Project description:A systems toxicology investigation comparing and integrating transcriptomic and proteomic results was conducted to pursue a holistic understanding of the effects of the explosives degradation product 2-amino-4,6-dinitrotoluene (2A-DNT) dosing on the health of the wildlife bird model, Northern bobwhite (Colinus virginianus). A subchronic 60d toxicology bioassay was leveraged where both sexes were dosed via daily gavage with 0, 3, 14, or 30 mg/kg-d 2-ADNT. 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 the proteome expression were investigated in liver for both sexes and kidney in males, all at the 30 mg/kg-d dose. 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 platforms when investigating higher-order functional responses including statistically enriched gene networks and canonical pathways, especially when connected to toxicological outcomes of 2A-DNT exposure. Specifically, comparison of gene networks statistically enriched from differentially expressed transcripts and for proteins showed 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, transcript expression and protein expression assays each implicated PPAR nuclear signaling as a primary molecular target in the 2A-DNT exposure with significant downstream enrichment of PPAR-regulated pathways including various lipid metabolic pathways and gluconeogenesis suggesting impaired bioenergetic potential. Although the relative expression of transcripts and proteins within enriched pathways was at times divergent, transcript expression assays identified many critical metabolic pathways involved in 2A-DNT toxicity as well as impaired PPAR signaling, a key molecular initiating event known to be affected in di- and tri-nitrotoluene exposures.

Project description:BackgroundA 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 60 d 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.ResultsAs 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.ConclusionAlthough 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.

Project description:A systems toxicology investigation comparing and integrating transcriptomic and proteomic results was conducted to pursue a holistic understanding of the effects of the explosives degradation product 2-amino-4,6-dinitrotoluene (2A-DNT) dosing on the health of the wildlife bird model, Northern bobwhite (Colinus virginianus). A subchronic 60d toxicology bioassay was leveraged where both sexes were dosed via daily gavage with 0, 3, 14, or 30 mg/kg-d 2-ADNT. 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 the proteome expression were investigated in liver for both sexes and kidney in males, all at the 30 mg/kg-d dose. 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 platforms when investigating higher-order functional responses including statistically enriched gene networks and canonical pathways, especially when connected to toxicological outcomes of 2A-DNT exposure. Specifically, comparison of gene networks statistically enriched from differentially expressed transcripts and for proteins showed 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, transcript expression and protein expression assays each implicated PPAR nuclear signaling as a primary molecular target in the 2A-DNT exposure with significant downstream enrichment of PPAR-regulated pathways including various lipid metabolic pathways and gluconeogenesis suggesting impaired bioenergetic potential. Although the relative expression of transcripts and proteins within enriched pathways was at times divergent, transcript expression assays identified many critical metabolic pathways involved in 2A-DNT toxicity as well as impaired PPAR signaling, a key molecular initiating event known to be affected in di- and tri-nitrotoluene exposures. The animal exposure design is presented in a study by Quinn et al (2010). Five treatment groups consisting of 12 male and 12 female bobwhites each were administered 2A-DNT at 0, 0.5, 3, 14, or 30 mg/kg/day via oral gavage for 60 days. Controls received a volume of corn oil equivalent to the mean volume given to birds in the highest dose group without compound. Microarray hybridizations were conducted using completely randomized design experiments including a 2 x 4 factorial treatment arrangement to investigate the conditions: sex (male and female) and 2A-DNT dose (control, 3, 14, and 30 mg/kg-d) for both liver and kidney tissues. All conditions included 4 biological replicates. REFERENCE: Quinn Jr. MJ, McFarland CA, LaFiandra EM, Bazar MA, Johnson MS (2010) Acute, subacute, and subchronic exposure to 2A-DNT (2-amino-4,6-dinitrotoluene) in the northern bobwhite (Colinus virginianus) Ecotoxicology 19:945-952.

Dataset Information

Quantitative Systems Toxicology Analysis of In Vitro Mechanistic Assays Reveals Importance of Bile Acid Accumulation and Mitochondrial Dysfunction in TAK-875-Induced Liver Injury.

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Quantitative Systems Toxicology Analysis of In Vitro Mechanistic Assays Reveals Importance of Bile Acid Accumulation and Mitochondrial Dysfunction in TAK-875-Induced Liver Injury.

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