Assessment of genotoxic potential of Cr(VI) in the mouse duodenum: An in silico comparison with mutagenic and nonmutagenic carcinogens across tissues

Abstract

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.

A chronic oral reference dose for hexavalent chromium‐induced intestinal cancer

“…To investigate the MOA for intestinal carcinogenesis, a series of studies were conducted to collect histological, biochemical, toxicogenomic and pharmacokinetic data in the rodent SI (Kirman et al ., ; Kirman et al ., ; Kopec et al ., , ; O'Brien et al ., ; Proctor et al ., ; Thompson et al ., , , , , ). These data were evaluated along with other relevant literature (including the NTP study findings) to develop a MOA for intestinal carcinogenesis (Thompson et al ., ).…”

Assessment of the mode of action underlying development of rodent small intestinal tumors following oral exposure to hexavalent chromium and relevance to humans

“…The four mutagenic carcinogens are 2-nitrofluorene, dimethylnitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and aflatoxin B1; the four nonmutagenic carcinogens are methapyrilene, diethylstilbestrol, Wy-14643 and piperonylbutoxide. Panel B is adapted from Thompson et al (2012b). …”

“…The reader is referred to Thompson et al . (2012b) for further details of this analysis. Overall, the genomic response induced by 520 mg/l SDD at day 8 was more similar to that induced by nonmutagenic than by mutagenic carcinogens (Figure 6B; Thompson et al .…”

“…Overall, the genomic response induced by 520 mg/l SDD at day 8 was more similar to that induced by nonmutagenic than by mutagenic carcinogens (Figure 6B; Thompson et al . 2012b). These findings lend additional support to the WOE indicating that the intestinal tumors in the mouse duodenum were the result of a nonmutagenic MOA.…”

“…The study design, described in detail in Thompson et al (2011b, 2012c), employed the same drinking water concentrations as the NTP 2-year bioassay (NTP, 2008b) as well as two lower drinking water concentrations; one of which was 100 μg/l, the federal maximum contaminant level (MCL) for total chromium (US EPA, 1991). Histopathological, biochemical, toxicogenomic and pharmacokinetic data were collected in the target tissues after 7 and 90 days of exposure, and many of the study results have been published (Kirman et al, 2012; Kopec et al, 2012a,b; Proctor et al, 2012; Thompson et al, 2011b, 2012a,b,c). …”