Assessment of genotoxic potential of Cr(VI) in the mouse duodenum: an in silico comparison with mutagenic and nonmutagenic carcinogens across tissues.
In vitro studies on hexavalent chromium [Cr(VI)] indicate that reduced forms of this metal can interact with DNA and cause mutations. Recently, Cr(VI) was shown to induce intestinal tumors in mice; however, Cr(VI) elicited redox changes, cytotoxicity and hyperplasia - suggesting involvement of tissue injury rather than direct mutagenesis. Moreover, toxicogenomic analyses indicated limited evidence for DNA damage responses. Herein, we extend these toxicogenomic analyses by comparing the gene expression patterns elicited by Cr(VI) with those of four mutagenic and four nonmutagenic carcinogens. To date, toxicogenomic profiles for mutagenic and nonmutagenic duodenal carcinogens do not exist, thus duodenal gene changes in mice were compared to those elicited by hepatocarcinogens. Specifically, duodenal gene changes in mice following exposure to Cr(VI) in drinking water were compared to hepatic gene changes previously identified as potentially discriminating mutagenic and nonmutagenic hepatocarcinogens. Using multivariate statistical analyses (including logistic regression classification), the Cr(VI) gene responses clustered apart from mutagenic carcinogens and closely with nonmutagenic carcinogens. These findings are consistent with other intestinal data supporting a nonmutagenic mode of action (MOA). These findings may be useful as part of a full weight of evidence MOA evaluation for Cr(VI)-induced intestinal carcinogenesis. Limitations to this analysis will also be discussed.
ToxStrategies, Inc., Katy, TX 77494, USA. cthompson@toxstrategies.com
Chad M
CM
Thompson
J
J
Gregory Hixon
Deborah M
DM
Proctor
Laurie C
LC
Haws
Mina
M
Suh
Jonathan D
JD
Urban
Mark A
MA
Harris
D000818:Animals; D002274:Carcinogens, Environmental / Q000145:classification / Q000633:toxicity*; D002840:Chromates / Q000145:classification / Q000633:toxicity; D002857:Chromium / Q000145:classification / Q000633:toxicity*; D003198:Computer Simulation; D004249:DNA Damage; D004386:Duodenum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055106:Genome-Wide Association Study; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016015:Logistic Models; D051379:Mice; D008815:Mice, Inbred Strains; D009152:Mutagenicity Tests; D009153:Mutagens / Q000145:classification / Q000633:toxicity*; D020411:Oligonucleotide Array Sequence Analysis; D025341:Principal Component Analysis; D018570:Risk Assessment; D043922:Toxicogenetics / Q000379:methods*
D002274:Carcinogens, Environmental; D002840:Chromates; D009153:Mutagens; D002857:Chromium; C074702:chromium hexavalent ion; C016104:sodium bichromate