Modifying effects of butylated hydroxyanisole, di(2-ethylhexyl)phthalate or indomethacin on mouse hepatocarcinogenesis initiated by N-nitrosodiethylamine.
Preneoplastic and neoplastic liver and lung lesions were studied in male B6C3F1 mice given a single injection (80 mg/kg) of N-nitrosodiethylamine (DEN) intraperitoneally at 4 weeks of age, followed 1 week later by oral exposure to di(2-ethylhexyl)-phthalate (DEHP; at 6000 ppm in the diet), butylated hydroxyanisole (BHA; 7500 ppm in the diet) or indomethacin (10 ppm in the drinking water) alone or in combination (DEHP and BHA or DEHP and indomethacin), and continued for 29 weeks. DEHP or BHA alone and the combination of DEHP and BHA increased the incidence of DEN-initiated focal hepatocellular proliferative lesions (FHPL), including both microscopic hyperplastic foci and hepatocellular adenomas. Mice that received BHA alone or DEHP plus BHA had FHPL that were composed predominantly of eosinophilic hepatocytes, while FHPL in DEHP-exposed mice were basophilic. Indomethacin showed neither promotional or antipromotional effects, except for lung tumors. Mice receiving DEHP and indomethacin after DEN had significantly fewer lung lesions. A high incidence of renal papillary necrosis and nephropathy was observed in the indomethacin-DEHP exposed mice, while these lesions were not found in mice treated with indomethacin alone or DEHP alone. These findings suggest that BHA, an antioxidant, promoted pre-neoplastic liver lesions while indomethacin, a known inhibitor of prostaglandin synthesis and a chemopreventive agent for colon and mammary tumors in other studies, had no effect on liver tumor promotion by DEHP.
D000236:Adenoma / Q000139:chemically induced; D000818:Animals; D002083:Butylated Hydroxyanisole / Q000633:toxicity*; D003043:Cocarcinogenesis; D004051:Diethylhexyl Phthalate / Q000633:toxicity*; D004052:Diethylnitrosamine; D007213:Indomethacin / Q000633:toxicity*; D007681:Kidney Papillary Necrosis / Q000139:chemically induced; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008175:Lung Neoplasms / Q000139:chemically induced; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010795:Phthalic Acids / Q000633:toxicity*
D010795:Phthalic Acids; D002083:Butylated Hydroxyanisole; D004052:Diethylnitrosamine; D004051:Diethylhexyl Phthalate; D007213:Indomethacin