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

Prokopec, Stephenie D.; Houlahan, Kathleen E.; Sun, Ren; Watson, John D.; Yao, Cindy Q.; Lee, Jamie; P’ng, Christine; Pang, Renee; Wu, Alexander H.; Chong, Lauren C.; Smith, Ashley B.; Harding, Nicholas J.; Moffat, Ivy D.; Lindén, Jere; Lensu, Sanna; Okey, Allan B.; Pohjanvirta, Raimo; Boutros, Paul C.

doi:10.1186/s12864-016-3446-z

Cited by 18 publications

(20 citation statements)

References 55 publications

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“…An additional four of these genes had differential RNA abundance in at least two groups: Cyp1a2 in C57BL/6 and DBA/2 (borderline significant (log 2 fold change = 0.99) in rWT) and Fmo3 , Nqo1 and Ugt1a9 only in the TCDD-sensitive cohorts. Inmt shows significant repression in only rWT at this early time point, while Aldh3a1 shows no response in mice (consistent with previous studies [29,37,38]). We next examined sets of genes which demonstrated altered RNA abundance in the TCDD-resistant DBA/2 mouse liver or TCDD-sensitive cohorts (Fig 2D-E).…”

Section: Resultssupporting

confidence: 92%

“…Publicly available data for male Han/Wistar (H/W) and Long-Evans (L-E) rats, as well as two lines (Ln-A and Ln-C) derived from L-E × H/W crosses, were used for comparison [22,23,30,38]. Data consisted of the hepatic transcriptomic responses of rats to a single dose of TCDD (100 μg/kg in corn oil) at three time points (19 hours, 4 and 10 days).…”

Section: Methodsmentioning

confidence: 99%

“…Data consisted of the hepatic transcriptomic responses of rats to a single dose of TCDD (100 μg/kg in corn oil) at three time points (19 hours, 4 and 10 days). All data were available from the TCDD.Transcriptomics (v2.2.5) package [38] for R. Due to the use of different microarrays between studies, HomoloGene (build 68) was used to identify orthologous genes. Homologene IDs which mapped to multiple EntrezGeneIDs were discarded.…”

Section: Methodsmentioning

confidence: 99%

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Identifying TCDD-resistance genes via murine and rat comparative genomics and transcriptomics

Lü

Lee

et al. 2019

Preprint

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AbstractThe aryl hydrocarbon receptor (AHR) mediates many of the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, the AHR alone is insufficient to explain the widely different outcomes among organisms. Attempts to identify unknown factor(s) have been confounded by genetic variability of model organisms. Here, we evaluated three transgenic mouse lines, each expressing a different rat AHR isoform (rWT, DEL, and INS), as well as C57BL/6 and DBA/2 mice. We supplement these with whole-genome sequencing and transcriptomic analyses of the corresponding rat models: Long-Evans (L-E) and Han/Wistar (H/W) rats. These integrated multi-species genomic and transcriptomic data were used to identify genes associated with TCDD-response phenotypes.We identified several genes that show consistent transcriptional changes in both transgenic mice and rats. Hepatic Pxdc1 was significantly repressed by TCDD in C57BL/6, rWT mice, and in L-E rat. Three genes demonstrated different AHRE-1 (full) motif occurrences within their promoter regions: Cxxc5 had fewer occurrences in H/W, as compared with L-E; Sugp1 and Hgfac (in either L-E or H/W respectively). These genes also showed different patterns of mRNA abundance across strains.The AHR isoform explains much of the transcriptional variability: up to 50% of genes with altered mRNA abundance following TCDD exposure are associated with a single AHR isoform (30% and 10% unique to DEL and rWT respectively following 500 μg/kg TCDD). Genomic and transcriptomic evidence allowed identification of genes potentially involved in phenotypic outcomes: Pxdc1 had differential mRNA abundance by phenotype; Cxxc5 had altered AHR binding sites and differential mRNA abundance.Author SummaryEnvironmental contaminants such as dioxins cause many toxic responses, anything from chloracne (common in humans) to death. These toxic responses are mostly regulated by the Ahr, a ligand-activated transcription factor with roles in drug metabolism and immune responses, however other contributing factors remain unclear. Studies are complicated by the underlying genetic heterogeneity of model organisms. Our team evaluated a number of mouse and rat models, including two strains of mouse, two strains of rat and three transgenic mouse lines which differ only at the Ahr locus, that present widely different sensitivities to the most potent dioxin: 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD). We identified a number of changes to gene expression that were associated with different toxic responses. We then contrasted these findings with results from whole-genome sequencing of the H/W and L-E rats and found some key genes, such as Cxxc5 and Mafb, which might contribute to TCDD toxicity. These transcriptomic and genomic datasets will provide a valuable resource for future studies into the mechanisms of dioxin toxicities.

