Induction of uterine adenocarcinoma in CD-1 mice by catechol estrogens.
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, 17beta-estradiol, or 17alpha-ethinyl estradiol on days 1-5 of neonatal life (2 microg/pup/day) and sacrificed at 12 or 18 months of age. Mice treated with 17beta-estradiol or 17a-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.
Newbold
R R
RR
Developmental Endocrinology Section, Reproductive Toxicology Group, Laboratory of Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA. newbold1@niehs.nih.gov
Liehr
J G
JG
D000230:Adenocarcinoma / Q000139:chemically induced* / Q000473:pathology; D000818:Animals; D000831:Animals, Newborn; D002273:Carcinogens; D006224:Cricetinae; D004958:Estradiol / Q000031:analogs & derivatives* / Q000633:toxicity; D002393:Estrogens, Catechol / Q000633:toxicity*; D004997:Ethinyl Estradiol / Q000633:toxicity; D005260:Female; D051379:Mice; D014594:Uterine Neoplasms / Q000139:chemically induced* / Q000473:pathology; D014599:Uterus / Q000187:drug effects / Q000473:pathology*
D002273:Carcinogens; D002393:Estrogens, Catechol; D004997:Ethinyl Estradiol; D004958:Estradiol; C001390:2-hydroxyestradiol; C014036:4-hydroxyestradiol