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[Cancer Research 60, 235-237, January 15, 2000]
© 2000 American Association for Cancer Research

Advances in Brief

Induction of Uterine Adenocarcinoma in CD-1 Mice by Catechol Estrogens1

Retha R. Newbold2 and Joachim G. Liehr

Developmental Endocrinology Section, Reproductive Toxicology Group, Laboratory of Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709 [R. R. N.], and Stehlin Foundation for Cancer Research, Houston, Texas 77003 [J. G. L.]

Catechol estrogens may mediate estrogen-induced carcinogenesis because 4-hydroxyestradiol induces DNA damage and renal tumors in hamsters, and this metabolite is formed in the kidney and estrogen target tissues by a specific estrogen 4-hydroxylase. We examined the carcinogenic potential of catechol estrogen in an experimental model previously reported to result in a high incidence of uterine adenocarcinoma after neonatal exposure to diethylstilbestrol. Outbred female CD-1 mice were treated with 2- or 4-hydroxyestradiol, 17ß-estradiol, or 17{alpha}-ethinyl estradiol on days 1–5 of neonatal life (2 µg/pup/day) and sacrificed at 12 or 18 months of age. Mice treated with 17ß-estradiol or 17{alpha}-ethinyl estradiol had a total uterine tumor incidence of 7% or 43%, respectively. 2-Hydroxyestradiol induced tumors in 12% of the mice, but 4-hydroxyestradiol was the most carcinogenic estrogen, with a 66% incidence of uterine adenocarcinoma. Both 2- and 4-hydroxylated catechols were estrogenic and increased uterine wet weights in these neonates. These data demonstrate that both 2- and 4-hydroxyestradiol are carcinogenic metabolites. The high tumor incidence induced by 4-hydroxyestradiol supports the postulated role of this metabolite in hormone-associated cancers.




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