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Toxicological Sciences 71, 112-123 (2003)
Copyright © 2003 by the Society of Toxicology

SYSTEMS TOXICOLOGY

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-Induced Accumulation of Biliverdin and Hepatic Peliosis in Rats

Marjo Niittynen*,1, Jouni T. Tuomisto*, Seppo Auriola{dagger}, Raimo Pohjanvirta*,{ddagger},§, Paula Syrjälä{ddagger}, Ulla Simanainen*, Matti Viluksela* and Jouko Tuomisto*

* Department of Environmental Health, Laboratory of Toxicology, National Public Health Institute, Box 95, FIN-70701 Kuopio, Finland; {dagger} Department of Pharmaceutical Chemistry, University of Kuopio, Box 1627, FIN-70211 Kuopio, Finland; {ddagger} National Food and Veterinary Research Institute, Kuopio Department, Box 92, FIN-70701 Kuopio, Finland; and § Department of Food and Environmental Hygiene, Faculty of Veterinary Medicine, Box 57, FIN-00014 University of Helsinki, Helsinki, Finland

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 µg/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 geneB), but never occurred in rats expressing only the Han/Wistar (Kuopio)-type Ah receptor with an altered transactivation domain structure.

Key Words: TCDD; biliverdin; bilirubin; hepatotoxicity; accumulation; porphyrin metabolism; peliosis.


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