making. RRRs are endpoints that are the basis for risk assessment and may or may not be at the level of pathways. Workshop participants discussed the criteria for determining whether, at the RPTC level, an effect is potentially adverse or potentially indicative of adaptability, and how the use of prototypical, data-rich compounds could lead to a greater understanding of RPTCs and their use as RRRs. Also discussed was the use of RPTCs in a weight-of-evidence approach to risk assessment. Inclusion of data at this level could decrease uncertainty in risk assessments but will require the use of detailed dosimetry and consideration of exposure context and the time and dose continuum to yield scientifically based decisions. The results of this project point to the need for an extensive effort to characterize RPTCs and their use in risk assessment to make the vision of the 2007 NRC report a reality.

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“…Calls to eliminate animal tests in favor of human in vitro models increase the need to understand the relevance of conclusions from gene expression studies across models and species [ 10 – 12 ]. Several small scale studies have compared in vitro vs. in vivo gene expression profiles following drug treatment [ 13 – 17 ]. Discrepancies observed in those studies have been attributed to pharmacokinetics [ 18 , 19 ] and differences in the baseline state of liver vs. its constituent cells in culture [ 20 – 22 ].…”

Section: Introductionmentioning

confidence: 99%

Assessing Concordance of Drug-Induced Transcriptional Response in Rodent Liver and Cultured Hepatocytes

et al. 2016

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The effect of drugs, disease and other perturbations on mRNA levels are studied using gene expression microarrays or RNA-seq, with the goal of understanding molecular effects arising from the perturbation. Previous comparisons of reproducibility across laboratories have been limited in scale and focused on a single model. The use of model systems, such as cultured primary cells or cancer cell lines, assumes that mechanistic insights derived from the models would have been observed via in vivo studies. We examined the concordance of compound-induced transcriptional changes using data from several sources: rat liver and rat primary hepatocytes (RPH) from Drug Matrix (DM) and open TG-GATEs (TG), human primary hepatocytes (HPH) from TG, and mouse liver / HepG2 results from the Gene Expression Omnibus (GEO) repository. Gene expression changes for treatments were normalized to controls and analyzed with three methods: 1) gene level for 9071 high expression genes in rat liver, 2) gene set analysis (GSA) using canonical pathways and gene ontology sets, 3) weighted gene co-expression network analysis (WGCNA). Co-expression networks performed better than genes or GSA when comparing treatment effects within rat liver and rat vs. mouse liver. Genes and modules performed similarly at Connectivity Map-style analyses, where success at identifying similar treatments among a collection of reference profiles is the goal. Comparisons between rat liver and RPH, and those between RPH, HPH and HepG2 cells reveal lower concordance for all methods. We observe that the baseline state of untreated cultured cells relative to untreated rat liver shows striking similarity with toxicant-exposed cells in vivo, indicating that gross systems level perturbation in the underlying networks in culture may contribute to the low concordance.

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Identification of interspecies concordance of mechanisms of arsenic-induced bladder cancer

Cited by 15 publications

References 41 publications

Severe systemic toxicity and urinary bladder cytotoxicity and regenerative hyperplasia induced by arsenite in arsenic (+3 oxidation state) methyltransferase knockout mice. A preliminary report

Severe systemic toxicity and urinary bladder cytotoxicity and regenerative hyperplasia induced by arsenite in arsenic (+3 oxidation state) methyltransferase knockout mice. A preliminary report

Identification and Characterization of Adverse Effects in 21st Century Toxicology

Assessing Concordance of Drug-Induced Transcriptional Response in Rodent Liver and Cultured Hepatocytes

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