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

Boutros, Paul C.; Yao, Cindy Q.; Watson, John D.; Wu, Alexander H.; Moffat, Ivy D.; Prokopec, Stephenie D.; Smith, Ashley B.; Okey, Allan B.; Pohjanvirta, Raimo

doi:10.1016/j.taap.2010.12.010

Cited by 39 publications

(55 citation statements)

References 73 publications

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“…The second most altered transcript in both compound treatments was that coding for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly(ADP-ribose) polymerase (TIPARP), which was 2.1-fold lower in treated cells (P Ͻ 4 ϫ 10 Ϫ5 for both compounds). TIPARP is involved in cellular responses to exposure to dioxin (12), although it is typically upregulated by toxin exposure rather than being downregulated as we saw in our experiments (21). Overall, the effects of these compounds on uninfected human fibroblasts in vitro appears to be subtle, and the changes that do occur are in a small number of genes involved in dealing with chemical-induced stress.…”

Section: F1792-0016 Destroys Parasite-containing Vacuolesmentioning

confidence: 52%

A Novel Benzodioxole-Containing Inhibitor of Toxoplasma gondii Growth Alters the Parasite Cell Cycle

Kamau

Meehan

Lavine

et al. 2011

Antimicrob Agents Chemother

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Toxoplasma gondii is an obligate intracellular parasite that can cause disease in the developing fetus and in immunocompromised humans. Infections can last for the life of the individual, and to date there are no drugs that eliminate the chronic cyst stages that are characteristic of this parasite. In an effort to identify new chemical scaffolds that could form the basis for new therapeutics, we carried out a chemoinformatic screen for compounds that had the potential to interact with members of a superfamily of parasite-secreted kinases and assayed them for growth inhibition in vitro. Of 17 candidate compounds, we identified one with potent antiparasitic activity. The compound has a 50% inhibitory concentration (IC 50 ) of ϳ2 nM, and structurefunction analyses implicate the benzodioxole moiety in its action. The compound does not appear to be cytotoxic to host cells. Using microarray analyses of both parasites and host cells treated with the compound, we found that the levels of very few host cell transcripts are altered by the compound, while a large number of parasite transcripts have a different abundance after compound treatment. Gene ontology analyses of parasite transcripts with a different abundance revealed an enrichment of cell cycle-related genes, suggesting that the compound alters progression of the parasite through the cell cycle. Assaying the nuclear content of treated parasites demonstrated that compound treatment significantly increased the percentage of parasites in the S/M phase of the cell cycle compared to controls. This compound and its analogs represent a novel scaffold with antiparasitic activity.

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Section: F1792-0016 Destroys Parasite-containing Vacuolesmentioning

confidence: 52%

A Novel Benzodioxole-Containing Inhibitor of Toxoplasma gondii Growth Alters the Parasite Cell Cycle

Kamau

Meehan

Lavine

et al. 2011

Antimicrob Agents Chemother

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“…These plots also display the reliability of each platform by producing results with the expected trends. Previous literature indicates up-regulation of Cyp1b1 (Walker et al 1999;Boutros et al 2008Boutros et al , 2011 and downregulation of Inmt by TCDD in rodent liver. Our qPCR data for Cyp1b1 show downregulation at low doses (<0.1 mg/kg at 19 h) of TCDD and up-regulation at higher doses in both the TCDDsensitive and TCDD-resistant strains, with OpenArray showing a similar response in just the TCDD-sensitive strain.…”

Section: Discussionmentioning

confidence: 86%

“…These toxicities are fundamentally due to dysregulation of gene expression mediated by the aryl hydrocarbon receptor (for review, see Okey 2007). Numerous high-throughput studies have been conducted to identify the key genes whose altered expression underlies dioxin toxicity Boutros et al 2008Boutros et al , 2011Franc et al 2008;Ovando et al 2010). TCDD causes very large changes in expression of several genesup to 1000-fold or more along with modest changes in expression of numerous other genes (Tijet et al 2006;Franc et al 2008;Moffat et al 2010).…”

Section: Mrna Profilingmentioning

confidence: 99%

“…L-E and H/W rats were chosen for their differential TCDD sensitivity: L-E rats are highly sensitive to the acute lethality of TCDD (LD 50 % 10 mg/kg) (Pohjanvirta 1990), while H/W rats are extremely resistant (LD 50 > 9600 mg/kg) (Unkila et al 1994). These strains have been extensively studied and have well-characterized TCDD-induced differential expression patterns (Franc et al 2008;Boutros et al 2011). A total of 38 genes were commonly analyzed by qPCR, NanoString, and OpenArray RT-PCR (Fig.…”

