title: 1,3-dinitrobenzene induces age- and region-specific oxidation to mitochondria-related proteins in brain.
abstract: Regions of the brain with high energy requirements are especially sensitive to perturbations in mitochondrial function. Hence, neurotoxicant exposures that target mitochondria in regions of high energy demand have the potential to accelerate mitochondrial damage inherently occurring during the aging process. 1,3-Dinitrobenzene (DNB) is a model neurotoxicant that selectively targets mitochondria in brainstem nuclei innervated by the eighth cranial nerve. This study investigates the role of age in the regional susceptibility of brain mitochondria-related proteins (MRPs) to oxidation following exposure to DNB. Male F344 rats (1 month old [young], 3 months old [adult], 18 months old [aged]) were exposed to 10 mg/kg DNB prior to mitochondrial isolation and histopathology experiments. Using a high-throughput proteomic approach, 3 important region- and age-related increases in DNB-induced MRP oxidation were determined: (1) brainstem mitochondria are ×3 more sensitive to DNB-induced oxidation than cortical mitochondria; (2) oxidation of brainstem MRPs is significantly higher than in cortical counterparts; and (3) MRPs from the brainstems of older rats are significantly more oxidized than those from young or adult rats. Furthermore, lower levels of DNB cause signs of intoxication (ataxia, chromodacryorrhea) and vacuolation of the susceptible neuropil in aged animals, while neither is observed in DNB-exposed young rats. Additionally, methemoglobin levels increase significantly in DNB-exposed adult and aged animals, but not young DNB-exposed animals. This suggests that oxidation of key MRPs observed in brainstem of aged animals is necessary for DNB-induced signs of intoxication and lesion formation. These results provide compelling evidence that environmental chemicals such as DNB may aid in the acceleration of injury to specific brain regions by inducing oxidation of sensitive mitochondrial proteins.
authors.affiliation: *Toxicology Program, Department of Environmental Health Sciences, School of Public Health, Department of Biological Chemistry and Unit for Laboratory Animal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Kubik
authors.affiliation: *Toxicology Program, Department of Environmental Health Sciences, School of Public Health, Department of Biological Chemistry and Unit for Laboratory Animal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109.
authors.forename: Rory W
authors.initials: RW
authors.lastname: Landis
authors.affiliation: *Toxicology Program, Department of Environmental Health Sciences, School of Public Health, Department of Biological Chemistry and Unit for Laboratory Animal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109.
authors.forename: Henriette
authors.initials: H
authors.lastname: Remmer
authors.affiliation: *Toxicology Program, Department of Environmental Health Sciences, School of Public Health, Department of Biological Chemistry and Unit for Laboratory Animal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109.
authors.forename: Ingrid L
authors.initials: IL
authors.lastname: Bergin
authors.affiliation: *Toxicology Program, Department of Environmental Health Sciences, School of Public Health, Department of Biological Chemistry and Unit for Laboratory Animal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109 philbert@umich.edu.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Philbert
mesh_terms: D000367:Age Factors; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004136:Dinitrobenzenes / Q000494:pharmacology*; D008297:Male; D024101:Mitochondrial Proteins / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D004136:Dinitrobenzenes; D024101:Mitochondrial Proteins; C017906:3-dinitrobenzene
keywords: 1,3-dinitrobenzene; aging; mitochondria; neurotoxicity; regional susceptibility