{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T02:59:49Z","timestamp":1740106789445,"version":"3.37.3"},"reference-count":55,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2021,12,22]],"date-time":"2021-12-22T00:00:00Z","timestamp":1640131200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,2,28]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Oral exposure to hexavalent chromium (Cr(VI)) induces tumors in the mouse duodenum. Previous microarray-based transcriptomic analyses of homogenized mouse duodenal tissue have demonstrated Cr(VI)-induced alterations in various cellular pathways and processes. However, X-ray fluorescence microscopy indicates that chromium localizes primarily to the duodenal villi following exposure to Cr(VI), suggesting that previous transcriptomic analyses of homogenized tissue provide an incomplete picture of transcriptomic responses in the duodenum. Herein, transcriptomic analyses were conducted separately on crypt and villus tissue from formalin-fixed paraffin-embedded transverse duodenal sections from the same study in which microarray-based analyses were previously conducted. A total of 28 groups (7 doses \u00d7 2 timepoints \u00d7 2 tissue compartments) were analyzed for differential gene expression, dose-response, and gene set enrichment. Tissue compartment isolation was confirmed by differences in expression of typical markers of crypt and villus compartments. Fewer than 21 genes were altered in the crypt compartment of mice exposed to 0.1-5\u2009ppm Cr(VI) for 7 or 90\u2009days, which increased to hundreds or thousands of genes at \u226520\u2009ppm Cr(VI). Consistent with histological evidence for crypt proliferation, a significant, dose-dependent increase in genes that regulate mitotic cell cycle was prominent in the crypt, while subtle in the villus, when compared with samples from time-matched controls. Minimal transcriptomic evidence of DNA damage response in either the crypts or the villi is consistent with published in vivo genotoxicity data. These results are also discussed in the context of modes of action that have been proposed for Cr(VI)-induced small intestine tumors in mice.<\/jats:p>","DOI":"10.1093\/toxsci\/kfab152","type":"journal-article","created":{"date-parts":[[2021,12,16]],"date-time":"2021-12-16T12:09:19Z","timestamp":1639656559000},"page":"43-57","source":"Crossref","is-referenced-by-count":1,"title":["Crypt and Villus Transcriptomic Responses in Mouse Small Intestine Following Oral Exposure to Hexavalent Chromium"],"prefix":"10.1093","volume":"186","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7543-8336","authenticated-orcid":false,"given":"Grace A","family":"Chappell","sequence":"first","affiliation":[{"name":"ToxStrategies, Inc, Asheville, North Carolina 28801, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey C","family":"Wolf","sequence":"additional","affiliation":[{"name":"EPL, Sterling, Virginia 20166, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chad M","family":"Thompson","sequence":"additional","affiliation":[{"name":"ToxStrategies, Inc., Katy, Texas 77494, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,12,22]]},"reference":[{"key":"2022022809421502700_kfab152-B1","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1007\/978-981-10-6955-0_19","article-title":"Regulation of mammalian DNA replication via the ubiquitin-proteasome system","volume":"1042","author":"Abbas","year":"2017","journal-title":"Adv. Exp. Med. Biol"},{"key":"2022022809421502700_kfab152-B2","doi-asserted-by":"crossref","first-page":"2","DOI":"10.14252\/foodsafetyfscj.2018014","article-title":"Mutant frequency is not increased in mice orally exposed to sodium dichromate","volume":"7","author":"Aoki","year":"2019","journal-title":"Food Saf. (Tokyo)"},{"key":"2022022809421502700_kfab152-B3","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1080\/10408444.2020.1823934","article-title":"An adverse outcome pathway for small intestinal tumors in mice involving chronic cytotoxicity and regenerative hyperplasia: A case study with hexavalent chromium, captan, and folpet","volume":"50","author":"Bhat","year":"2020","journal-title":"Crit. Rev. Toxicol"},{"key":"2022022809421502700_kfab152-B4","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.3389\/fphys.2019.01484","article-title":"Intestinal epithelial cells respond to chronic inflammation and dysbiosis by synthesizing H2O2","volume":"10","author":"Burgueno","year":"2019","journal-title":"Front. Physiol"},{"key":"2022022809421502700_kfab152-B5","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1177\/0192623319873882","article-title":"Comparison of gene expression responses in the small intestine of mice following exposure to 3 carcinogens using the S1500+ gene set informs a potential common