title: TCDD dysregulation of 13 AHR-target genes in rat liver.
abstract: Despite several decades of research, the complete mechanism by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other xenobiotic agonists of the aryl hydrocarbon receptor (AHR) cause toxicity remains unclear. While it has been shown that the AHR is required for all major manifestations of toxicity, the specific downstream changes involved in the development of toxic phenotypes remain unknown. Here we examine a panel of 13 genes that are AHR-regulated in many species and tissues. We profiled their hepatic mRNA abundances in two rat strains with very different sensitivities to TCDD: the TCDD-sensitive Long-Evans (Turku/AB; L-E) and the TCDD-resistant Han/Wistar (Kuopio; H/W). We evaluated doses ranging from 0 to 3000μg/kg at 19h after TCDD exposure and time points ranging from 1.5 to 384h after exposure to 100μg/kg TCDD. Twelve of 13 genes responded to TCDD in at least one strain, and seven of these showed statistically significant inter-strain differences in the time course analysis (Aldh3a1, Cyp1a2, Cyp1b1, Cyp2a1, Fmo1, Nfe2l2 and Nqo1). Cyp2s1 did not respond to TCDD in either rat strain. Five genes exhibited biphasic responses to TCDD insult (Ahrr, Aldh3a1, Cyp1b1, Nfe2l2 and Nqo1), suggesting a secondary event, such as association with additional transcriptional modulators. Of the 12 genes that responded to TCDD during the dose-response analysis, none had an ED50 equivalent to that of Cyp1a1, the most sensitive gene in this study, while nine genes responded to doses at least 10-100 fold higher, in at least one strain (Ahrr (L-E), Aldh3a1 (both), Cyp1a2 (both), Cyp1b1 (both), Cyp2a1 (L-E), Inmt (both), Nfe2l2 (L-E), Nqo1 (L-E) and Tiparp (both)). These data shed new light on the association of the AHR target genes with TCDD toxicity, and in particular the seven genes exhibiting strain-specific differences represent strong candidate mediators of Type-II toxicities.
authors.affiliation: Ontario Institute for Cancer Research, Department of Informatics and Bio-computing Program, Toronto, Canada. Electronic address: john.watson@oicr.on.ca.
authors.forename: John D
authors.initials: JD
authors.lastname: Watson
authors.affiliation: Ontario Institute for Cancer Research, Department of Informatics and Bio-computing Program, Toronto, Canada. Electronic address: stephenie.prokopec@oicr.on.ca.
authors.forename: Stephenie D
authors.initials: SD
authors.lastname: Prokopec
authors.affiliation: Ontario Institute for Cancer Research, Department of Informatics and Bio-computing Program, Toronto, Canada. Electronic address: ashleyblaines@gmail.com.
authors.forename: Ashley B
authors.initials: AB
authors.lastname: Smith
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada. Electronic address: allan.okey@utoronto.ca.
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. Electronic address: raimo.pohjanvirta@helsinki.fi.
authors.forename: Raimo
authors.initials: R
authors.lastname: Pohjanvirta
authors.affiliation: Ontario Institute for Cancer Research, Department of Informatics and Bio-computing Program, Toronto, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Canada. Electronic address: paul.boutros@oicr.on.ca.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Boutros
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2; D065633:Cytochrome P-450 CYP1B1; D000072467:Cytochrome P450 Family 2; D003580:Cytochromes / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D017208:Rats, Wistar; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism; D015262:Xenobiotics / Q000633:toxicity
chemical_list: D003580:Cytochromes; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D015262:Xenobiotics; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C017170:Cyp1a2 protein, rat; C585499:Cyp1b1 protein, rat; C456179:Cyp2a1 protein, rat; D019388:Cytochrome P-450 CYP1A2; D065633:Cytochrome P-450 CYP1B1; D000072467:Cytochrome P450 Family 2; D016660:NAD(P)H Dehydrogenase (Quinone); C507703:NQO1 protein, rat
keywords: 2,3,7,8-Tetrachlorodibenzo-p-dioxin; Aryl hydrocarbon receptor; Dose–response; TCDD-induced toxicity; Time course; mRNA abundance