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Involvement of genotoxic effects in the initiation of estrogen‐induced cellular transformation: Studies using Syrian hamster embryo cells treated with 17β‐estradiol and eight of its metabolites
Author(s) -
Tsutsui Takeki,
Tamura Yukiko,
Yagi Eiichi,
Barrett J. Carl
Publication year - 2000
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(20000401)86:1<8::aid-ijc2>3.0.co;2-v
Subject(s) - estriol , estrone , estrogen , endocrinology , medicine , carcinogen , biology , carcinogenesis , hamster , clastogen , genotoxicity , chemistry , genetics , toxicity , cancer
To examine a direct involvement of genotoxic effects of estrogens in the initiation of hormonal carcinogenesis, the abilities of 17β‐estradiol (E 2 ) and 8 of its metabolites to induce cellular transformation and genetic effects were studied using the Syrian hamster embryo (SHE) cell model. Treatment with E 2 , estrone (E 1 ), 2‐hydroxyestrone (2‐OHE 1 ), 4‐hydroxyestrone (4‐OHE 1 ), 2‐methoxyestrone (2‐MeOE 1 ), 16α‐hydroxyestrone (16α‐OHE 1 ), 2‐hydroxyestradiol (2‐OHE 2 ), 4‐hydroxyestradiol (4‐OHE 2 ) or estriol (E 3 ) for 1 to 3 days inhibited SHE cell growth in a concentration‐dependent manner. Concentration‐dependent increases in the frequency of morphological transformation in SHE cells were exhibited by treatment for 48 hr with each of all estrogens examined, except for E 3 . The transforming activities of the estrogens, determined by the induced transformation frequencies, were ranked as follows: 4‐OHE 1 > 2‐OHE 1 > 4‐OHE 2 > 2‐OHE 2 ≥ E 2 or E 1 > 2‐MeOE 1 or 16α‐OHE 1 > E 3 . Somatic mutations in SHE cells at the Na + /K + ATPase and /or hprt loci were induced only when the cells were treated with 4‐OHE 1 , 2‐MeOE 1 or 4‐OHE 2 for 48 hr. Some estrogen metabolites induced chromosome aberrations in SHE cells following treatment for 24 hr. The rank order of the clastogenic activities of the estrogens that induced chromosome aberrations was 4‐OHE 1 > 2‐OHE 1 or 4‐OHE 2 > 2‐OHE 2 > E 1 . Significant increases in the percentage of aneuploid cells in the near diploid range were exhibited in SHE cells treated for 48 hr or 72 hr with each of the estrogens, except for 4‐OHE 1 and E 3 . Our results indicate that the transforming activities of all estrogens tested correspond to at least one of the genotoxic effects by each estrogen, i.e., chromosome aberrations, aneuploidy or gene mutations, suggesting the possible involvement of genotoxicity in the initiation of estrogen‐induced carcinogenesis. Int. J. Cancer 86:8–14, 2000. © 2000 Wiley‐Liss, Inc.