| Sign In to gain access to subscriptions and/or personal tools. |
Diethylstilbestrol (DES): Carcinogenic Potential in Xpa–/–, Xpa–/–/p53+/–, and Wild-Type Mice During 9 Months’ Dietary ExposureSCANTOX (LAB Research International), Ejby, DK-4623 Lille Skensved, Denmark Correspondence: Address correspondence to: Dr. Peter A McAnulty, Ferring Pharmaceuticals A/S, Kay Fiskers Plads 11, DK-2300 Copenhagen S, Denmark; e-mail:peter.mcanulty{at}ferring.com 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.
Key Words: Diethylstilbestrol • carcinogenicity • Xpa mice • Xpa/p53 mice • osteosarcoma • fibro-osseous lesions Abbreviations: ACT, Alternatives to Carcinogenicity Testing • ALP, alkaline phosphatase • ALT, alanine aminotransferase • AST, aspartate aminotransferase • B[a]P, benzo[a]pyrene • DES, diethylstilbestrol • DNA, deoxyribonucleic acid • FOL, fibro-osseous lesion • IARC, International Agency for Research on Cancer • ILSI, International Life Sciences Institute • LDH, lactate dehydrogenase • MTD, maximum tolerated dose • NER, nucelotide excision repair • ppb, parts per billion • RITA, Registry of Industrial Toxicology Animal-Data • RIVM, Rijksinstituut voor Volksgezondheid en Milieu (National Institute of Public Health and the Environment, The Netherlands) •
Toxicologic Pathology, Vol. 33, No. 5,
609-620 (2005) This article has been cited by other articles:
|
||||||||||||||||||||||||||||
 |
|
|
 |
|
Sign In to gain access to subscriptions and/or personal tools.
GT, gamma-glutamyl transferase • µkat, microkatal
