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 significan

SUBMITTER: Wilbanks MS 

PROVIDER: S-EPMC4833098 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature