Promoting effect of the peroxisome proliferator, clofibrate, but not di(2-ethylhexyl)phthalate, on urinary bladder carcinogenesis in F344 rats initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine.
The modifying potential of clofibrate and di(2-ethylhexyl)phthalate (DEHP) on second stage, N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-initiated urinary bladder carcinogenesis was investigated in male F344 rats, using a uracil-accelerated transitional cell proliferation model. Six-week-old animals received 0.05% BBN in their drinking water for 4 weeks and then clofibrate (1.0, 0.5, and 0.25%) and DEHP (1.2, 0.6, and 0.3%) were given during experimental weeks 5-8 and weeks 12-20. Uracil was administered during weeks 9-11 at a dietary level of 3.0%. Control rats were treated with BBN and uracil without peroxisome proliferator. Surviving animals were killed at the end of week 20 of the experiment, when the densities of putative preneoplastic, papillary or nodular (PN) hyperplasias (numbers per 10 cm of basement membrane) were significantly increased in all clofibrate-treated, but not the DEHP groups. The incidences of PN hyperplasia were similar in both treated animals and controls. In a second experiment, rats fed diets containing 1.0% clofibrate or 1.2% DEHP were assessed for levels of DNA synthesis in urinary bladder epithelium by 5-bromo-2-deoxyuridine immunohistochemistry. Numbers of labeled nuclei remained within normal levels, and no proliferative changes were evident. Thus, the present experiments indicated that while clofibrate, but not DEHP, exerts weak enhancing effects on BBN-initiated urinary bladder carcinogenesis in rats this is not associated with increased levels of DNA synthesis in the affected epithelium.
Hagiwara
A
A
First Department of Pathology, Nagoya City University Medical School.
Tamano
S
S
Ogiso
T
T
Asakawa
E
E
Fukushima
S
S
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002085:Butylhydroxybutylnitrosamine; D002273:Carcinogens; D002994:Clofibrate / Q000008:administration & dosage / Q000633:toxicity*; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004051:Diethylhexyl Phthalate / Q000008:administration & dosage / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D014498:Uracil / Q000008:administration & dosage; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced* / Q000473:pathology
D002273:Carcinogens; D004273:DNA, Neoplasm; D002085:Butylhydroxybutylnitrosamine; D014498:Uracil; D004051:Diethylhexyl Phthalate; D002994:Clofibrate