Systems toxicology identifies mechanistic impacts of 2-amino-4, 6-dinitrotoluene (2A-DNT) exposure in Northern Bobwhite

Persistent Link:
http://hdl.handle.net/10150/610284
Title:
Systems toxicology identifies mechanistic impacts of 2-amino-4, 6-dinitrotoluene (2A-DNT) exposure in Northern Bobwhite
Author:
Gust, Kurt A.; Nanduri, Bindu; Rawat, Arun; Wilbanks, Mitchell S.; Ang, Choo Y.; Johnson, David R.; Pendarvis, Ken; Chen, Xianfeng; Quinn, Michael J.; Johnson, Mark S.; Burgess, Shane C.; Perkins, Edward J.
Affiliation:
Environmental Laboratory, US Army Engineer Research and Development Center; Institute for Digital Biology, Mississippi State University; Translational Genomics Research Institute; Badger Technical Services; Conestoga-Rovers & Associates; University of Arizona, School of Animal and Comparative Biomedical Sciences; Bio5 Institute, University of Arizona; IFXworks LLC; US Army Public Health Command, Aberdeen Proving Ground; University of Arizona, College of Agriculture and Life Sciences
Issue Date:
2015
Publisher:
BioMed Central Ltd
Citation:
Gust et al. BMC Genomics (2015) 16:587 DOI 10.1186/s12864-015-1798-4
Journal:
BMC Genomics
Rights:
© 2015 Gust et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/)
Collection Information:
This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.
Abstract:
BACKGROUND: A systems toxicology investigation comparing and integrating transcriptomic and proteomic results was conducted to develop holistic effects characterizations for the wildlife bird model, Northern bobwhite (Colinus virginianus) dosed with the explosives degradation product 2-amino-4,6-dinitrotoluene (2A-DNT). A subchronic 60d toxicology bioassay was leveraged where both sexes were dosed via daily gavage with 0, 3, 14, or 30 mg/kg-d 2A-DNT. Effects on global transcript expression were investigated in liver and kidney tissue using custom microarrays for C. virginianus in both sexes at all doses, while effects on proteome expression were investigated in liver for both sexes and kidney in males, at 30 mg/kg-d. RESULTS: As expected, transcript expression was not directly indicative of protein expression in response to 2A-DNT. However, a high degree of correspondence was observed among gene and protein expression when investigating higher-order functional responses including statistically enriched gene networks and canonical pathways, especially when connected to toxicological outcomes of 2A-DNT exposure. Analysis of networks statistically enriched for both transcripts and proteins demonstrated common responses including inhibition of programmed cell death and arrest of cell cycle in liver tissues at 2A-DNT doses that caused liver necrosis and death in females. Additionally, both transcript and protein expression in liver tissue was indicative of induced phase I and II xenobiotic metabolism potentially as a mechanism to detoxify and excrete 2A-DNT. Nuclear signaling assays, transcript expression and protein expression each implicated peroxisome proliferator-activated receptor (PPAR) nuclear signaling as a primary molecular target in the 2A-DNT exposure with significant downstream enrichment of PPAR-regulated pathways including lipid metabolic pathways and gluconeogenesis suggesting impaired bioenergetic potential. CONCLUSION: Although the differential expression of transcripts and proteins was largely unique, the consensus of functional pathways and gene networks enriched among transcriptomic and proteomic datasets provided the identification of many critical metabolic functions underlying 2A-DNT toxicity as well as impaired PPAR signaling, a key molecular initiating event known to be affected in di- and trinitrotoluene exposures.
EISSN:
1471-2164
DOI:
10.1186/s12864-015-1798-4
Keywords:
Transcriptomics; Proteomics; Systems toxicology; Nitrotoluenes; Northern Bobwhite; PPAR signaling
Version:
Final published version
Additional Links:
http://www.biomedcentral.com/1471-2164/16/587

