Quantitative Metabolomic Analysis of Chronic Exposures to Environmental Toxicants

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DESCRIPTION (provided by applicant) Data compiled over the last two decades indicate that chronic exposure to persistent environmental toxicants, including polychlorinated biphenyls (PCBs) and chlorinated organic insecticides, increases the risk of developing neurodegenerative disease, such as Parkinson's disease (PD). