2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced accumulation of biliverdin and hepatic peliosis in rats.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a widespread, persistent, and highly toxic environmental pollutant. The most TCDD-sensitive and the most TCDD-resistant rat strains (Long-Evans [Turku/AB] and Han/Wistar [Kuopio], respectively) were crossbred to separate the alleles of two genes (Ahrand an unidentified gene "B") mediating resistance against TCDD toxicity. During crossbreeding, a new type of toxicity in livers of both sexes was detected, characterized macroscopically by intense dark green to black color and swelling that appeared most frequently after a large dose (300 micro g/kg or more as a single intragastric dose) and a follow-up period of more than three weeks. Therefore, studies were undertaken to identify the causative pigment chemically and to examine the hepatotoxicity histologically. The pigment fractions were separated by thin layer chromatography and then analyzed by HPLC and electrospray mass spectrometry. The pigment was found to consist of biliverdin and several biliverdin-related compounds. In liver histopathology carried out on male rats, progressive sinusoidal distension and hepatic peliosis with membrane-bound cysts were seen. The clinical manifestations of pigment accumulation were recorded most often in intermediately resistant rat lines such as line B (homozygous for the gene B), but never occurred in rats expressing only the Han/Wistar (Kuopio)-type Ah receptor with an altered transactivation domain structure.
Niittynen
Marjo
M
Department of Environmental Health, Laboratory of Toxicology, National Public Health Institute, Box 95, FIN-70701 Kuopio, Finland. marjo.niitynen@ktl.fi
Tuomisto
Jouni T
JT
Auriola
Seppo
S
Pohjanvirta
Raimo
R
Syrjälä
Paula
P
Simanainen
Ulla
U
Viluksela
Matti
M
Tuomisto
Jouko
J
D000818:Animals; D001664:Biliverdine / Q000378:metabolism*; D001947:Breeding / Q000379:methods; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D020022:Genetic Predisposition to Disease; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D010382:Peliosis Hepatis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D020318:Rats, Long-Evans; D017208:Rats, Wistar; D021241:Spectrometry, Mass, Electrospray Ionization
D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D001664:Biliverdine