Absence of uterine tumours in CD-1 mice treated neonatally with subcutaneous tamoxifen or 4-hydroxyoestradiol.
The effects of subcutaneous dosing of neonatal CD-1 mice with tamoxifen on days 1-5 after birth at doses of 0, 5, 10, 25 or 50 microg/pup or with 4-hydroxyoestradiol at 2 microg/pup have been investigated. Animals were culled at 1.5, 3, 6, 12 and 18 months after dosing and changes in uterine and ovarian pathology examined. Results showed both compounds to result in uterine hypoplasia relative to controls. At 18 months after dosing in the uterus, there was a fairly marked atrophy of the muscle layer, mild to moderate glandular hyperplasia of the endometrium even though these irregularly shaped glands did not penetrate through the myometrium and no adenocarcinomas were detected. At 18 months after dosing, oviducts showed mild focal adenomatous changes characterized by penetration epithelial hyperplasia, changes similar to those previously reported as 'diverticulosis and salpingitis isthmica nodosa' following diethylstilbestrol treatment of mice. At this time, both tamoxifen and 4-hydroxyoestradiol also affected the ovaries which showed a paucity of follicles and no corpora lutea, suggesting that there had been disruption to the oestrus cycle, particularly with tamoxifen at the highest dose where the ovaries of mice contained no developing follicles. At 18 months, control mice were cycling normally. Results failed to substantiate that tamoxifen and 4-hydroxyoestradiol are uterine carcinogens in this neonatal mouse model.
Razvi
Nihal
N
MRC Molecular Endocrinology Group, Department of Cancer Studies and Molecular Medicine, University of Leicester, Robert Kilpatrick Building, Leicester LE2 7LX, UK.
Greaves
Peter
P
Styles
Jerry
J
Edwards
Richard
R
White
Ian N H
IN
D000818:Animals; D000831:Animals, Newborn; D018931:Antineoplastic Agents, Hormonal / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004717:Endometrium / Q000187:drug effects / Q000473:pathology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000633:toxicity; D002393:Estrogens, Catechol; D005260:Female; D007279:Injections, Subcutaneous; D051379:Mice; D008815:Mice, Inbred Strains; D009929:Organ Size / Q000187:drug effects; D010053:Ovary / Q000187:drug effects / Q000473:pathology; D013629:Tamoxifen / Q000633:toxicity*; D014594:Uterine Neoplasms / Q000473:pathology*; D014599:Uterus / Q000002:abnormalities / Q000187:drug effects* / Q000473:pathology