Abstract
BackgroundThe major toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) appear to result from dysregulation of mRNA levels mediated by the aryl hydrocarbon receptor (AHR). Dioxin-like chemicals alter expression of numerous genes in liver, but it remains unknown which lie in pathways leading to major toxicities such as hepatotoxicity, wasting and lethality. To identify genes involved in these responses we exploited a rat genetic model. Rats expressing an AHR splice-variant lacking a portion of the transactivation domain are highly resistant to dioxin-induced toxicities. We examined changes in hepatic mRNA abundances 19 hours after TCDD treatment in two dioxin-resistant rat strains/lines and two dioxin-sensitive rat strains/lines.ResultsResistant rat strains/lines exhibited fewer transcriptional changes in response to TCDD than did rats with wildtype AHR. However, well-known AHR-regulated and dioxin-inducible genes such as CYP1A1, CYP1A2, and CYP1B1 remained fully responsive to TCDD in all strains/lines. Pathway analysis indicated that the genes which respond differently to TCDD between sensitive and resistant rats are mainly involved in lipid metabolism, cellular membrane function and energy metabolism. These pathways previously have been shown to respond differently to dioxin treatment in dioxin-sensitive versus dioxin-resistant rats at a biochemical level and in the differential phenotype of toxicologic responses.ConclusionThe transactivation-domain deletion in dioxin-resistant rats does not abolish global AHR transactivational activity but selectively interferes with expression of subsets of genes that are candidates to mediate or protect from major dioxin toxicities such as hepatotoxicity, wasting and death.
Highlights
The major toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) appear to result from dysregulation of mRNA levels mediated by the aryl hydrocarbon receptor (AHR)
Extensive evidence demonstrates that virtually all toxic effects of TCDD and related dioxin-like compounds are mediated by a liganddependent transcription factor, the aryl hydrocarbon receptor (AHR)
We focused on hepatic mRNA levels because liver displays a broad spectrum of mRNAs that are responsive to dioxins and/or to AHR genotype [20] and because liver is a prime site of dioxin toxicity, displaying many phenotypic differences between sensitive and resistant rats [29]
Summary
The major toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) appear to result from dysregulation of mRNA levels mediated by the aryl hydrocarbon receptor (AHR). Dioxin-like chemicals alter expression of numerous genes in liver, but it remains unknown which lie in pathways leading to major toxicities such as hepatotoxicity, wasting and lethality. Exposure to dioxins results in major toxicities, including thymic atrophy, teratogenesis, hepatotoxicity, wasting syndrome and death. These toxicities are dependent on both the AHR. Microarray technologies have accelerated identification of genes that depend on the AHR for constitutive expression or for response to TCDD in vivo [14,15,16,17,18,19,20,21,22,23], but the key genes whose dysregulation by dioxin leads to most toxicities remain unknown
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