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

Boutros, Paul C.; Yan, Rui; Moffat, Ivy D.; Pohjanvirta, Raimo; Okey, Allan B.

doi:10.1186/1471-2164-9-419

Cited by 70 publications

(97 citation statements)

References 62 publications

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“…Our current work shows that TCDD down-regulates hepatic GHR, JAK2, and STAT5a/b mRNA levels in an AHR-dependent manner. A similar result was reported in the original microarray study for GHR mRNA (Boutros et al 2008) and we now provide confirmation by real-time quantitative RT-PCR. Our findings suggest that AHR activation by TCDD leads to lowered mRNA levels for GHR, JAK2, and STAT5a/b, and this may potentially play a role in the observed suppression of STAT5b target genes such as Cyp2d9 and Mup2.…”

Section: Discussionsupporting

confidence: 74%

“…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%

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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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Section: Discussionsupporting

confidence: 74%

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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“…Moreover, for FMO1 the effect of TCDD is opposite in the two rodent species: FMO1 is significantly up-regulated in mouse liver (this study; Boutros et al, 2008) and significantly down-regulated in rat liver (Boutros et al, 2008). Our experiments in mice that express transgenic wild-type AHR show that the rat AHR is fully competent to drive induction of FMO2 and FMO3 in mice, indicating that the lack of FMO induction in rat resides in differences in non-AHR regulatory factors between rat and mouse, perhaps in the FMO gene structures themselves.…”

Section: Discussionmentioning

confidence: 99%

Aryl Hydrocarbon Receptor-Dependent Induction of Flavin-Containing Monooxygenase mRNAs in Mouse Liver

Celius¹,

Roblin²,

Harper³

et al. 2008

Drug Metab Dispos

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ABSTRACT:Flavin-containing monooxygenases (FMOs) are important in detoxication but generally are considered not to be inducible by xenobiotics. Our recent microarray studies revealed induction of FMO2 and FMO3 mRNAs by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in liver of mice with wild-type aryl hydrocarbon receptor (AHR) but not in Ahr-null mice. The aim of the present study was to delineate mechanisms of FMO regulation. In adult male mice, basal FMO3 mRNA is low but was induced 6-fold at 4 h and 6000-fold at 24 h. The ED50 was approximately 1 g/kg for FMO2 and FMO3, similar to that for the classic AHR-regulated gene, Cyp1a1. In adult female mice basal FMO3 mRNA is high and was not induced at 4 h but was elevated 8-fold at 24 h. FMO5 mRNA was significantly downregulated by TCDD in both male and female adult mice. Juvenile mice show no sex difference in response to TCDD; FMO3 was induced 4 to 6-fold by TCDD in both sexes. Chromatin immunoprecipitation demonstrated recruitment of AHR and aryl hydrocarbon nuclear translocator proteins to Fmo3 regulatory regions, suggesting that induction by TCDD is a primary AHR-mediated event. Although FMO2 and FMO3 mRNAs were highly induced by TCDD in adult males, overall FMO catalytic activity increased only modestly. In contrast to the striking up-regulation of FMO2 and FMO3 in mouse liver, TCDD has little effect on FMO mRNA in rat liver. However, FMO2 and FMO3 mRNAs were highly induced in transgenic mice that express wild-type rat AHR, indicating that lack of induction in rat is not due to an incompetent AHR in this species.

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“…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%

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

Cited by 70 publications

References 62 publications

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

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

Aryl Hydrocarbon Receptor-Dependent Induction of Flavin-Containing Monooxygenase mRNAs in Mouse Liver

Systematic evaluation of medium-throughput mRNA abundance platforms

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