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Target Organ Specificity of Cell Proliferation Induced by Various Carcinogens

First Department of Pathology, Nagoya City University Medical School, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467, Japan

Masae Tatematsu

First Department of Pathology, Nagoya City University Medical School, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467, Japan, Laboratory of Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464, Japan

Katsumi Takaba

First Department of Pathology, Nagoya City University Medical School, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467, Japan

Shogo Iwasaki

First Department of Pathology, Nagoya City University Medical School, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467, Japan

Nobuyuki Ito

First Department of Pathology, Nagoya City University Medical School, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467, Japan

The target organ specificities of cell proliferation and histopathological lesion induction by 5 carcinogens having different target organs were evaluated using a multiorgan carcinogenesis bioassay. In Group 1, male F-344 rats aged 6 wk were sequentially treated with N-diethylnitrosamine (DEN, single 100-mg/kg ip injection, week 0), N-methyl-N-nitrosourea (MNU, 4 20-mg/kg ip injections, weeks 0-2), N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN, 0.05% in drinking water, weeks 0-2), N,N'-dimethylhydrazine (DMH, 4 40-mg/kg sc injections, weeks 2-4), and dihydroxy-di-N-propylnitrosamine (DHPN, 0.1% in drinking water, weeks 2-4) during the first 4 wk. In Groups 2-6, rats were treated with only one of the above initiators, applied as in Group 1. Group 7 served as the no-treatment control. Bromouracil deoxyriboside (BUdR) labeling indices (LI) were counted in various organs at weeks 2 and 4. Numbers and areas of glutathione S-transferase placental form positive (GST-P⁺) liver foci were measured at weeks 2, 4, and 28. Preneoplastic or neoplastic lesion development was assessed at week 28. With regard to specific elevation of cell proliferation in target organs, BUdR LIs in the urinary bladder, liver, and colon were, respectively, increased in the BBN alone, DEN alone, and DMH alone treated groups as well as in Group 1. However, LIs of thyroid, lung, and kidney were also elevated by several carcinogens not including these organs in their carcinogenic target specificity. On the other hand, morphological lesions and GST-P+ foci were limited to Group 1 and the target organs of the corresponding carcinogen-treated groups. Renal lesions were only observed in Group 1. These results demonstrate that carcinogenic target organs of chemicals should be evaluated not simply on the basis of cell proliferation but rather in terms of the essential parameter of preneoplastic or neoplastic lesion induction.

Key Words: Multiorgan carcinogenesis • rats • synergism of carcinogens

Toxicologic Pathology, Vol. 21, No. 5, 436-442 (1993)
DOI: 10.1177/019262339302100502


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