Section: Mrna Profilingmentioning

confidence: 99%

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Systematic evaluation of medium-throughput mRNA abundance platforms

Prokopec

Watson

Waggott

et al. 2012

RNA

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Profiling of mRNA abundances with high-throughput platforms such as microarrays and RNA-seq has become an important tool in both basic and biomedical research. However, these platforms remain prone to systematic errors and have challenges in clinical and industrial applications. As a result, it is standard practice to validate a subset of key results using alternate technologies. Similarly, clinical and industrial applications typically involve transitions from a high-throughput discovery platform to medium-throughput validation ones. These medium-throughput validation platforms have high technical reproducibility and reduced sample input needs, and low sensitivity to sample quality (e.g., for processing FFPE specimens). Unfortunately, while medium-throughput platforms have proliferated, there are no comprehensive comparisons of them. Here we fill that gap by comparing two key medium-throughput platforms-NanoString's nCounter Analysis System and ABI's OpenArray System-to gold-standard quantitative real-time RT-PCR. We quantified 38 genes and positive and negative controls in 165 samples. Signal:noise ratios, correlations, dynamic range, and detection accuracy were compared across platforms. All three measurement technologies showed good concordance, but with divergent price/time/sensitivity trade-offs. This study provides the first detailed comparison of medium-throughput RNA quantification platforms and provides a template and a standard data set for the evaluation of additional technologies.

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“…The suppression of SAP and GHR mRNA by TCDD in mice are responses that are conserved in rats (Boutros et al 2008), occur in selected rat strains bearing the variant or wild-type AHR (Moffat et al 2010;Yao et al 2012), and persist for up to 10 days after TCDD exposure (Boutros et al 2011b). Microarray studies suggest that TCDD treatment in rats does not alter hepatic mRNA levels for SOCS3, JAK2, STAT5a/b, and CIS (Boutros et al 2008;Moffat et al 2010;Boutros et al 2011b;Yao et al 2012), providing examples of both inter-species similarity (in the case of SOCS3 and CIS) and difference (in the case of JAK2 and STAT5a/b).…”

Section: Discussionmentioning

confidence: 99%

Aryl hydrocarbon receptor-dependence of dioxin’s effects on constitutive mouse hepatic cytochromes P450 and growth hormone signaling components

Lee

Riddick

2012

Can. J. Physiol. Pharmacol.

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The aryl hydrocarbon receptor (AHR) has physiological roles in the absence of exposure to exogenous ligands and mediates adaptive and toxic responses to the environmental pollutant, 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD). A readily metabolized AHR agonist, 3-methylcholanthrene, disrupts expression of mouse hepatic growth hormone (GH) signaling components and suppresses cytochrome P450 2D9 (Cyp2d9), a male-specific gene controlled by pulsatile GH via signal transducer and activator of transcription 5b (STAT5b). Using TCDD as an essentially non-metabolized AHR agonist and Ahr −/− mice as the preferred model to determine the AHR-dependence of biological responses, we now show that two mouse hepatic STAT5b target genes, Cyp2d9 and major urinary protein 2 (Mup2), are suppressed by TCDD in an AHRdependent manner. TCDD also decreased hepatic mRNA levels for GH receptor, Janus kinase 2, and STAT5a/b with AHR-dependence. Without inducing selected hepatic inflammatory markers, TCDD caused AHR-dependent induction of Cyp1a1 and NADPH-cytochrome P450 oxidoreductase (Por) and suppression of Cyp3a11. In vehicle-treated mice, basal mRNA levels for CYP2D9, CYP3A11, POR, serum amyloid protein P, and MUP2 were influenced by Ahr genetic status. We conclude that AHR activation per se leads to dysregulation of hepatic GH signaling components and suppression of some, but not all, STAT5b target genes. Keywordsaryl hydrocarbon receptor; 2,3,7,8-tetrachlorodibenzo-p-dioxin; cytochrome P450; growth hormone receptor; Janus kinase 2; signal transducer and activator of transcription 5b; cytokineinducible Src homology 2 domain-containing protein; major urinary protein 2; inflammatory markers; NADPH-cytochrome P450 oxidoreductase

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

Cited by 39 publications

References 73 publications

A Novel Benzodioxole-Containing Inhibitor of Toxoplasma gondii Growth Alters the Parasite Cell Cycle

A Novel Benzodioxole-Containing Inhibitor of Toxoplasma gondii Growth Alters the Parasite Cell Cycle

Systematic evaluation of medium-throughput mRNA abundance platforms

Aryl hydrocarbon receptor-dependence of dioxin’s effects on constitutive mouse hepatic cytochromes P450 and growth hormone signaling components

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