Effects of toremifene on neonatal rat uterine growth and differentiation.
In the developing rodent uterus, the estrogen agonist activity of triphenylethylene antiestrogens such as tamoxifen alters uterine luminal epithelium morphology and inhibits uterine gland genesis. We examined uterine growth and differentiation in female offspring from date-mated Sprague-Dawley rats given the structurally related antiestrogen, toremifene, by s.c. injection in 10 microl of sesame oil on postnatal days (PND) 1-5, 10-14, or 20-24. Toremifene given on PND 10-14, a period of rapid uterine gland differentiation, caused a dose-related increase in uterine weight, tripled luminal epithelium cell height, and completely inhibited uterine gland development on PND 14 at doses of 10 microg or higher. Based on this dose-response analysis, a 10-microg dose of toremifene was chosen to assess uterine development after neonatal exposure (PND 1-5). Uterine weights and luminal epithelium cell heights were significantly increased by toremifene on PND 5 but returned to control levels by PND 26. Uterine gland numbers were reduced to 50% those of controls on PND 26. Dose-related uterine weight and luminal epithelium cell height increases were also observed in rats given toremifene on PND 20-24. This estrogen agonist activity of toremifene, revealed primarily in the uterine luminal epithelium, indicates that toremifene is developmentally toxic.
Medlock
K L
KL
Department of Health and Human Services, Food and Drug Administration, National Center for Toxicological Research, Jefferson, Arkansas 72079-9502, USA.
Branham
W S
WS
Sheehan
D M
DM
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D004848:Epithelium / Q000187:drug effects / Q000254:growth & development; D004965:Estrogen Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D051381:Rats; D017207:Rats, Sprague-Dawley; D017312:Toremifene / Q000008:administration & dosage / Q000494:pharmacology*; D014599:Uterus / Q000187:drug effects* / Q000254:growth & development*
D004965:Estrogen Antagonists; D017312:Toremifene