adverse outcome pathway","volume":"47","author":"Chappell","year":"2019","journal-title":"Toxicol. Pathol"},{"key":"2022022809421502700_kfab152-B6","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1177\/0192623315611501","article-title":"Reevaluation and classification of duodenal lesions in B6C3F1 mice and F344 rats from 4 studies of hexavalent chromium in drinking water","volume":"44","author":"Cullen","year":"2016","journal-title":"Toxicol. Pathol"},{"key":"2022022809421502700_kfab152-B7","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1006\/rtph.1996.0116","article-title":"Evolution of science-based uncertainty factors in noncancer risk assessment","volume":"24","author":"Dourson","year":"1996","journal-title":"Regul. Toxicol. Pharmacol"},{"key":"2022022809421502700_kfab152-B8","doi-asserted-by":"crossref","first-page":"3943","DOI":"10.1038\/onc.2016.502","article-title":"Census and evaluation of p53 target genes","volume":"36","author":"Fischer","year":"2017","journal-title":"Oncogene"},{"key":"2022022809421502700_kfab152-B9","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/j.canep.2010.03.013","article-title":"Occupational exposure to hexavalent chromium and cancers of the gastrointestinal tract: A meta-analysis","volume":"34","author":"Gatto","year":"2010","journal-title":"Cancer Epidemiol"},{"key":"2022022809421502700_kfab152-B10","first-page":"D498","article-title":"The reactome pathway knowledgebase","volume":"48","author":"Jassal","year":"2020","journal-title":"Nucleic Acids Res"},{"key":"2022022809421502700_kfab152-B82694028","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.cbi.2012.08.016","article-title":"Physiologically based pharmacokinetic model for rats and mice orally exposed to chromium","volume":"200","author":"Kirman","year":"2012","journal-title":"Chem. Biol. Interact."},{"key":"2022022809421502700_kfab152-B11","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.taap.2011.11.012","article-title":"Genome-wide gene expression effects in B6C3F1 mouse intestinal epithelia following 7 and 90days of exposure to hexavalent chromium in drinking water","volume":"259","author":"Kopec","year":"2012","journal-title":"Toxicol. Appl. Pharmacol"},{"key":"2022022809421502700_kfab152-B12","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.taap.2012.04.026","article-title":"Comparative toxicogenomic analysis of oral Cr(VI) exposure effects in rat and mouse small intestinal epithelia","volume":"262","author":"Kopec","year":"2012","journal-title":"Toxicol. Appl. Pharmacol"},{"key":"2022022809421502700_kfab152-B13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mrrev.2005.04.002","article-title":"Detailed review of transgenic rodent mutation assays","volume":"590","author":"Lambert","year":"2005","journal-title":"Mutat. Res"},{"key":"2022022809421502700_kfab152-B14","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol"},{"key":"2022022809421502700_kfab152-B15","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1002\/em.22080","article-title":"Dose and temporal evaluation of ethylene oxide-induced mutagenicity in the lungs of male big blue mice following inhalation exposure to carcinogenic concentrations","volume":"58","author":"Manjanatha","year":"2017","journal-title":"Environ. Mol. Mutagen"},{"key":"2022022809421502700_kfab152-B16","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1053\/j.gastro.2005.01.054","article-title":"Gene expression profiling of intestinal epithelial cell maturation along the crypt-villus axis","volume":"128","author":"Mariadason","year":"2005","journal-title":"Gastroenterology"},{"key":"2022022809421502700_kfab152-B17","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1002\/em.20525","article-title":"An evaluation of the mode of action framework for mutagenic carcinogens case study II: Chromium (VI)","volume":"51","author":"McCarroll","year":"2010","journal-title":"Environ. Mol. Mutagen"},{"key":"2022022809421502700_kfab152-B18","doi-asserted-by":"crossref","first-page":"E395","DOI":"10.5942\/jawwa.2012.104.0092","article-title":"Hexavalent chromium review, part 2: Chemistry, occurrence, and treatment","volume":"104","author":"McNeill","year":"2012","journal-title":"J. Am. Waterworks Assoc"},{"key":"2022022809421502700_kfab152-B19","doi-asserted-by":"crossref","first-page":"E22","DOI":"10.1002\/awwa.1044","article-title":"Hexavalent chromium in drinking water","volume":"110","author":"Moffat","year":"2018","journal-title":"J. AWWA"},{"key":"2022022809421502700_kfab152-B20","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1089\/152791601750294344","article-title":"BioCarta","volume":"2","author":"Nishimura","year":"2001","journal-title":"Biotech Softw. Internet Rep"},{"year":"2007","key":"2022022809421502700_kfab152-B21"},{"year":"2008","key":"2022022809421502700_kfab152-B22"},{"key":"2022022809421502700_kfab152-B23","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.mrgentox.2013.03.008","article-title":"Assessment of K-Ras mutant frequency and micronucleus incidence in the mouse duodenum following 90-days of exposure to Cr(VI) in drinking water","volume":"754","author":"O\u2019Brien","year":"2013","journal-title":"Mutat. Res"},{"key":"2022022809421502700_kfab152-B24","doi-asserted-by":"crossref","first-page":"883","DOI":"10.2741\/3652","article-title":"Replication protein A: Directing traffic at the intersection of replication and repair","volume":"15","author":"Oakley","year":"2010","journal-title":"Front. Biosci. (Landmark Ed.)"