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Induction of uterine adenocarcinoma in CD-1 mice by catechol estrogens
1Developmental 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
Abstract:
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.
Insights
4-hydroxyestradiol, a catechol estrogen metabolite, is the most potent carcinogen, significantly increasing uterine adenocarcinoma incidence in mice. This finding supports its role in hormone-associated cancers.
Area of Science:
- Endocrinology
- Carcinogenesis
- Toxicology
Background:
- Catechol estrogens are implicated in estrogen-induced carcinogenesis.
- 4-hydroxyestradiol (4-OHE2) metabolite induces DNA damage and renal tumors.
- Estrogen 4-hydroxylase forms 4-OHE2 in target tissues.
Purpose of the Study:
- To investigate the carcinogenic potential of catechol estrogens.
- To evaluate 2-hydroxyestradiol (2-OHE2) and 4-OHE2 in a neonatal mouse model.
- To compare the carcinogenicity of 2-OHE2, 4-OHE2, 17beta-estradiol, and 17alpha-ethinyl estradiol.
Main Methods:
- Neonatal CD-1 mice (days 1-5) were exposed to 2 microg/pup/day of 2-OHE2, 4-OHE2, 17beta-estradiol, or 17alpha-ethinyl estradiol.
- Animals were sacrificed at 12 or 18 months of age.
- Uterine tumor incidence and wet weights were assessed.
Main Results:
- 17alpha-ethinyl estradiol and 17beta-estradiol induced uterine tumors in 43% and 7% of mice, respectively.
- 2-OHE2 induced tumors in 12% of mice.
- 4-OHE2 was the most potent carcinogen, causing uterine adenocarcinoma in 66% of mice and increasing uterine weight.
Conclusions:
- Both 2-OHE2 and 4-OHE2 are carcinogenic estrogen metabolites.
- Neonatal exposure to 4-OHE2 results in a high incidence of uterine adenocarcinoma.
- These findings support the role of 4-OHE2 in hormone-associated cancers.