title: Transcriptional profiling of rat hypothalamus response to 2,3,7,8-tetrachlorodibenzo-ρ-dioxin.
abstract: In some mammals, halogenated aromatic hydrocarbon (HAH) exposure causes wasting syndrome, defined as significant weight loss associated with lethal outcomes. The most potent HAH in causing wasting is 2,3,7,8-tetrachlorodibenzo-ρ-dioxin (TCDD), which exerts its toxic effects through the aryl hydrocarbon receptor (AHR). Since TCDD toxicity is thought to predominantly arise from dysregulation of AHR-transcribed genes, it was hypothesized that wasting syndrome is a result of to TCDD-induced dysregulation of genes involved in regulation of food-intake. As the hypothalamus is the central nervous systems' regulatory center for food-intake and energy balance. Therefore, mRNA abundances in hypothalamic tissue from two rat strains with widely differing sensitivities to TCDD-induced wasting syndrome: TCDD-sensitive Long-Evans rats and TCDD-resistant Han/Wistar rats, 23h after exposure to TCDD (100μg/kg) or corn oil vehicle. TCDD exposure caused minimal transcriptional dysregulation in the hypothalamus, with only 6 genes significantly altered in Long-Evans rats and 15 genes in Han/Wistar rats. Two of the most dysregulated genes were Cyp1a1 and Nqo1, which are induced by TCDD across a wide range of tissues and are considered sensitive markers of TCDD exposure. The minimal response of the hypothalamic transcriptome to a lethal dose of TCDD at an early time-point suggests that the hypothalamus is not the predominant site of initial events leading to hypophagia and associated wasting. TCDD may affect feeding behaviour via events upstream or downstream of the hypothalamus, and further work is required to evaluate this at the level of individual hypothalamic nuclei and subregions.
authors.affiliation: Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Houlahan
authors.affiliation: Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Stephenie D
authors.initials: SD
authors.lastname: Prokopec
authors.affiliation: Department of Pharmacology & Toxicology, University of Toronto, Toronto, Canada.
authors.forename: Ivy D
authors.initials: ID
authors.lastname: Moffat
authors.affiliation: The Finnish Food Safety Authority, Helsinki, Finland.
authors.forename: Jere
authors.initials: J
authors.lastname: Lindén
authors.affiliation: Department of Biology of Physical Activity, University of Jyväskylä, Jyväskylä, Finland; Department of Environmental Health, National Institute for Health and Welfare, Kuopio, Finland.
authors.forename: Sanna
authors.initials: S
authors.lastname: Lensu
authors.affiliation: Department of Pharmacology & Toxicology, University of Toronto, Toronto, Canada.
authors.forename: Allan B
authors.initials: AB
authors.lastname: Okey
authors.affiliation: 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: Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Canada; Department of Pharmacology & 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; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation / Q000187:drug effects; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D020318:Rats, Long-Evans; D017208:Rats, Wistar; D013045:Species Specificity; D013997:Time Factors; D043922:Toxicogenetics / Q000379:methods*; D014158:Transcription, Genetic / Q000187:drug effects*; D019282:Wasting Syndrome / Q000139:chemically induced* / Q000235:genetics*
chemical_list: D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D019363:Cytochrome P-450 CYP1A1; D016660:NAD(P)H Dehydrogenase (Quinone); C507703:NQO1 protein, rat
keywords: AHR; Feed restriction; Hypothalamus; Microarray; TCDD