Aryl hydrocarbon receptor knockout rats are insensitive to the pathological effects of repeated oral exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.
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.
The Hamner Institutes for Health Sciences, Institute for Chemical Safety Sciences, Research Triangle Park, NC, 27709, USA.
Joshua A
JA
Harrill
The Hamner Institutes for Health Sciences, Institute for Chemical Safety Sciences, Research Triangle Park, NC, 27709, USA.
Debra
D
Layko
Consultant in Toxicologic Pathology, Sackler School of Medicine, Tel Aviv University, Timrat, 36576, Israel.
Abraham
A
Nyska
The Dow Chemical Company, Midland, MI, 48640, USA.
Renee R
RR
Hukkanen
Research Toxicology Centre, S.P.A., Pomezia, Rome, Italy.
Rosa Anna
RA
Manno
Research Toxicology Centre, S.P.A., Pomezia, Rome, Italy.
Andrea
A
Grassetti
The Dow Chemical Company, Midland, MI, 48640, USA.
Marie
M
Lawson
The Dow Chemical Company, Midland, MI, 48640, USA.
Greg
G
Martin
The Dow Chemical Company, Midland, MI, 48640, USA.
Robert A
RA
Budinsky
The Dow Chemical Company, Midland, MI, 48640, USA.
J Craig
JC
Rowlands
The Hamner Institutes for Health Sciences, Institute for Chemical Safety Sciences, Research Triangle Park, NC, 27709, USA.
Russell S
RS
Thomas
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000284:Administration, Oral; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D063646:Carcinogenesis / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D055786:Gene Knockout Techniques; D006965:Hyperplasia / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D006984:Hypertrophy / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D011230:Precancerous Conditions / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013723:Teratogens / Q000378:metabolism / Q000633:toxicity*; D013950:Thymus Gland / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014018:Tissue Distribution; D066007:Toxicokinetics
D051792:Basic Helix-Loop-Helix Proteins; D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D013723:Teratogens; C000595703:Ahr protein, rat
AHR knockout rat; aryl hydrocarbon receptor; liver pathology; serum chemistry; thymic atrophy