Modifying effects of &beta-estradiol 3-benzoate on thyroid tumorigenesis in gonadectomized rats induced by N-bis(2-hydroxypropyl)nitrosamine

A. Nishikawa, MD, PhD a, H-Y. Son, DVM, PhD b, T. Imazawa, PhD a, K. Okazaki, MS a and M. Hirose, MD, PhD a

a Division of Pathology, National Institute of Health Sciences, Tokyo, Japan; b College of Veterinary Medicine, Chungnam National University, Daejon, Korea

AIM: The modifying effects of &beta -estradiol 3-benzoate (EB), a synthetic estrogenic compound, on thyroid tumorigenesis were investigated in a rat two-stage model using N-bis(2-hydroxypropyl)nitrosamine (DHPN) in order to determine the characterization of estrogenic activity on thyroid effects. METHODS: Gonadectomized F344 rats of both sexes were implanted subcutaneously with fused pellets containing EB for 32 weeks. Variable doses of EB (0, 0.004, 0.02 and 0.1 mg) were achieved by varying the ratio of EB to cholesterol in the pellet. Major organs including the thyroid, pituitary, liver, kidneys, testes, uterus and brain were weighed and histopathological observation was performed. Serum was assayed for hormones such as T3, T4 and TSH. RESULTS: Thyroid weights were increased by the EB pellet implantation in a dose-dependent manner and significantly (p<0.05) elevated in both sexes of the 0.1 mg EB group regardless of the DHPN pretreatment. The EB treatment suppressed serum T4 levels and inversely elevated serum TSH levels with or without the DHPN pretreatment in both males and females, although EB had little effects on T3 levels in both sexes. Histopathologically, EB increased the occurrence of thyroid proliferative lesions in males and showed a tendency for increase in females, but only at the highest level of 0.1mg, accompanying pituitary adenomas. CONCLUSION: These results indicate that prolonged EB stimulation promotes thyroid tumorigenesis at doses as high as 0.1mg although thyroid weights and serum TSH levels were dose-dependently elevated at lower doses.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Carcinogenesis.