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Section: Resultssupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Identifying TCDD-resistance genes via murine and rat comparative genomics and transcriptomics

Lü

Lee

et al. 2019

Preprint

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“…Three genes ( Cyp1a1 , Cyp1a2 , and Nqo1 ) were found to have altered mRNA abundance in the same direction in both groups. These represent xenobiotic response genes and members of the ‘AHR-core’ battery [15,16,19,20,21,22], suggesting that C2 exposure leads to hepatic AHR activation (Figure 2c, top panel).…”

Section: Resultsmentioning

confidence: 99%

“…This AHR-ARNT dimer then binds specific recognition motifs on DNA, called AHR response elements (AHREs) and can regulate the transcription of target genes [18]. In particular, this complex will consistently induce (or repress) expression of a collection of genes, deemed the ‘AHR-core’ battery of genes [15,16,19,20,21,22]. In addition to this canonical signaling pathway, the AHR can also influence gene expression by alternative pathways including epigenetic mechanisms (e.g., DNA methylation, histone modifications, miRNA, and noncoding long-RNA induction as reviewed in [23,24,25]), functioning as a nuclear E3 ubiquitin ligase, and cross-talk with other transcription factors [26,27,28,29].…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic Impact of IMA-08401, a Novel AHR Agonist Resembling Laquinimod, on Rat Liver

Prokopec

Pohjanvirta

Mahiout

et al. 2019

IJMS

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IMA-08401 (C2) is a novel aryl hydrocarbon receptor (AHR) agonist and selective AHR modulator (SAHRM) that is structurally similar to laquinimod (LAQ). Both compounds are converted to the AHR-active metabolite DELAQ (IMA-06201) in vivo. SAHRMs have been proposed as therapeutic options for various autoimmune disorders. Clinical trials on LAQ have not reported any significant toxic outcomes and C2 has shown low toxicity in rats; however, their functional resemblance to the highly toxic AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) raises questions. Here, we characterize the hepatic transcriptomic changes induced by acute (single-dose) and subacute exposure (repeated dosing for 5 days followed by a 5-day recovery period) to C2 in Sprague-Dawley rats. Exposure to C2 leads to activation of the AHR, as shown by altered transcription of Cyp1a1. We identify a heightened response early after exposure that drops off by day 10. Acute exposure to C2 leads to changes to transcription of genes involved in antiviral and antibacterial responses, which highlights the immunomodulator effects of this AHR agonist. Subacute exposure causes an oxidative stress response in the liver, the consequences of which require further study on target tissues such as the CNS and immune system, both of which may be compromised in this patient population.

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Comparative toxicoproteogenomics of mouse and rat liver identifies TCDD-resistance genes

Prokopec

Lee

et al. 2019

Arch Toxicol

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The aryl hydrocarbon receptor (AHR) mediates many toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, the AHR alone does not explain the widely different outcomes among organisms. To identify the other factors involved, we evaluated three transgenic mouse lines, each expressing a different rat AHR isoform (rWT, DEL, and INS) providing widely different resistance to TCDD toxicity, as well as C57BL/6 and DBA/2 mice which exhibit a ~ tenfold divergence in TCDD sensitivity (exposures of 5-1000 μg/kg TCDD). We supplement these with whole-genome sequencing, together with transcriptomic and proteomic analyses of the corresponding rat models, Long-Evans (L-E) and Han/Wistar (H/W) rats (having a ~ 1000-fold difference in their TCDD sensitivities; 100 μg/kg TCDD), to identify genes associated with TCDDresponse phenotypes. Overall, we identified up to 50% of genes with altered mRNA abundance following TCDD exposure are associated with a single AHR isoform (33.8%, 11.7%, 5.2% and 0.3% of 3076 genes altered unique to rWT, DEL, C57BL/6 and INS respectively following 1000 μg/kg TCDD). Hepatic Pxdc1 was significantly repressed in all three TCDD-sensitive animal models (C57BL/6 and rWT mice, and L-E rat) after TCDD exposure. Three genes, including Cxxc5, Sugp1 and Hgfac, demonstrated different AHRE-1 (full) motif occurrences within their promoter regions between rat strains, as well as different patterns of mRNA abundance. Several hepatic proteins showed parallel up-or downward alterations with their RNAs, with three genes (SNRK, IGTP and IMPA2) showing consistent, strain-dependent changes. These data show the value of integrating genomic, transcriptomic and proteomic evidence across multi-species models in toxicologic studies.

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

Cited by 18 publications

References 55 publications

Identifying TCDD-resistance genes via murine and rat comparative genomics and transcriptomics

Identifying TCDD-resistance genes via murine and rat comparative genomics and transcriptomics

Transcriptomic Impact of IMA-08401, a Novel AHR Agonist Resembling Laquinimod, on Rat Liver

Comparative toxicoproteogenomics of mouse and rat liver identifies TCDD-resistance genes

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