title: Long-term effects of subcutaneously injected 2,3,7,8-tetrachlorodibenzo-p-dioxin on the liver of rhesus monkeys.
abstract: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) accumulates and remains stable in the fatty tissues and liver of rodents for a long time. Considering the pronounced difference between species, long-term, low dose hepatic effects of TCDD were investigated after subcutaneous administration of TCDD into rhesus monkeys during pregnancy. Macroscopic and histopathological examination of the liver carried out 4 y after TCDD administration demonstrated intrahepatic focal fatty changes, infarction, hemorrhage, microthrombi-formation, sinusoidal ectasia, small hepatocyte hyperplasia, and increased number of alpha-smooth muscle actin (alpha-SMA)-positive cells. An electron microscopic study disclosed sinusoidal endothelial cell degeneration and injury in the liver of TCDD-treated monkeys. Western blot analysis showed downregulation of aryl hydrocarbon receptor (AhR) protein expression and decreased level of vascular endothelial (VE) cadherin but increased expression levels of CYP1A1 and transforming growth factor beta (TGF-beta) protein in the liver tissues. These changes observed in TCDD-exposed monkeys indicated sinusoidal endothelial cell injury and impairment in intrasinusoidal microcirculation. Infarction, focal fatty change, and microthrombi-formation are considered to be closely associated with intrahepatic circulatory impairment. Increased number of alpha-SMA-positive cells and decreased level of VE cadherin expression in the liver tissues might also be associated with sinusoidal endothelial cell injury. In addition, downregulation of AhR expression and increased CYP1A1 protein levels in the liver were consistent with persistent effects of TCDD. Although it has been reported that TCDD induced endothelial cell injury, this is the first report to describe vascular disorders and protein expression in the liver after injection with TCDD in a primate model.
authors.affiliation: Department of Pathology, Teikyo University School of Medicine, 2-11-1 Kaga, Tokyo 173-8606, Japan.
authors.forename: Tatsumi
authors.initials: T
authors.lastname: Korenaga
authors.forename: Toshio
authors.initials: T
authors.lastname: Fukusato
authors.forename: Mari
authors.initials: M
authors.lastname: Ohta
authors.forename: Kazuo
authors.initials: K
authors.lastname: Asaoka
authors.forename: Nobuo
authors.initials: N
authors.lastname: Murata
authors.forename: Akihiro
authors.initials: A
authors.lastname: Arima
authors.forename: Shunichiro
authors.initials: S
authors.lastname: Kubota
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015152:Blotting, Northern; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000473:pathology; D005234:Fatty Liver / Q000139:chemically induced / Q000473:pathology; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced / Q000473:pathology; D007238:Infarction / Q000139:chemically induced / Q000473:pathology; D007279:Injections, Subcutaneous; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology; D008253:Macaca mulatta; D008854:Microscopy, Electron; D009130:Muscle, Smooth / Q000378:metabolism / Q000473:pathology; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000633:toxicity*; D011247:Pregnancy; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism; D013927:Thrombosis / Q000139:chemically induced / Q000473:pathology; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D019363:Cytochrome P-450 CYP1A1; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D016212:Transforming Growth Factor beta; D000099152:Cadherin 5