title: Investigation of the mode of action underlying the tumorigenic response induced in B6C3F1 mice exposed orally to hexavalent chromium.
abstract: Chronic ingestion of high concentrations of hexavalent chromium [Cr(VI)] in drinking water induces intestinal tumors in mice. To investigate the mode of action (MOA) underlying these tumors, a 90-day drinking water study was conducted using similar exposure conditions as in a previous cancer bioassay, as well as lower (heretofore unexamined) drinking water concentrations. Tissue samples were collected in mice exposed for 7 or 90 days and subjected to histopathological, biochemical, toxicogenomic, and toxicokinetic analyses. Described herein are the results of toxicokinetic, biochemical, and pathological findings. Following 90 days of exposure to 0.3-520 mg/l of sodium dichromate dihydrate (SDD), total chromium concentrations in the duodenum were significantly elevated at ≥ 14 mg/l. At these concentrations, significant decreases in the reduced-to-oxidized glutathione ratio (GSH/GSSG) were observed. Beginning at 60 mg/l, intestinal lesions were observed including villous cytoplasmic vacuolization. Atrophy, apoptosis, and crypt hyperplasia were evident at ≥ 170 mg/l. Protein carbonyls were elevated at concentrations ≥ 4 mg/l SDD, whereas oxidative DNA damage, as assessed by 8-hydroxydeoxyguanosine, was not increased in any treatment group. Significant decreases in the GSH/GSSG ratio and similar histopathological lesions as observed in the duodenum were also observed in the jejunum following 90 days of exposure. Cytokine levels (e.g., interleukin-1β) were generally depressed or unaltered at the termination of the study. Overall, the data suggest that Cr(VI) in drinking water can induce oxidative stress, villous cytotoxicity, and crypt hyperplasia in the mouse intestine and may underlie the MOA of intestinal carcinogenesis in mice.
authors.affiliation: ToxStrategies, Inc., Katy, Texas 77494, USA. cthompson@toxstrategies.com
authors.forename: Chad M
authors.initials: CM
authors.lastname: Thompson
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Proctor
authors.forename: Laurie C
authors.initials: LC
authors.lastname: Haws
authors.forename: Charles D
authors.initials: CD
authors.lastname: Hébert
authors.forename: Sheila D
authors.initials: SD
authors.lastname: Grimes
authors.forename: Howard G
authors.initials: HG
authors.lastname: Shertzer
authors.forename: Anna K
authors.initials: AK
authors.lastname: Kopec
authors.forename: J Gregory
authors.initials: JG
authors.lastname: Hixon
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Zacharewski
authors.forename: Mark A
authors.initials: MA
authors.lastname: Harris
mesh_terms: D058739:Aberrant Crypt Foci / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015197:Carcinogenicity Tests; D002274:Carcinogens, Environmental / Q000493:pharmacokinetics / Q000633:toxicity*; D002840:Chromates / Q000493:pharmacokinetics / Q000633:toxicity*; D002857:Chromium / Q000493:pharmacokinetics / Q000633:toxicity*; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004249:DNA Damage; D060766:Drinking Water; D005260:Female; D007422:Intestines / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D018384:Oxidative Stress / Q000187:drug effects; D018570:Risk Assessment
chemical_list: D002274:Carcinogens, Environmental; D002840:Chromates; D016207:Cytokines; D060766:Drinking Water; D002857:Chromium; C074702:chromium hexavalent ion; C016104:sodium bichromate