title: 2,3,7,8 Tetrachlorodibenzo-p-dioxin-induced RNA abundance changes identify Ackr3, Col18a1, Cyb5a and Glud1 as candidate mediators of toxicity.
abstract: 2,3,7,8 Tetrachlorodibenzo-p-dioxin (TCDD) is an aromatic, long-lived environmental contaminant. While the pathogenesis of TCDD-induced toxicity is poorly understood, it has been shown that the aryl hydrocarbon receptor (AHR) is required. However, the specific transcriptomic changes that lead to toxic outcomes have not yet been identified. We previously identified a panel of 33 genes that respond to TCDD treatment in two TCDD-sensitive rodent species. To identify genes involved in the onset of hepatic toxicity, we explored 25 of these in-depth using liver from two rat strains: the TCDD-resistant Han/Wistar (H/W) and the TCDD-sensitive Long-Evans (L-E). Time course and dose-response analyses of mRNA abundance following TCDD insult indicate that eight genes are similarly regulated in livers of both strains of rat, suggesting that they are not central to the severe L-E-specific TCDD-induced toxicities. The remaining 17 genes exhibited various divergent mRNA abundances between L-E and H/W strains after TCDD treatment. Several genes displayed a biphasic response where the initial response to TCDD treatment was followed by a secondary response, usually of larger magnitude in L-E liver. This secondary response was most often an exaggeration of the original TCDD-induced response. Only cytochrome b5 type A (microsomal) (Cyb5a) had equivalent TCDD sensitivity to the prototypic AHR-responsive cytochrome P450, family 1, subfamily a, polypeptide 1 (Cyp1a1), while six genes were less sensitive. Four genes showed an early inter-strain difference that was sustained throughout most of the time course (atypical chemokine receptor 3 (Ackr3), collagen, type XVIII, alpha 1 (Col18a1), Cyb5a and glutamate dehydrogenase 1 (Glud1)), and of those genes examined in this study, are most likely to represent genes involved in the pathogenesis of TCDD-induced hepatotoxicity in L-E rats.
authors.affiliation: Informatics and Bio-computing Program, MaRS Centre, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, ON, M5G 0A3, Canada.
authors.forename: John D
authors.initials: JD
authors.lastname: Watson
authors.affiliation: Informatics and Bio-computing Program, MaRS Centre, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, ON, M5G 0A3, Canada.
authors.forename: Stephenie D
authors.initials: SD
authors.lastname: Prokopec
authors.affiliation: Informatics and Bio-computing Program, MaRS Centre, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, ON, M5G 0A3, Canada.
authors.forename: Ashley B
authors.initials: AB
authors.lastname: Smith
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada.
authors.forename: Allan B
authors.initials: AB
authors.lastname: Okey
authors.affiliation: Laboratory of Toxicology, National Institute for Health and Welfare, Kuopio, Finland.|Department of Food Hygiene and Environmental Health, University of Helsinki, Helsinki, Finland.
authors.forename: Raimo
authors.initials: R
authors.lastname: Pohjanvirta
authors.affiliation: Informatics and Bio-computing Program, MaRS Centre, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, ON, M5G 0A3, Canada. Paul.Boutros@oicr.on.ca.|Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada. Paul.Boutros@oicr.on.ca.|Department of Medical Biophysics, University of Toronto, Toronto, Canada. Paul.Boutros@oicr.on.ca.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Boutros
mesh_terms: D000818:Animals; D021461:Animals, Outbred Strains; D002274:Carcinogens, Environmental / Q000008:administration & dosage / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000378:metabolism*; D024102:Collagen Type VIII / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015786:Cytochromes b5 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D005969:Glutamate Dehydrogenase; D007700:Kinetics; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism*; D020318:Rats, Long-Evans; D054387:Receptors, CXCR / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017470:Receptors, Glutamate / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D002274:Carcinogens, Environmental; D024102:Collagen Type VIII; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D054387:Receptors, CXCR; D017470:Receptors, Glutamate; D015786:Cytochromes b5; C570817:GluD1 protein, mouse; D005969:Glutamate Dehydrogenase
keywords: 2,3,7,8 Tetrachlorodibenzo-p-dioxin; Aryl hydrocarbon receptor; NanoString; TCDD; Toxicity; mRNA abundance