Compendium of TCDD-mediated transcriptomic response datasets in mammalian model systems.

Background: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the most potent congener of the dioxin class of environmental contaminants. Exposure to TCDD causes a wide range of toxic outcomes, ranging from chloracne to acute lethality. The severity of toxicity is highly dependent on the aryl hydrocarbon receptor (AHR).

Transcriptional profiling of rat white adipose tissue response to 2,3,7,8-tetrachlorodibenzo-ρ-dioxin.

Polychlorinated dibenzodioxins are environmental contaminants commonly produced as a by-product of industrial processes. The most potent of these, 2,3,7,8-tetrachlorodibenzo-ρ-dioxin (TCDD), is highly lipophilic, leading to bioaccumulation. White adipose tissue (WAT) is a major site for energy storage, and is one of the organs in which TCDD accumulates.

Neurotoxicity may be an overlooked consequence of benzo[a]pyrene exposure that is relevant to human health risk assessment.

Benzo[a]pyrene (BaP) is a well-studied environmental compound that requires metabolic activation to have a carcinogenic effect. The neurotoxicity of BaP has received considerably less attention than its carcinogenicity. Environmental exposure to BaP correlates with impaired learning and memory in adults, and poor neurodevelopment in children.

Technical guide for applications of gene expression profiling in human health risk assessment of environmental chemicals.

Toxicogenomics promises to be an important part of future human health risk assessment of environmental chemicals. The application of gene expression profiles (e.g.

Integrating toxicogenomics into human health risk assessment: lessons learned from the benzo[a]pyrene case study.

The use of short-term toxicogenomic tests to predict cancer (or other health effects) offers considerable advantages relative to traditional toxicity testing methods. The advantages include increased throughput, increased mechanistic data, and significantly reduced costs. However, precisely how toxicogenomics data can be used to support human health risk assessment (RA) is unclear.

Transcriptional profiling of rat hypothalamus response to 2,3,7,8-tetrachlorodibenzo-ρ-dioxin.

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.

Cross-species transcriptomic analysis elucidates constitutive aryl hydrocarbon receptor activity.

Background: Research on the aryl hydrocarbon receptor (AHR) has largely focused on variations in toxic outcomes resulting from its activation by halogenated aromatic hydrocarbons. But the AHR also plays key roles in regulating pathways critical for development, and after decades of research the mechanisms underlying physiological regulation by the AHR remain poorly characterized. Previous studies identified several core genes that respond to xenobiotic AHR ligands across a broad range of species and tissues.

mRNA levels in control rat liver display strain-specific, hereditary, and AHR-dependent components.

Rat is a major model organism in toxicogenomics and pharmacogenomics. Hepatic mRNA profiles after treatment with xenobiotic chemicals are used to predict and understand drug toxicity and mechanisms. Surprisingly, neither inter- and intra-strain variability of mRNA abundances in control rats nor the heritability of rat mRNA abundances yet been established.

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

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 LD₅₀ of > 9600 μg/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.

Aryl hydrocarbon receptor (AHR)-regulated transcriptomic changes in rats sensitive or resistant to major dioxin toxicities.

Background: 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. To identify genes involved in these responses we exploited a rat genetic model.

Transcriptomic responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in liver: comparison of rat and mouse.

Background: Mouse and rat models are mainstays in pharmacology, toxicology and drug development -- but differences between strains and between species complicate data interpretation and application to human health. Dioxin-like polyhalogenated aromatic hydrocarbons represent a major class of environmentally and economically relevant toxicants. In mammals dioxin exposure leads to a broad spectrum of adverse affects, including hepatotoxicity of varying severity.

Patterns of dioxin-altered mRNA expression in livers of dioxin-sensitive versus dioxin-resistant rats.

Dioxins exert their major toxicologic effects by binding to the aryl hydrocarbon receptor (AHR) and altering gene transcription. Numerous dioxin-responsive genes previously were identified both by conventional biochemical and molecular techniques and by recent mRNA expression microarray studies. However, of the large set of dioxin-responsive genes the specific genes whose dysregulation leads to death remain unknown.

