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Analysis of Common and Specific Mechanisms of Liver Function Affected by Nitrotoluene Compounds

BACKGROUND: Nitrotoluenes are widely used chemical manufacturing and munitions applications. This group of chemicals has been shown to cause a range of effects from anemia and hypercholesterolemia to testicular atrophy. We have examined the molecular and functional effects of five different, but str...

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Autores principales: Deng, Youping, Meyer, Sharon A., Guan, Xin, Escalon, Barbara Lynn, Ai, Junmei, Wilbanks, Mitchell S., Welti, Ruth, Garcia-Reyero, Natàlia, Perkins, Edward J.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3035612/
https://www.ncbi.nlm.nih.gov/pubmed/21346803
http://dx.doi.org/10.1371/journal.pone.0014662
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author Deng, Youping
Meyer, Sharon A.
Guan, Xin
Escalon, Barbara Lynn
Ai, Junmei
Wilbanks, Mitchell S.
Welti, Ruth
Garcia-Reyero, Natàlia
Perkins, Edward J.
author_facet Deng, Youping
Meyer, Sharon A.
Guan, Xin
Escalon, Barbara Lynn
Ai, Junmei
Wilbanks, Mitchell S.
Welti, Ruth
Garcia-Reyero, Natàlia
Perkins, Edward J.
author_sort Deng, Youping
collection PubMed
description BACKGROUND: Nitrotoluenes are widely used chemical manufacturing and munitions applications. This group of chemicals has been shown to cause a range of effects from anemia and hypercholesterolemia to testicular atrophy. We have examined the molecular and functional effects of five different, but structurally related, nitrotoluenes on using an integrative systems biology approach to gain insight into common and disparate mechanisms underlying effects caused by these chemicals. METHODOLOGY/PRINCIPAL FINDINGS: Sprague-Dawley female rats were exposed via gavage to one of five concentrations of one of five nitrotoluenes [2,4,6-trinitrotoluene (TNT), 2-amino-4,6-dinitrotoluene (2ADNT) 4-amino-2,6-dinitrotoulene (4ADNT), 2,4-dinitrotoluene (2,4DNT) and 2,6-dinitrotoluene (2,6DNT)] with necropsy and tissue collection at 24 or 48 h. Gene expression profile results correlated well with clinical data and liver histopathology that lead to the concept that hematotoxicity was followed by hepatotoxicity. Overall, 2,4DNT, 2,6DNT and TNT had stronger effects than 2ADNT and 4ADNT. Common functional terms, gene expression patterns, pathways and networks were regulated across all nitrotoluenes. These pathways included NRF2-mediated oxidative stress response, aryl hydrocarbon receptor signaling, LPS/IL-1 mediated inhibition of RXR function, xenobiotic metabolism signaling and metabolism of xenobiotics by cytochrome P450. One biological process common to all compounds, lipid metabolism, was found to be impacted both at the transcriptional and lipid production level. CONCLUSIONS/SIGNIFICANCE: A systems biology strategy was used to identify biochemical pathways affected by five nitroaromatic compounds and to integrate data that tie biochemical alterations to pathological changes. An integrative graphical network model was constructed by combining genomic, gene pathway, lipidomic, and physiological endpoint results to better understand mechanisms of liver toxicity and physiological endpoints affected by these compounds.
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spelling pubmed-30356122011-02-23 Analysis of Common and Specific Mechanisms of Liver Function Affected by Nitrotoluene Compounds Deng, Youping Meyer, Sharon A. Guan, Xin Escalon, Barbara Lynn Ai, Junmei Wilbanks, Mitchell S. Welti, Ruth Garcia-Reyero, Natàlia Perkins, Edward J. PLoS One Research Article BACKGROUND: Nitrotoluenes are widely used chemical manufacturing and munitions applications. This group of chemicals has been shown to cause a range of effects from anemia and hypercholesterolemia to testicular atrophy. We have examined the molecular and functional effects of five different, but structurally related, nitrotoluenes on using an integrative systems biology approach to gain insight into common and disparate mechanisms underlying effects caused by these chemicals. METHODOLOGY/PRINCIPAL FINDINGS: Sprague-Dawley female rats were exposed via gavage to one of five concentrations of one of five nitrotoluenes [2,4,6-trinitrotoluene (TNT), 2-amino-4,6-dinitrotoluene (2ADNT) 4-amino-2,6-dinitrotoulene (4ADNT), 2,4-dinitrotoluene (2,4DNT) and 2,6-dinitrotoluene (2,6DNT)] with necropsy and tissue collection at 24 or 48 h. Gene expression profile results correlated well with clinical data and liver histopathology that lead to the concept that hematotoxicity was followed by hepatotoxicity. Overall, 2,4DNT, 2,6DNT and TNT had stronger effects than 2ADNT and 4ADNT. Common functional terms, gene expression patterns, pathways and networks were regulated across all nitrotoluenes. These pathways included NRF2-mediated oxidative stress response, aryl hydrocarbon receptor signaling, LPS/IL-1 mediated inhibition of RXR function, xenobiotic metabolism signaling and metabolism of xenobiotics by cytochrome P450. One biological process common to all compounds, lipid metabolism, was found to be impacted both at the transcriptional and lipid production level. CONCLUSIONS/SIGNIFICANCE: A systems biology strategy was used to identify biochemical pathways affected by five nitroaromatic compounds and to integrate data that tie biochemical alterations to pathological changes. An integrative graphical network model was constructed by combining genomic, gene pathway, lipidomic, and physiological endpoint results to better understand mechanisms of liver toxicity and physiological endpoints affected by these compounds. Public Library of Science 2011-02-08 /pmc/articles/PMC3035612/ /pubmed/21346803 http://dx.doi.org/10.1371/journal.pone.0014662 Text en Deng et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Deng, Youping
Meyer, Sharon A.
Guan, Xin
Escalon, Barbara Lynn
Ai, Junmei
Wilbanks, Mitchell S.
Welti, Ruth
Garcia-Reyero, Natàlia
Perkins, Edward J.
Analysis of Common and Specific Mechanisms of Liver Function Affected by Nitrotoluene Compounds
title Analysis of Common and Specific Mechanisms of Liver Function Affected by Nitrotoluene Compounds
title_full Analysis of Common and Specific Mechanisms of Liver Function Affected by Nitrotoluene Compounds
title_fullStr Analysis of Common and Specific Mechanisms of Liver Function Affected by Nitrotoluene Compounds
title_full_unstemmed Analysis of Common and Specific Mechanisms of Liver Function Affected by Nitrotoluene Compounds
title_short Analysis of Common and Specific Mechanisms of Liver Function Affected by Nitrotoluene Compounds
title_sort analysis of common and specific mechanisms of liver function affected by nitrotoluene compounds
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3035612/
https://www.ncbi.nlm.nih.gov/pubmed/21346803
http://dx.doi.org/10.1371/journal.pone.0014662
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