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Mechanisms of Promotion and Progression of Preneoplastic Lesions in Hepatocarcinogenesis by DDT in F344 Rats

Institute of Environmental Toxicology, Mitsukaido-shi, Ibaraki 303-0043, Japan, harada{at}iet.or.jp

Satoru Yamaguchi

Institute of Environmental Toxicology, Mitsukaido-shi, Ibaraki 303-0043, Japan

Ryoichi Ohtsuka

Institute of Environmental Toxicology, Mitsukaido-shi, Ibaraki 303-0043, Japan

Makio Takeda

Institute of Environmental Toxicology, Mitsukaido-shi, Ibaraki 303-0043, Japan

Hideki Fujisawa

Institute of Environmental Toxicology, Mitsukaido-shi, Ibaraki 303-0043, Japan

Toshinori Yoshida

Institute of Environmental Toxicology, Mitsukaido-shi, Ibaraki 303-0043, Japan

Akiko Enomoto

Institute of Environmental Toxicology, Mitsukaido-shi, Ibaraki 303-0043, Japan

Yuko Chiba

Institute of Environmental Toxicology, Mitsukaido-shi, Ibaraki 303-0043, Japan

Junko Fukumori

Institute of Environmental Toxicology, Mitsukaido-shi, Ibaraki 303-0043, Japan

Sayuri Kojima

Institute of Environmental Toxicology, Mitsukaido-shi, Ibaraki 303-0043, Japan

Naruto Tomiyama

Institute of Environmental Toxicology, Mitsukaido-shi, Ibaraki 303-0043, Japan

Machiko Saka

Institute of Environmental Toxicology, Mitsukaido-shi, Ibaraki 303-0043, Japan

Masakazu Ozaki

Sumika Technoservice Corporation, Osaka 554-8558, Japan

Keizo Maita

Institute of Environmental Toxicology, Mitsukaido-shi, Ibaraki 303-0043, Japan

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.

Key Words: DDT • hepatocarcinogenesis • cell proliferation • intercellular communication • enzyme induction • oxidative stress • eosinophilic foci • F344 rat.

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