title: Mechanisms of promotion and progression of preneoplastic lesions in hepatocarcinogenesis by DDT in F344 rats.
abstract: Time-related changes in potential factors involved in hepatocarcinogenesis by DDT were investigated in a 4-week and a 2-year feeding studies of p,p'-DDT with F344 rats. In the 4-week study with males at doses of 50, 160, and 500 ppm, cell proliferation and gap junctional intercellular communication (GJIC) were examined after 1, 2, 3, 7, 14, and 28 days. Cell proliferation was enhanced within 3 days at any dose level, but returned to normal after 7 days, whereas GJIC was inhibited throughout the study. In the 2-year study with both sexes at doses of 5, 50, and 500 ppm, cell proliferation, GJIC, enzyme induction, and oxidative stress were investigated after 26, 52, 78, and 104 weeks. Males and females showed an inhibition of GJIC and increases in P450 isozymes (CYP2B1 and CYP3A2) in a dose-dependent manner at all time points, but no significant change in cell proliferation. Lipid peroxide for males at 50 and 500 ppm and 8-hydroxydeoxyguanosine for both sexes at 500 ppm were elevated throughout the study. Histologically, eosinophilic foci and hepatocellular adenomas increased in males at 50 ppm and both sexes at 500 ppm. Hepatocellular carcinomas also developed in males at 500 ppm. These results indicate that DDT may induce eosinophilic foci as a result of oxidative DNA damage and leads them to neoplasms in combination with its mitogenic activity and inhibitory effect on GJIC. Oxidative stress could be a key factor in hepatocarcinogenesis by DDT.
authors.affiliation: Institute of Environmental Toxicology, Mitsukaido-shi, Ibaraki 303-0043, Japan. harada@iet.or.jp
authors.forename: Takanori
authors.initials: T
authors.lastname: Harada
authors.forename: Satoru
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Ohtsuka
authors.forename: Makio
authors.initials: M
authors.lastname: Takeda
authors.forename: Hideki
authors.initials: H
authors.lastname: Fujisawa
authors.forename: Toshinori
authors.initials: T
authors.lastname: Yoshida
authors.forename: Akiko
authors.initials: A
authors.lastname: Enomoto
authors.forename: Yuko
authors.initials: Y
authors.lastname: Chiba
authors.forename: Junko
authors.initials: J
authors.lastname: Fukumori
authors.forename: Sayuri
authors.initials: S
authors.lastname: Kojima
authors.forename: Naruto
authors.initials: N
authors.lastname: Tomiyama
authors.forename: Machiko
authors.initials: M
authors.lastname: Saka
authors.forename: Masakazu
authors.initials: M
authors.lastname: Ozaki
authors.forename: Keizo
authors.initials: K
authors.lastname: Maita
mesh_terms: D000818:Animals; D015197:Carcinogenicity Tests; D002455:Cell Division / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003634:DDT / Q000633:toxicity*; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005260:Female; D017629:Gap Junctions / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D011230:Precancerous Conditions / Q000139:chemically induced* / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D003577:Cytochrome P-450 Enzyme System; D003634:DDT