Validation of a Genomics-Based Hypothetical Adverse Outcome Pathway: 2,4-Dinitrotoluene Perturbs PPAR Signaling Thus Impairing Energy Metabolism and Exercise Endurance

Abstract

2,4-dinitrotoluene (2,4-DNT) is a nitroaromatic used in industrial dyes and explosives manufacturing processes that is found as a contaminant in the environment. Previous studies have implicated antagonism of PPARα signaling as a principal process affected by 2,4-DNT. Here, we test the hypothesis that 2,4-DNT-induced perturbations in PPARα signaling and resultant downstream deficits in energy metabolism, especially from lipids, cause organism-level impacts on exercise endurance. PPAR nuclear activation bioassays demonstrated inhibition of PPARα signaling by 2,4-DNT whereas PPARγ signaling increased. PPARα (-/-) and wild-type (WT) female mice were exposed for 14 days to vehicle or 2,4-DNT (134 mg/kg/day) and performed a forced swim to exhaustion 1 day after the last dose. 2,4-DNT significantly decreased body weights and swim times in WTs, but effects were significantly mitigated in PPARα (-/-) mice. 2,4-DNT decreased transcript expression for genes downstream in the PPARα signaling pathway, principally genes involved in fatty acid transport. Results indicate that PPARγ signaling increased resulting in enhanced cycling of lipid and carbohydrate substrates into glycolytic/gluconeogenic pathways favoring energy production versus storage in 2,4-DNT-exposed WT and PPARα (-/-) mice. PPARα (-/-) mice appear to have compensated for the loss of PPARα by shifting energy metabolism to PPARα-independent pathways resulting in lower sensitivity to 2,4-DNT when compared with WT mice. Our results validate 2,4-DNT-induced perturbation of PPARα signaling as the molecular initiating event for impaired energy metabolism, weight loss, and decreased exercise performance.

Transcriptome analysis of castrated Bovine reveals the characters of protein accumulation

“…(3) The KOBAS (v2.0) was used to mapping the transcripts to KEGG pathways with default parameters (Maharani et al, 2012). mRNA quantitation and tissue specificity analysis: The tissue specificity of the expression pattern was evaluated with a previously proposed index (Wilbanks et al, 2014), which varies between 0 and 1 for tissue-restricted genes: where n is the number of tissues, expi is the expression value in tissue i, and expmax the maximum expression level over all tissues. RPKM and log2-transformed RPKM+1 were used for expression values, reaching the same conclusions.…”

“…In previous study, the activation of PPAR prevented inûammation in white adipose tissue and that dual activation of PPAR and - enhanced the action of adiponectin by increasing both adiponectin and adipose, which can result in the amelioration of obesity-induced insulin resistance. PPAR is one of the key regulators of glucose homeostasis, and the molecular mechanisms concerning how the activation of PPAR improves insulin sensitivity have been well investigated (Tsuchida et al, 2005;Wilbanks et al, 2014). PPAR was involved in the regulation of expression of myriad genes that regulate energy metabolism, cell differentiation, apoptosis and inûammation.…”

The update on transcriptional regulation of autophagy in normal and pathologic cells: A novel therapeutic target

“…Many studies have confirmed that PPARs played a vital role in controlling lipid [46][47][48] and glucose metabolism [48][49][50], energy homeostasis [51][52][53], adipocyte [54,55], and macrophage [56][57][58] differentiation through regulation of specific target gene transcription. Recent basic and clinical investigations [22,23] also revealed that PPARs were involved in the transcriptional regulation of autophagy.…”

Limitations of toxicity characterization in life cycle assessment: Can adverse outcome pathways provide a new foundation?

“…Ultimately, the AOP concept is positioned to provide a framework for integrating otherwise disparate toxicological information into a single unified assessment. Many conceptual AOPs have been developed and published, which cover a wide variety of modes of actions (Ankley et al ; Watanabe et al ; Breen et al ; Lalone et al ; Mackay et al ; Villeneuve et al ; Vinken et al ; Maxwell et al ; Wilbanks et al ; Willett et al ). As a means to enable global harmonization of AOP development efforts, an AOP subgroup has been formed within the Organisation for Economic Cooperation and Development (OECD) to facilitate AOP framework development, provide guidance on developing specific AOPs, and curate a peer‐reviewed knowledgebase of AOPs for public use (https://aopkb.org/).…”