dc.date.accessioned | 2022-01-28T18:43:05Z | |
dc.date.available | 2022-01-28T18:43:05Z | |
dc.date.created | 2021-09-28T21:30:49Z | |
dc.date.issued | 2021 | |
dc.identifier.citation | Hutin, David Long, Alexandra S Sugamori, Kim Shao, Peng Singh, Sachin Kumar Rasmussen, Marit Olafsen, Ninni Elise Pettersen, Solveig Grimaldi, Giulia Grant, Denis M Matthews, Jason Bruce . 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD)-Inducible Poly-ADP-Ribose Polymerase (TIPARP/PARP7) Catalytic Mutant Mice (TiparpH532A) Exhibit Increased Sensitivity to TCDD-Induced Hepatotoxicity and Lethality. Toxicological Sciences. 2021, 183(1), 154-169 | |
dc.identifier.uri | http://hdl.handle.net/10852/90261 | |
dc.description.abstract | Abstract
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly-adenosine diphosphate (ADP)-ribose polymerase (TIPARP/PARP7), an aryl hydrocarbon receptor (AHR) target gene and mono-ADP-ribosyltransferase, acts as part of a negative feedback loop to repress AHR signaling. This process is prevented by a single H532A mutation in TIPARP that destroys its catalytic activity. We hypothesized that the loss of TIPARP catalytic activity would increase sensitivity to TCDD-induced toxicity in vivo. To test this, we created a catalytically deficient mouse line (TiparpH532A) by introducing a single H532A mutation in TIPARP. Treatment of mouse embryonic fibroblasts or hepatocytes isolated from TiparpH532A mice confirmed the increased TCDD-induced expression of the AHR target genes Cyp1a1, Cyp1b1, and Tiparp. TiparpH532A mice given a single injection of 10 µg/kg TCDD, a nonlethal dose in Tiparp+/+ mice, did not survive beyond day 10. All Tiparp+/+ mice survived the 30-day treatment. TCDD-treated TiparpH532A mice displayed increased expression of AHR target genes, increased steatohepatitis and hepatotoxicity. Hepatic RNA-sequencing revealed 7-fold more differentially expressed genes in TiparpH532A mice than in Tiparp+/+ mice (4542 vs 647 genes) 6 days after TCDD treatment. Differentially expressed genes included genes involved in xenobiotic metabolism, lipid homeostasis and inflammation. Taken together, these data further support TIPARP as a critical negative regulator of AHR activity and show that loss of its catalytic activity is sufficient to increase sensitivity to TCDD-induced steatohepatitis and lethality. Since TIPARP inhibition has recently emerged as a potential anticancer therapy, the impact on AHR signaling, TCDD and polycyclic aromatic hydrocarbon toxicity will need to be carefully considered under conditions of therapeutic TIPARP inhibition. | |
dc.language | EN | |
dc.rights | Attribution 4.0 International | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | |
dc.title | 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD)-Inducible Poly-ADP-Ribose Polymerase (TIPARP/PARP7) Catalytic Mutant Mice (TiparpH532A) Exhibit Increased Sensitivity to TCDD-Induced Hepatotoxicity and Lethality | |
dc.type | Journal article | |
dc.creator.author | Hutin, David | |
dc.creator.author | Long, Alexandra S | |
dc.creator.author | Sugamori, Kim | |
dc.creator.author | Shao, Peng | |
dc.creator.author | Singh, Sachin Kumar | |
dc.creator.author | Rasmussen, Marit | |
dc.creator.author | Olafsen, Ninni Elise | |
dc.creator.author | Pettersen, Solveig | |
dc.creator.author | Grimaldi, Giulia | |
dc.creator.author | Grant, Denis M | |
dc.creator.author | Matthews, Jason Bruce | |
cristin.unitcode | 185,51,13,40 | |
cristin.unitname | Seksjon for molekylær ernæring | |
cristin.ispublished | true | |
cristin.fulltext | original | |
cristin.qualitycode | 2 | |
dc.identifier.cristin | 1940147 | |
dc.identifier.bibliographiccitation | info:ofi/fmt:kev:mtx:ctx&ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Toxicological Sciences&rft.volume=183&rft.spage=154&rft.date=2021 | |
dc.identifier.jtitle | Toxicological Sciences | |
dc.identifier.volume | 183 | |
dc.identifier.issue | 1 | |
dc.identifier.startpage | 154 | |
dc.identifier.endpage | 169 | |
dc.identifier.doi | https://doi.org/10.1093/toxsci/kfab075 | |
dc.identifier.urn | URN:NBN:no-92855 | |
dc.type.document | Tidsskriftartikkel | |
dc.type.peerreviewed | Peer reviewed | |
dc.source.issn | 1096-6080 | |
dc.identifier.fulltext | Fulltext https://www.duo.uio.no/bitstream/handle/10852/90261/1/kfab075.pdf | |
dc.type.version | PublishedVersion | |