Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Arsenate Sub-chronic Drinking Water Study

ABSTRACT: Concentration- and time-dependent genomic changes in the mouse urinary bladder following exposure to arsenate in drinking water for up to twelve weeks. Inorganic arsenic (Asi) is a known human bladder carcinogen. The objective of this study was to examine the concentration dependence of the genomic response to Asi in the urinary bladders of mice. C57BL/6J mice were exposed for 1 or 12 weeks to arsenate in drinking water at concentrations of 0.5, 2, 10, and 50 mg As/L. Urinary bladders were analyzed using gene expression microarrays. A consistent reversal was observed in the direction of gene expression change: from predominantly decreased expression at 1 week to predominantly increased expression at 12 weeks. These results are consistent with evidence from in vitro studies of an acute adaptive response that is suppressed on longer exposure due to down-regulation of Fos. Pathways with the highest enrichment in gene expression changes were associated with epithelial-to-mesenchymal transition, inflammation, and proliferation. Benchmark dose (BMD) analysis determined that the lowest median BMD values for pathways were above 5 mg As/L, despite the fact that pathway enrichment was observed at the 0.5 mg As/L exposure concentration. This disparity may result from the non-monotonic nature of the concentration-responses for the expression changes of a number of genes, as evidenced by the much fewer gene expression changes at 2 mg As/L compared to lower or higher concentrations. Pathway categories with concentration-related gene expression changes included cellular morphogenesis, inflammation, apoptosis/survival, cell cycle control, and DNA damage response. The results of this study provide evidence of a concentration-dependent transition in the mode of action for the subchronic effects of Asi in mouse bladder cells in the vicinity of 2 mg Asi/L. Female C57Bl/J mice will be exposed to COLD Arsenate in drinking water. One week interium sac on 7/18/06. 100 samples including liver, lung, kidney and bladder. Bladder will be analyzed with microarrays, 24 samples. Twelve week terminal sac on 10/05/06. 75 total samples including lung, kidney, and bladder. Bladdler will be analyzed by microarray, 25 samples. Drinking water containing As will be prepared weekly with monitoring to determine amount used by mice. Following tissues will be available for genomic study: Bladder, liver, lung, and kidney.

ORGANISM(S): Mus musculus

SUBMITTER: Harvey Clewell

PROVIDER: E-GEOD-32102 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:The number of legacy chemicals without toxicity reference values combined with the rate of new chemical development are overwhelming the capacity of the traditional risk assessment paradigm. More efficient approaches are needed to quantitatively estimate chemical risks. In this study, rats were dosed orally with multiple doses of six chemicals for 5 days, 2, 4, and 13 weeks. Target organs were analyzed for traditional histological and organ weight changes and transcriptional changes using microarrays. Histological and organ weight changes in this study and the tumor incidences in the original cancer bioassays were analyzed using benchmark dose (BMD) methods to identify noncancer and cancer points-of-departure. The dose-response changes in gene expression were also analyzed using BMD methods and the responses grouped based on signaling pathways. A comparison of transcriptional BMD values for the most sensitive pathway with BMD values for the noncancer and cancer apical endpoints showed a high degree of correlation at all time points. When the analysis included data from an earlier study with 8 additional chemicals, transcriptional BMD values for the most sensitive pathway were significantly correlated with noncancer (r = 0.827, p = 0.0031) and cancer-related (r = 0.940, p = 0.0002) BMD values at 13 weeks. The average ratio of apical-to-transcriptional BMD values was less than two suggesting that for the current chemicals, transcriptional perturbation did not occur at significantly lower doses than apical responses. Based on our results, we propose a practical framework for application of transcriptomic data to chemical risk assessment. Four to five week-old rats were exposed in dose-response and for multiple durations to 6 chemicals. The chemicals were 1,2,4-tribromobenzene (CAS No. 615-54-3), 2,3,4,6-tetrachlorophenol (CAS No. 58-90-2), bromobenzene (CAS No. 108-86-1), 4,4'-methylenebis(N,N-dimethyl)benzenamine (CAS No. 101-61-1), hydrazobenzene (CAS No. 122-66-7), N-nitrosodiphenylamine (CAS No. 86-30-6). For 1,2,4-tribromobenzene and 2,3,4,6-tetrachlorophenol, male Sprague Dawley (Rat/Crl:CD(SD)) rats were used. For bromobenzene and hydroazobenzene, male F344/DuCrl rats were used. For 4,4'-methylenebis(N,N-dimethyl)benzenamine and N-nitrosodiphenylamine, female F344/DuCrl rats were used. The exposure durations were 5 days, 2 weeks, 4 weeks, and 13 weeks. The dose and route of exposure are provided with the individual sample annotations. With each chemical treatment, a matched vehicle control group was run concurrently with the exposure. Gavage exposures were administered 7 days per week and feed exposures were provided 7 days per week. At the appropriate time point, animals were euthanized with a lethal intraperitoneal injection of sodium pentobarbital. For the liver, slices from each of the lobes were mixed together and used for microarray analysis. For the thyroid, the gland was transversely sectioned and the bottom portion was used for microarray analysis. For the bladder, the organ was longitudinally bisected, a slice was removed for histology and the remainder of the organ was minced and used for microarray analysis. Microarrays were run on five rats per dose per time point.

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Dataset Information

Arsenate Sub-chronic Drinking Water Study

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