Journal
ENVIRONMENTAL HEALTH PERSPECTIVES
Volume 120, Issue 12, Pages 1684-1691Publisher
US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE
DOI: 10.1289/ehp.1104857
Keywords
attention deficit/hyperactivity disorder; carbohydrate metabolism; cerebellum; environmental tobacco smoke; mitochondrial biogenesis; mitochondrial energetics; neurodevelopment; proteomics; secondhand smoke; systems biology
Funding
- National Institutes of Health, National Institute of Neurological Disorders and Stroke (NIH-NINDS) [NS047463, NS055012]
- NIH National Center for Advancing Translational Sciences, Clinical and Translational Science Award program [TR000058]
- AD Williams' Fund
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BACKGROUND: Environmental tobacco smoke (ETS) exposure is linked to developmental deficits and disorders with known cerebellar involvement. However, direct biological effects and underlying neurochemical mechanisms remain unclear. OBJECTIVES: We sought to identify and evaluate underlying neurochemical change in the rat cerebellum with ETS exposure during critical period development. METHODS: We exposed rats to daily ETS (300, 100, and 01 mu g/m(3) total suspended particulate) from postnatal day 8 (PD8) to PD23 and then assayed the response at the behavioral, netiroproteomic, and cellular levels. RESULTS: Postnatal ETS exposure induced heightened locomotor response in a novel environment on par initially with amphetamine stimulation. The cerebellar mitochondrial subproteome was significantly perturbed in the ETS-exposed rats. Findings revealed a dose-dependent up-regulation of aerobic processes through the modification and increased translocation of Hk1 to the mitochondrion with corresponding heightened ATP synthase expression. ETS exposure also induced a dose-dependent increase in total Dnm1l mitochondrial fission factor; although more active membrane-bound Dnm1l was found at the lower dose. Dnm1l activation was associated with greater mitochondrial staining, particularly in the molecular layer, which was independent of stress-induced Bcl-2 family dynamics. Further, electron microscopy associated Dnm1l-mediated mitochondrial fission with increased biogenesis, rather than fragmentation. CONCLUSIONS: The critical postnatal period of cerebellar development is vulnerable to the effects of ETS exposure, resulting in altered behavior. The biological effect of ETS is underlain in part by a Dnm1l-mediated mitochondrial energetic response at a time of normally tight control. These findings represent a novel mechanism by which environmental exposure can impact neurodevelopment and function.
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