Hepatic transcriptomic responses to TCDD in dioxin-sensitive and dioxin-resistant rats during the onset of toxicity

Journal Article · Tue Mar 01 04:00:00 EST 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2010.12.010· OSTI ID:21535246

Boutros, Paul C; Yao, Cindy Q; Watson, John D; Wu, Alexander H ^[1]; Moffat, Ivy D ^[2]; Prokopec, Stephenie D; Smith, Ashley B ^[1]; Okey, Allan B ^[2]; Pohjanvirta, Raimo ^[3]

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1. Informatics and Bio-computing Platform, Ontario Institute for Cancer Research, Toronto (Canada)
2. Department of Pharmacology and Toxicology, University of Toronto, Toronto (Canada)
3. Laboratory of Toxicology, National Institute for Health and Welfare, Kuopio (Finland)

The dioxin congener 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes a wide range of toxic effects in rodent species, all of which are mediated by a ligand-dependent transcription-factor, the aryl hydrocarbon receptor (AHR). The Han/Wistar (Kuopio) (H/W) strain shows exceptional resistance to many TCDD-induced toxicities; the LD{sub 50} of > 9600 {mu}g/kg for H/W rats is higher than for any other wild-type mammal known. We previously showed that this resistance primarily results from H/W rats expressing a variant AHR isoform that has a substantial portion of the AHR transactivation domain deleted. Despite this large deletion, H/W rats are not entirely refractory to the effects of TCDD; the variant AHR in these animals remains fully competent to up-regulate well-known dioxin-inducible genes. TCDD-sensitive (Long-Evans, L-E) and resistant (H/W) rats were treated with either corn-oil (with or without feed-restriction) or 100 {mu}g/kg TCDD for either four or ten days. Hepatic transcriptional profiling was done using microarrays, and was validated by RT-PCR analysis of 41 genes. A core set of genes was altered in both strains at all time points tested, including CYP1A1, CYP1A2, CYP1B1, Nqo1, Aldh3a1, Tiparp, Exoc3, and Inmt. Outside this core, the strains differed significantly in the breadth of response: three-fold more genes were altered in L-E than H/W rats. At ten days almost all expressed genes were dysregulated in L-E rats, likely reflecting emerging toxic responses. Far fewer genes were affected by feed-restriction, suggesting that only a minority of the TCDD-induced changes are secondary to the wasting syndrome.

• OSTI ID: 21535246
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2 Vol. 251; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANIMALS
BODY
CORN OIL
DIGESTIVE SYSTEM
DIOXIN
ESTERS
GENE AMPLIFICATION
GENES
GLANDS
HETEROCYCLIC COMPOUNDS
HYDROCARBONS
LIPIDS
LIVER
MAMMALS
MEMBRANE PROTEINS
MESSENGER-RNA
NUCLEIC ACIDS
OILS
ORGANIC COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
ORGANS
OTHER ORGANIC COMPOUNDS
POLYMERASE CHAIN REACTION
PROTEINS
RATS
RECEPTORS
RNA
RODENTS
TOXICITY
TRANSCRIPTION FACTORS
TRIGLYCERIDES
VEGETABLE OILS
VERTEBRATES