title: Mechanism of 1,3-dichloropropene-induced rat liver carcinogenesis.
abstract: 1,3-Dichloropropene (1,3-D) is a soil fumigant used primarily for preplanting control of parasitic nematodes. In a previous chronic dietary exposure study, 1,3-D induced an increased incidence of hepatocellular adenomas in male rats at a dose of 25 mg/kg/day. Although the mechanism for tumor induction in the rat liver by 1,3-D has not been specifically elucidated, available data suggested that the observed liver tumorigenesis was through a nongenotoxic mode of action at the tumor promotion stage. Fischer 344 rats containing preneoplastic lesions were treated (via gavage) with 25 mg/kg/day 1,3-D or 80 mg/kg/day phenobarbital (PB) for 30 days and 60 days, or for 30 days followed by a 30-day recovery period (no compound exposure). Following treatment, placental form glutathione S-transferase (GSTP) positive and GSTP-negative liver focal lesions were quantitated as to size and number. 1,3-D treatment had no effect on GSTP-positive foci number or relative size but significantly increased the number, labeling index, and relative size of GSTP-negative focal lesions (identified by H and E staining) after 30 and 60 days of treatment. Following the 30-day recovery period, the number, labeling index, and relative size of the GSTP-negative lesions in 1,3-D-treated animals returned to control levels. As expected, PB treatment produced an increase in number and relative size of the GSTP-positive lesions. The results of this study are consistent with 1,3-D inducing liver carcinogenesis through a nongenotoxic mode of action by functioning as a tumor promoter specifically through induction of a non-GSTP staining focal hepatocyte population.
authors.affiliation: *Department of Environmental Health, Indiana University, Bloomington, Indiana 47405, Department of Pharmacology/Toxicology, Indiana University, Indianapolis, Indiana 46202, and Dow Agro Sciences, Indianapolis, Indiana 46268 *Department of Environmental Health, Indiana University, Bloomington, Indiana 47405, Department of Pharmacology/Toxicology, Indiana University, Indianapolis, Indiana 46202, and Dow Agro Sciences, Indianapolis, Indiana 46268 jklauni@indiana.edu.
authors.forename: James E
authors.initials: JE
authors.lastname: Klaunig
authors.affiliation: *Department of Environmental Health, Indiana University, Bloomington, Indiana 47405, Department of Pharmacology/Toxicology, Indiana University, Indianapolis, Indiana 46202, and Dow Agro Sciences, Indianapolis, Indiana 46268.
authors.forename: Sean C
authors.initials: SC
authors.lastname: Gehen
authors.affiliation: *Department of Environmental Health, Indiana University, Bloomington, Indiana 47405, Department of Pharmacology/Toxicology, Indiana University, Indianapolis, Indiana 46202, and Dow Agro Sciences, Indianapolis, Indiana 46268 *Department of Environmental Health, Indiana University, Bloomington, Indiana 47405, Department of Pharmacology/Toxicology, Indiana University, Indianapolis, Indiana 46202, and Dow Agro Sciences, Indianapolis, Indiana 46268.
authors.forename: Zemin
authors.initials: Z
authors.lastname: Wang
authors.affiliation: *Department of Environmental Health, Indiana University, Bloomington, Indiana 47405, Department of Pharmacology/Toxicology, Indiana University, Indianapolis, Indiana 46202, and Dow Agro Sciences, Indianapolis, Indiana 46268.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Klein
authors.affiliation: *Department of Environmental Health, Indiana University, Bloomington, Indiana 47405, Department of Pharmacology/Toxicology, Indiana University, Indianapolis, Indiana 46202, and Dow Agro Sciences, Indianapolis, Indiana 46268.
authors.forename: Richard
authors.initials: R
authors.lastname: Billington
mesh_terms: D018248:Adenoma, Liver Cell / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D000498:Allyl Compounds / Q000633:toxicity*; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D004261:DNA Replication / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D051549:Glutathione S-Transferase pi / Q000378:metabolism; D006843:Hydrocarbons, Chlorinated; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010634:Phenobarbital / Q000633:toxicity; D011230:Precancerous Conditions / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D011916:Rats, Inbred F344; D018570:Risk Assessment; D013997:Time Factors
chemical_list: D000498:Allyl Compounds; D014408:Biomarkers, Tumor; D006843:Hydrocarbons, Chlorinated; C023891:1,3-dichloro-1-propene; D051549:Glutathione S-Transferase pi; C496558:Gstp1 protein, rat; D005978:Glutathione; D010634:Phenobarbital
keywords: 1,3-dichloropropene; liver tumor promotion; nongenotoxic; preneoplastic focal lesions