Genome-wide effects of acute progressive feed restriction in liver and white adipose tissue.

Acute progressive feed restriction (APFR) represents a specific form of caloric restriction in which feed availability is increasingly curtailed over a period of a few days to a few weeks. It is often used for control animals in toxicological and pharmacological studies on compounds causing body weight loss to equalize weight changes between experimental and control groups and thereby, intuitively, to also set their metabolic states to the same phase. However, scientific justification for this procedure is lacking.

microRNAs in adult rodent liver are refractory to dioxin treatment.

Dioxin-like chemicals are well known for their ability to upregulate expression of numerous genes via the AH receptor (AHR). However, recent transcriptomic analyses in several laboratories indicate that dioxin-like chemicals or AHR genotype itself also can downregulate levels of mRNAs encoded by numerous genes. The mechanism responsible for such downregulation is unknown.

Aryl hydrocarbon receptor splice variants in the dioxin-resistant rat: tissue expression and transactivational activity.

The AHR locus encodes the aryl hydrocarbon receptor (AHR), a transcriptional regulator of multiple drug-metabolizing enzymes and mediator of toxicity of dioxin-like chemicals. The Han/Wistar (Kuopio) rat strain (H/W) is remarkably resistant to lethal effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) because of a point mutation in the exon/intron 10 boundary in AHR genomic structure that leads to use of 3 alternative cryptic splice sites, potentially creating 3 alternative transcripts and 2 protein products. The deletion variant (DV), which lacks 43 amino acids in the transactivation domain, has the highest intrinsic transactivation activity in vitro; amino acids 766 to 783 suppress transactivation function.

Differential expression profiling of the hepatic proteome in a rat model of dioxin resistance: correlation with genomic and transcriptomic analyses.

One characteristic feature of acute 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity is dramatic interspecies and interstrain variability in sensitivity. This complicates dioxin risk assessment for humans. However, this variability also provides a means of characterizing mechanisms of dioxin toxicity.

Evaluation of various housekeeping genes for their applicability for normalization of mRNA expression in dioxin-treated rats.

Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) is an extremely sensitive, convenient and rapid method to measure mRNA levels in cells and tissues, and is gaining popularity in toxicology. To correct for sample-to-sample variation, normalization of the expression data is required. The conventional way to perform normalization is to select a reference gene whose expression is believed to remain stable across all experimental conditions, then relate the concentrations of gene(s) of interest to those of this housekeeping gene.

Aryl hydrocarbon receptor regulates distinct dioxin-dependent and dioxin-independent gene batteries.

Conventional biochemical and molecular techniques identified previously several genes whose expression is regulated by the aryl hydrocarbon receptor (AHR). We sought to map the complete spectrum of AHR-dependent genes in male adult liver using expression arrays to contrast mRNA profiles in Ahr-null mice (Ahr(-/-)) with those in mice with wild-type AHR (Ahr(+)(/)(+)). Transcript profiles were determined both in untreated mice and in mice treated 19 h earlier with 1000 microg/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

Toxicological implications of polymorphisms in receptors for xenobiotic chemicals: the case of the aryl hydrocarbon receptor.

Mechanistic toxicology has predominantly been focused on adverse effects that are caused by reactive metabolites or by reactive oxygen species. However, many important xenobiotics exert their toxicity, not by generating reactive products, but rather by altering expression of specific genes. In particular, some environmental contaminants target nuclear receptors that function as regulators of transcription.

Dioxin-responsive AHRE-II gene battery: identification by phylogenetic footprinting.

We identified a set of genes that respond to dioxins through the recently discovered AHRE-II ("XRE-II") enhancer element. A total of 36 genes containing AHRE-II motifs conserved across human, mouse, and rat gene orthologs were identified by genome-wide transcription-factor binding-site searches and phylogenetic footprinting. Microarray experiments on liver from rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin revealed statistically significant changes in mRNA levels for 13 of these 36 genes after three hours and 15 genes after 19h.