},{"year":"2016","key":"2022022809421502700_kfab152-B25"},{"year":"2016","key":"2022022809421502700_kfab152-B26"},{"year":"2016","key":"2022022809421502700_kfab152-B27"},{"year":"2020","key":"2022022809421502700_kfab152-B28"},{"key":"2022022809421502700_kfab152-B29","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1093\/nar\/27.1.29","article-title":"KEGG: Kyoto encyclopedia of genes and genomes","volume":"27","author":"Ogata","year":"1999","journal-title":"Nucleic Acids Res"},{"key":"2022022809421502700_kfab152-B30","doi-asserted-by":"crossref","first-page":"6544","DOI":"10.1073\/pnas.0701085104","article-title":"Genesis of hexavalent chromium from natural sources in soil and groundwater","volume":"104","author":"Oze","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2022022809421502700_kfab152-B31","doi-asserted-by":"crossref","first-page":"1780","DOI":"10.1093\/bioinformatics\/bty878","article-title":"BMDExpress 2: Enhanced transcriptomic dose-response analysis workflow","volume":"35","author":"Phillips","year":"2019","journal-title":"Bioinformatics"},{"key":"2022022809421502700_kfab152-B32","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1093\/toxsci\/kfx085","article-title":"High-throughput screening data interpretation in the context of in vivo transcriptomic responses to oral Cr(VI) exposure","volume":"158","author":"Rager","year":"2017","journal-title":"Toxicol. Sci"},{"key":"2022022809421502700_kfab152-B33","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1158\/1541-7786.MCR-13-0628","article-title":"Hypoxic stress facilitates acute activation and chronic downregulation of fanconi anemia proteins","volume":"12","author":"Scanlon","year":"2014","journal-title":"Mol. Cancer Res"},{"key":"2022022809421502700_kfab152-B34","doi-asserted-by":"crossref","first-page":"D674","DOI":"10.1093\/nar\/gkn653","article-title":"PID: The pathway interaction database","volume":"37","author":"Schaefer","year":"2009","journal-title":"Nucleic Acids Res"},{"key":"2022022809421502700_kfab152-B35","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1289\/ehp.0800208","article-title":"Hexavalent chromium is carcinogenic to F344\/N rats and B6C3F1 mice after chronic oral exposure","volume":"117","author":"Stout","year":"2009","journal-title":"Environ. Health Perspect"},{"key":"2022022809421502700_kfab152-B36","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"author":"Thompson","key":"2022022809421502700_kfab152-B37"},{"key":"2022022809421502700_kfab152-B38","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1093\/toxsci\/kfq320","article-title":"Application of the U.S. EPA mode of action Framework for purposes of guiding future research: A case study involving the oral carcinogenicity of hexavalent chromium","volume":"119","author":"Thompson","year":"2011","journal-title":"Toxicol. Sci"},{"key":"2022022809421502700_kfab152-B39","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1093\/toxsci\/kfr164","article-title":"Investigation of the mode of action underlying the tumorigenic response induced in B6C3F1 mice exposed orally to hexavalent chromium","volume":"123","author":"Thompson","year":"2011","journal-title":"Toxicol. Sci"},{"key":"2022022809421502700_kfab152-B41","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1093\/toxsci\/kfr280","article-title":"Comparison of the effects of hexavalent chromium in the alimentary canal of F344 rats and B6C3F1 mice following exposure in drinking water: Implications for carcinogenic modes of action","volume":"125","author":"Thompson","year":"2012","journal-title":"Toxicol. Sci"},{"key":"2022022809421502700_kfab152-B42","doi-asserted-by":"crossref","first-page":"244","DOI":"10.3109\/10408444.2013.768596","article-title":"Assessment of the mode of action underlying development of rodent small intestinal tumors following oral exposure to hexavalent chromium and relevance to humans","volume":"43","author":"Thompson","year":"2013","journal-title":"Crit. Rev. Toxicol"},{"key":"2022022809421502700_kfab152-B43","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1093\/toxsci\/kfu206","article-title":"Synchrotron-based