1. Aryl hydrocarbon receptor knockout rats are insensitive to the pathological effects of repeated oral exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.
- Author
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Harrill JA, Layko D, Nyska A, Hukkanen RR, Manno RA, Grassetti A, Lawson M, Martin G, Budinsky RA, Rowlands JC, and Thomas RS
- Subjects
- Adipose Tissue drug effects, Adipose Tissue metabolism, Adipose Tissue pathology, Administration, Oral, Animals, Basic Helix-Loop-Helix Transcription Factors genetics, Basic Helix-Loop-Helix Transcription Factors metabolism, Dose-Response Relationship, Drug, Environmental Pollutants administration & dosage, Environmental Pollutants metabolism, Female, Gene Knockout Techniques, Hyperplasia chemically induced, Hyperplasia metabolism, Hyperplasia pathology, Hypertrophy chemically induced, Hypertrophy metabolism, Hypertrophy pathology, Liver drug effects, Liver metabolism, Liver pathology, Lung drug effects, Lung metabolism, Lung pathology, Polychlorinated Dibenzodioxins administration & dosage, Polychlorinated Dibenzodioxins metabolism, Precancerous Conditions metabolism, Precancerous Conditions pathology, Random Allocation, Rats, Sprague-Dawley, Rats, Transgenic, Receptors, Aryl Hydrocarbon genetics, Receptors, Aryl Hydrocarbon metabolism, Teratogens metabolism, Thymus Gland drug effects, Thymus Gland metabolism, Thymus Gland pathology, Tissue Distribution, Toxicokinetics, Basic Helix-Loop-Helix Transcription Factors agonists, Carcinogenesis drug effects, Environmental Pollutants toxicity, Polychlorinated Dibenzodioxins toxicity, Precancerous Conditions chemically induced, Receptors, Aryl Hydrocarbon agonists, Teratogens toxicity
- Abstract
Sustained activation of the aryl hydrocarbon receptor (AHR) is believed to be the initial key event in AHR receptor-mediated tumorigenesis in the rat liver. The role of AHR in mediating pathological changes in the liver prior to tumor formation was investigated in a 4-week, repeated-dose study using adult female wild-type (WT) and AHR knockout (AHR-KO) rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Beginning at 8 weeks of age, AHR-KO and WT rats were dosed by oral gavage with varying concentrations of TCDD (0, 3, 22, 100, 300 and 1000 ng kg(-1) day(-1) ). Lung, liver and thymus histopathology, hematology, serum chemistry and the distribution of TCDD in liver and adipose tissue were examined. Treatment-related increases in the severity of liver and thymus pathology were observed in WT, but not AHR-KO rats. In the liver, these included hepatocellular hypertrophy, bile duct hyperplasia, multinucleated hepatocytes and inflammatory cell foci. A loss of cellularity in the thymic cortex and thymic atrophy was observed. Treatment-related changes in serum chemistry parameters were also observed in WT, but not AHR-KO rats. Finally, dose-dependent accumulation of TCDD was observed primarily in the liver of WT rats and primarily in the adipose tissue of AHR-KO rats. The results suggest that AHR activation is the initial key event underlying the progression of histological effects leading to liver tumorigenesis following TCDD treatment. Copyright © 2015 John Wiley & Sons, Ltd., (Copyright © 2015 John Wiley & Sons, Ltd.)
- Published
- 2016
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