Modifying effects of ethinylestradiol but not methoxychlor on N-ethyl-N-nitrosourea-induced uterine carcinogenesis in heterozygous p53-deficient CBA mice.
It is unknown whether endocrine-disrupting chemicals (EDCs) with estrogenic activities have any modifying effects on uterine carcinogenesis. In our previous study, we established a uterine-carcinogenesis model that is useful for detecting tumor-modifying effects of EDCs by the administration of N-ethyl-N-nitrosourea (ENU) to female heterozygous p53-deficient CBA mice [p53 (+/-) mice]. To investigate the effects of ethinylestradiol (EE) and methoxychlor (MXC) on development of ENU-induced uterine tumors, female p53 (+/-) mice and their wild-type littermates [p53 (+/+) mice] received an intraperitoneal injection of 120 mg/kg body weight (bw) of ENU, followed, in Group 1, by no further treatment; in Group 2, by a diet containing 1 ppm EE; in Group 3, by a diet containing 5 ppm EE for 4 weeks and 2.5 ppm EE thereafter; and in Group 4, by a diet containing 2000 ppm MXC for 26 weeks. Uterine proliferative lesions that were induced were composed of both endometrial-stromal and epithelial-cell types. Endometrial stromal sarcomas were induced in p53 (+/-) mice of Groups 1 to 4, and the incidence (87%) in Group 3 was significantly increased compared to Group 1 (47%). Atypical hyperplasias (clear-cell type) of the endometrial gland in p53 (+/-) mice were seen at incidences of 0, 14, 60, and 0% in Groups 1, 2, 3, and 4, respectively, while their incidence in p53 (+/+) mice was 0, 7, 53, and 0%, respectively, with a significant difference between Groups 1 and 3 in both cases. One p53 (+/-) mouse in Group 3 also had an adenocarcinoma consisting of clear cells, and the PCNA labeling indices of the clear-cell atypical hyperplasias, and this endometrial adenocarcinoma, were higher than those of glandular hyperplasias. The present study suggests that 2.5 ppm EE, but not MXC, exerts tumor-promoting effects on stromal and epithelial proliferative lesions of the uteri in p53 (+/-) mice initiated with ENU.
Mitsumori
K
K
Division of Pathology, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan. mitsumor@nihs.go.jp
Shimo
T
T
Onodera
H
H
Takagi
H
H
Yasuhara
K
K
Tamura
T
T
Aoki
Y
Y
Nagata
O
O
Hirose
M
M
D018262:Adenocarcinoma, Clear Cell / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D003043:Cocarcinogenesis; D004032:Diet; D004357:Drug Synergism; D004714:Endometrial Hyperplasia / Q000139:chemically induced / Q000473:pathology; D016889:Endometrial Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D004997:Ethinyl Estradiol / Q000008:administration & dosage / Q000633:toxicity*; D005038:Ethylnitrosourea / Q000008:administration & dosage / Q000633:toxicity; D005260:Female; D016158:Genes, p53; D007124:Immunoenzyme Techniques; D007274:Injections, Intraperitoneal; D008731:Methoxychlor / Q000008:administration & dosage / Q000633:toxicity*; D051379:Mice; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D009929:Organ Size / Q000187:drug effects; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D018203:Sarcoma, Endometrial Stromal / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D014599:Uterus / Q000737:chemistry / Q000187:drug effects / Q000473:pathology
D002273:Carcinogens; D018809:Proliferating Cell Nuclear Antigen; D004997:Ethinyl Estradiol; D005038:Ethylnitrosourea; D008731:Methoxychlor