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

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-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-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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