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

Abstract

BackgroundNitrotoluenes 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 FindingsSprague-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/SignificanceA 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.

Time course of gene expression during mouse skeletal muscle hypertrophy

“…The proportion of upregulated genes was higher than that of downregulated genes at d1, d10, and d14, whereas the proportion of up-and downregulated genes was similar between d3 and d7. Taken together, the results from the PCA and the pattern of change in the number of differentially expressed genes provide parameters to assign three gene expression patterns for the hypertrophic response during mechanical overload as: early (1 day), intermediate (3,5, and 7 days), and late (10 and 14 days) patterns.…”

“…There were four pathways that were enriched across all three gene expression patterns of the time course: hepatic fibrosis/hepatic stellate cell activation, T-helper cell differentiation, LPS/IL-1-mediated inhibition of retinoid X receptor (RXR) function and liver X receptor (LXR)/RXR activation. The exact role of these pathways in the hypertrophic response in skeletal muscle is not readily apparent, as they have been primarily shown in the liver to regulate the production of connective tissue (hepatic fibrosis/hepatic stellate cell activation and T-helper cell differentiation) (10, 11), cholesterol metabolism (LPS/IL-1 mediated inhibition of RXR function and LXR/RXR activation) (3,34), and inflammation (T-helper cell differentiation) (11).…”

“…The global gene expression patterns were determined using a microarray analysis after 1, 3,5,7,10, and 14 days of functional overload in mouse plantaris muscle. We used two parameters, principal component analysis (PCA) of gene expression and the number of differentially expressed genes, to define three gene expression patterns of the hypertrophic response: early (1 day), intermediate (3,5, and 7 days), and late (10 and 14 days) patterns.…”

“…We used two parameters, principal component analysis (PCA) of gene expression and the number of differentially expressed genes, to define three gene expression patterns of the hypertrophic response: early (1 day), intermediate (3,5, and 7 days), and late (10 and 14 days) patterns. Moreover, the analysis of the canonical pathways revealed the involvement of specific pathways at each gene expression pattern in response to mechanical overload.…”

Endocrinology: Advances through omics and related technologies

“…Aggressive behavior Homarus americanus, Astacus astacus, Drosophila Huber et al (1997), Kravitz and Huber (2003) and Nilsen et al (2004) Aging Bivalves, Drosophila, C. elegans, Macrostonum lignano (2009) minnows, quail and rat, supporting the suitability of Daphnia as an alternative model species (Deng et al, 2011;Rawat et al, 2010;Wintz et al, 2006). Further supporting the Daphnia model, researchers from Japan (Kato et al, 2011) used Daphnia to reveal how environmental sex determination is implemented by selective expression of a fundamental genetic component that is functionally conserved in animals using genetic sex determination, inferring that there is an ancient link between genetic and environmental sex determination.…”