Modifying effects of ethinylestradiol but not methoxychlor on N-ethyl-N-nitrosourea-induced uterine carcinogenesis in heterozygous p53-deficient CBA mice.

Abstract

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.

• Authors: K Mitsumori, T Shimo, H Onodera, H Takagi, K Yasuhara, T Tamura, Y Aoki, O Nagata, M Hirose
• Journal: Toxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 58 Issue 1 Pg. 43-9 (Nov 2000) ISSN: 1096-6080 [Print] United States
• PMID: 11053539 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carcinogens
• Proliferating Cell Nuclear Antigen
• Ethinyl Estradiol
• Ethylnitrosourea
• Methoxychlor

Topics

• Adenocarcinoma, Clear Cell (chemically induced, genetics, pathology)
• Animals
• Body Weight (drug effects)
• Carcinogens (administration & dosage, toxicity)
• Cocarcinogenesis
• Diet
• Drug Synergism
• Endometrial Hyperplasia (chemically induced, pathology)
• Endometrial Neoplasms (chemically induced, genetics, pathology)
• Ethinyl Estradiol (administration & dosage, toxicity)
• Ethylnitrosourea (administration & dosage, toxicity)
• Female
• Genes, p53
• Immunoenzyme Techniques
• Injections, Intraperitoneal
• Methoxychlor (administration & dosage, toxicity)
• Mice
• Mice, Inbred CBA
• Mice, Knockout
• Organ Size (drug effects)
• Proliferating Cell Nuclear Antigen (analysis)
• Sarcoma, Endometrial Stromal (chemically induced, genetics, pathology)
• Uterus (chemistry, drug effects, pathology)