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

Kurt A. Gust, Bindu Nanduri, Arun Rawat, Mitchell S. Wilbanks, Choo Yaw Ang, David R. Johnson, Ken Pendarvis, Xianfeng Chen, Michael J. Quinn, Mark S. Johnson, Shane C. Burgess, Edward J. Perkins

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish
Article number587
JournalBMC Genomics
Volume16
Issue number1
DOIs
Publication statusPublished - 7 Aug 2015
Externally publishedYes

Fingerprint

Colinus
Toxicology
Peroxisome Proliferator-Activated Receptors
Liver
Proteins
Gene Regulatory Networks
Proteomics
Trinitrotoluene
Kidney
Gluconeogenesis
2-amino-4,6-dinitrotoluene
Xenobiotics
Proteome
Metabolic Networks and Pathways
Cell Cycle Checkpoints
Biological Assay
Energy Metabolism
Birds
Cell Death
Necrosis

Keywords

  • Nitrotoluenes
  • Northern Bobwhite
  • PPAR signaling
  • Proteomics
  • Systems toxicology
  • Transcriptomics

ASJC Scopus subject areas

  • Biotechnology
  • Genetics

Cite this

Systems toxicology identifies mechanistic impacts of 2-amino-4,6-dinitrotoluene (2A-DNT) exposure in Northern Bobwhite. / Gust, Kurt A.; Nanduri, Bindu; Rawat, Arun; Wilbanks, Mitchell S.; Ang, Choo Yaw; Johnson, David R.; Pendarvis, Ken; Chen, Xianfeng; Quinn, Michael J.; Johnson, Mark S.; Burgess, Shane C.; Perkins, Edward J.

In: BMC Genomics, Vol. 16, No. 1, 587, 07.08.2015.

Research output: Contribution to journalArticle

Gust, KA, Nanduri, B, Rawat, A, Wilbanks, MS, Ang, CY, Johnson, DR, Pendarvis, K, Chen, X, Quinn, MJ, Johnson, MS, Burgess, SC & Perkins, EJ 2015, 'Systems toxicology identifies mechanistic impacts of 2-amino-4,6-dinitrotoluene (2A-DNT) exposure in Northern Bobwhite', BMC Genomics, vol. 16, no. 1, 587. https://doi.org/10.1186/s12864-015-1798-4
Gust, Kurt A. ; Nanduri, Bindu ; Rawat, Arun ; Wilbanks, Mitchell S. ; Ang, Choo Yaw ; Johnson, David R. ; Pendarvis, Ken ; Chen, Xianfeng ; Quinn, Michael J. ; Johnson, Mark S. ; Burgess, Shane C. ; Perkins, Edward J. / Systems toxicology identifies mechanistic impacts of 2-amino-4,6-dinitrotoluene (2A-DNT) exposure in Northern Bobwhite. In: BMC Genomics. 2015 ; Vol. 16, No. 1.
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AU - Ang, Choo Yaw

AU - Johnson, David R.

AU - Pendarvis, Ken

AU - Chen, Xianfeng

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AU - Burgess, Shane C.

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