Full metadata record

DC FieldValue Language
dc.contributor.authorGust, Kurt A.en
dc.contributor.authorNanduri, Binduen
dc.contributor.authorRawat, Arunen
dc.contributor.authorWilbanks, Mitchell S.en
dc.contributor.authorAng, Choo Y.en
dc.contributor.authorJohnson, David R.en
dc.contributor.authorPendarvis, Kenen
dc.contributor.authorChen, Xianfengen
dc.contributor.authorQuinn, Michael J.en
dc.contributor.authorJohnson, Mark S.en
dc.contributor.authorBurgess, Shane C.en
dc.contributor.authorPerkins, Edward J.en
dc.date.accessioned2016-05-20T09:03:14Z-
dc.date.available2016-05-20T09:03:14Z-
dc.date.issued2015en
dc.identifier.citationGust et al. BMC Genomics (2015) 16:587 DOI 10.1186/s12864-015-1798-4en
dc.identifier.doi10.1186/s12864-015-1798-4en
dc.identifier.urihttp://hdl.handle.net/10150/610284-
dc.description.abstractBACKGROUND: A systems toxicology investigation comparing and integrating transcriptomic and proteomic results was conducted to develop holistic effects characterizations for the wildlife bird model, Northern bobwhite (Colinus virginianus) dosed with the explosives degradation product 2-amino-4,6-dinitrotoluene (2A-DNT). A subchronic 60d toxicology bioassay was leveraged where both sexes were dosed via daily gavage with 0, 3, 14, or 30 mg/kg-d 2A-DNT. Effects on global transcript expression were investigated in liver and kidney tissue using custom microarrays for C. virginianus in both sexes at all doses, while effects on proteome expression were investigated in liver for both sexes and kidney in males, at 30 mg/kg-d. RESULTS: As expected, transcript expression was not directly indicative of protein expression in response to 2A-DNT. However, a high degree of correspondence was observed among gene and protein expression when investigating higher-order functional responses including statistically enriched gene networks and canonical pathways, especially when connected to toxicological outcomes of 2A-DNT exposure. Analysis of networks statistically enriched for both transcripts and proteins demonstrated common responses including inhibition of programmed cell death and arrest of cell cycle in liver tissues at 2A-DNT doses that caused liver necrosis and death in females. Additionally, both transcript and protein expression in liver tissue was indicative of induced phase I and II xenobiotic metabolism potentially as a mechanism to detoxify and excrete 2A-DNT. Nuclear signaling assays, transcript expression and protein expression each implicated peroxisome proliferator-activated receptor (PPAR) nuclear signaling as a primary molecular target in the 2A-DNT exposure with significant downstream enrichment of PPAR-regulated pathways including lipid metabolic pathways and gluconeogenesis suggesting impaired bioenergetic potential. CONCLUSION: Although the differential expression of transcripts and proteins was largely unique, the consensus of functional pathways and gene networks enriched among transcriptomic and proteomic datasets provided the identification of many critical metabolic functions underlying 2A-DNT toxicity as well as impaired PPAR signaling, a key molecular initiating event known to be affected in di- and trinitrotoluene exposures.en
dc.language.isoenen
dc.publisherBioMed Central Ltden
dc.relation.urlhttp://www.biomedcentral.com/1471-2164/16/587en
dc.rights© 2015 Gust et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/)en
dc.subjectTranscriptomicsen
dc.subjectProteomicsen
dc.subjectSystems toxicologyen
dc.subjectNitrotoluenesen
dc.subjectNorthern Bobwhiteen
dc.subjectPPAR signalingen
dc.titleSystems toxicology identifies mechanistic impacts of 2-amino-4, 6-dinitrotoluene (2A-DNT) exposure in Northern Bobwhiteen
dc.typeArticleen
dc.identifier.eissn1471-2164en
dc.contributor.departmentEnvironmental Laboratory, US Army Engineer Research and Development Centeren
dc.contributor.departmentInstitute for Digital Biology, Mississippi State Universityen
dc.contributor.departmentTranslational Genomics Research Instituteen
dc.contributor.departmentBadger Technical Servicesen
dc.contributor.departmentConestoga-Rovers & Associatesen
dc.contributor.departmentUniversity of Arizona, School of Animal and Comparative Biomedical Sciencesen
dc.contributor.departmentBio5 Institute, University of Arizonaen
dc.contributor.departmentIFXworks LLCen
dc.contributor.departmentUS Army Public Health Command, Aberdeen Proving Grounden
dc.contributor.departmentUniversity of Arizona, College of Agriculture and Life Sciencesen
dc.identifier.journalBMC Genomicsen
dc.description.collectioninformationThis item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.en
dc.eprint.versionFinal published versionen
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