Defense Date

2011

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Biochemistry

First Advisor

Andrew Ottens

Abstract

Exposure to environmental tobacco smoke (ETS) has been recognized as a significant health risk for adults and children. In adults, ETS exposure has been linked to increased incidences of cardiovascular disease and dementia. In children, exposure has been linked to behavioral and cognitive deficits. Studies on the effects of ETS in the brain have been largely epidemiological, and have lacked a defined explanation of the molecular/biochemical effects of ETS. The present dissertation aims to test whether ETS exposure leads to altered biochemistry in the adult and developing mammalian brain. A rat ETS exposure model was employed to investigate changes at the molecular and cellular level. In an adult ETS exposure study, we focused on markers of astrogliosis , oxidative stress, and cell death. We observed altered GFAP suggestive of reactive astrogliosis. Yet, markers of oxidative and cell stress were unaffected by ETS exposure in the brain regions examined. Increased degradation of αII-spectrin and dephosphorylation of serine116 on PEA-15 indicated greater apoptotic cell death signaling in the brains of ETS exposed animals. β-synuclein was greatly upregulated by ETS, a neuroprotective protein previously reported to exhibit anti-apoptotic and anti-fibrillogenic properties. We next employed a rodent model of postnatal ETS exposure to investigate effects on developing cerebellum using a system biology approach involving mass spectrometry (MS). Proteins at statistically different abundance between groups were correlated with relevant biochemical processes and pathways by bioinformatics. ETS responsive data were enriched in elements associated with all aspects of aerobic respiration. These results were substantiated by orthogonal molecular measures, along with evidence for increase mitochondrial biogenesis/fission. These findings suggest an increase mitochondrial density driven by a demand for ATP. Further exploration of the ETS responsive proteome identified statistically significant associations of the ETS with neuron projections, in particular axon associated proteins and synaptic vesicles. Immunotbloting and microscopy experiments substantiated altered process outgrowth and synaptogenic processes. The presented data depict a striking modulation in cerebellar formation consequent to ETS exposure and the energy source to allow that modulation to occur. Our findings could provide a biochemical and cellular rational for adverse neurological effects observed in ETS exposed children.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

7-26-2011

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