Exposure of Rats to Environmental Tobacco Smoke during Cerebellar Development Alters Behavior and Perturbs Mitochondrial Energetics
Brian F. Fuller,1,2 Diego F. Cortes,1 Miranda K. Landis,1 Hiyab Yohannes,1 Hailey E. Griffin,1 Jillian E. Stafflinger,1 M. Scott Bowers,3 Mark H. Lewis,4 Michael A. Fox,1 and Andrew K. Ottens1,2
1Department of Anatomy and Neurobiology, and 2 Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia, USA; 3Department of Psychiatry, Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, USA; 4Department of Psychiatry, McKnight Brain Institute of the University of Florida, Gainesville, Florida, USA
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 0 µg/m3 total suspended particulate) from postnatal day 8 (PD8) to PD23 and then assayed the response at the behavioral, neuroproteomic, 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.
Key words: attention deficit/hyperactivity disorder, carbohydrate metabolism, cerebellum, environmental tobacco smoke, mitochondrial biogenesis, mitochondrial energetics, neurodevelopment, proteomics, secondhand smoke, systems biology.
Environ Health Perspect 120:1684–1691 (2012). http://dx.doi.org/10.1289/ehp.1104857 [Online 26 September 2012]
Address correspondence to A.K. Ottens, Department of Anatomy and Neurobiology, Virginia Commonwealth University, PO Box 980709, Richmond, VA 23298-0709 USA. Telephone: (804) 628-2972. Fax: (804) 828-9477. E-mail: email@example.com
Supplemental Material is available online (http://dx.doi.org/10.1289/ehp.1104857).
We are grateful for assistance from Y. Tanimura and B. McLaurin with animal handling; R. Hamm for behavioral testing; A. Lichtman and S. O’Neal for the use of the ANY-Maze system; S. Geromanos, H. Vissers, and M. Gorenstein for informatics; and J. Williamson, S. Henderson, P. Trimmer, L. Phillips, T. Reeves, and T. Smith for electron microscopy, performed at the VCU Department of Anatomy and Neurobiology Microscopy Facility, which is supported with funding from National Institutes of Health, National Institute of Neurological Disorders and Stroke (NIH-NINDS) grant NS047463.
This research was supported in part by NIH‑NINDS grant NS055012, NIH National Center for Advancing Translational Sciences, Clinical and Translational Science Award program grant TR000058, and the AD Williams’ Fund.
The authors declare they have no actual or potential competing financial interests.
Received 14 December 2011; Accepted 26 September 2012; Online 26 September 2012.
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