imaging of chromium and gamma-H2AX immunostaining in the duodenum following repeated exposure to Cr(VI) in drinking water","volume":"143","author":"Thompson","year":"2015","journal-title":"Toxicol. Sci"},{"key":"2022022809421502700_kfab152-B44","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.mrgentox.2017.08.004","article-title":"Ten factors for considering the mode of action of Cr(VI)-induced gastrointestinal tumors in rodents","volume":"823","author":"Thompson","year":"2017","journal-title":"Mut. Res"},{"key":"2022022809421502700_kfab152-B45","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.mrgentox.2015.05.004","article-title":"Duodenal crypt health following exposure to Cr(VI): Micronucleus scoring, gamma-H2AX immunostaining, and synchrotron X-ray fluorescence microscopy","volume":"789\u2013790","author":"Thompson","year":"2015","journal-title":"Mutat. Res. Genet. Toxicol. Environ. Mutagen"},{"key":"2022022809421502700_kfab152-B46","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1177\/0192623317742324","article-title":"Comparison of toxicity and recovery in the duodenum of B6C3F1 mice following treatment with intestinal carcinogens captan, folpet, and hexavalent chromium","volume":"45","author":"Thompson","year":"2017","journal-title":"Toxicol. Pathol"},{"key":"2022022809421502700_kfab152-B47","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.taap.2017.07.002","article-title":"Assessment of the mutagenic potential of hexavalent chromium in the duodenum of big blue(R) rats","volume":"330","author":"Thompson","year":"2017","journal-title":"Toxicol. Appl. Pharmacol"},{"key":"2022022809421502700_kfab152-B48","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1002\/em.21952","article-title":"Assessment of the mutagenic potential of Cr(VI) in the oral mucosa of Big Blue((R)) transgenic F344 rats","volume":"56","author":"Thompson","year":"2015","journal-title":"Environ. Mol. Mutagen"},{"year":"2017","key":"2022022809421502700_kfab152-B49"},{"key":"2022022809421502700_kfab152-B50","doi-asserted-by":"crossref","first-page":"4378","DOI":"10.1093\/nar\/gkt111","article-title":"Enriching the gene set analysis of genome-wide data by incorporating directionality of gene expression and combining statistical hypotheses and methods","volume":"41","author":"Varemo","year":"2013","journal-title":"Nucleic Acids Res"},{"key":"2022022809421502700_kfab152-B51","doi-asserted-by":"crossref","first-page":"10272","DOI":"10.1073\/pnas.1017668108","article-title":"Paneth cell marker expression in intestinal villi and colon crypts characterizes dietary induced risk for mouse sporadic intestinal cancer","volume":"108","author":"Wang","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2022022809421502700_kfab152-B52","first-page":"1","article-title":"Cell cycle-dependent expression of the mouse Rad51 gene in proliferating cells","volume":"251","author":"Yamamoto","year":"1996","journal-title":"Mol. Gen. Genet"},{"key":"2022022809421502700_kfab152-B53","doi-asserted-by":"crossref","first-page":"e0178302","DOI":"10.1371\/journal.pone.0178302","article-title":"A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling","volume":"12","author":"Yeakley","year":"2017","journal-title":"PLoS One"},{"volume-title":"DNA Repair - On the Pathways to Fixing DNA Damage and Errors","year":"2011","author":"Zannis-Hadjopoulos","key":"2022022809421502700_kfab152-B54"},{"key":"2022022809421502700_kfab152-B55","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1021\/tx200251t","article-title":"Chromium in drinking water: Sources, metabolism, and cancer risks","volume":"24","author":"Zhitkovich","year":"2011","journal-title":"Chem. Res. Toxicol"}],"container-title":["Toxicological Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/toxsci\/advance-article-pdf\/doi\/10.1093\/toxsci\/kfab152\/42194350\/kfab152.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/toxsci\/article-pdf\/186\/1\/43\/42633436\/kfab152.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/toxsci\/article-pdf\/186\/1\/43\/42633436\/kfab152.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,14]],"date-time":"2024-09-14T15:30:09Z","timestamp":1726327809000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/toxsci\/article\/186\/1\/43\/6478305"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,22]]},"references-count":55,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12,22]]},"published-print":{"date-parts":[[2022,2,28]]}},"URL":"https:\/\/doi.org\/10.1093\/toxsci\/kfab152","relation":{},"ISSN":["1096-6080","1096-0929"],"issn-type":[{"type":"print","value":"1096-6080"},{"type":"electronic","value":"1096-0929"}],"subject":[],"published-other":{"date-parts":[[2022,3,1]]},"published":{"date-parts":[[2021,12,22]]}}}