Diethylstilbestrol (DES): carcinogenic potential in Xpa-/-, Xpa-/- / p53+/-, and wild-type mice during 9 months' dietary exposure.
DES carcinogenicity has been investigated in 2 mouse knockout models, the Xpa homozygous knockout, and the combined Xpa homozygous and p53 heterozygous knockout. Wild-type (WT) mice were also included. Xpa mice received diets containing DES at concentrations of 0, 100, 300, and 1500 ppb for 39 weeks; Xpa/p53 and WT mice received diets containing 0 or 1500 ppb. There were 15 of each sex per group. Both Xpa and WT mice had a similar incidence of tumors at the high dosage of 1500 ppb, including pituitary adenomas in 4 WT mice and 7 Xpa mice, and single incidences of osteosarcoma (Xpa), T-cell lymphoma (WT and Xpa), and testicular interstitial cell adenoma (WT and Xpa). The incidence of tumors was higher in the Xpa/p53 mice at 1500 ppb, mainly attributable to 5 osteosarcomas in males and 2 in females, but also 4 pituitary adenomas, testicular interstitial cell adenomas in 4 males, and single incidences of cerebral glioma, phaeochromocytoma, and cervical fibrosarcoma. The incidence of osteosarcomas was related to the severity of fibro-osseous lesions in the bone marrow. It was concluded that for carcinogenicity screening, Xpa mice were no more sensitive than wild-type mice for compounds like DES, but the Xpa/p53 model showed an increased sensitivity.
McAnulty
Peter A
PA
SCANTOX (LAB Research International), Ejby, DK-4623, Lille Skensved, Denmark. peter.mcanulty@ferring.com
Skydsgaard
Mikala
M
D000284:Administration, Oral; D000818:Animals; D002273:Carcinogens / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D004032:Diet; D004054:Diethylstilbestrol / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000139:chemically induced* / Q000473:pathology; D012516:Osteosarcoma / Q000139:chemically induced* / Q000473:pathology; D013997:Time Factors; D036401:Toxicity Tests, Chronic; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D002273:Carcinogens; D016159:Tumor Suppressor Protein p53; D004054:Diethylstilbestrol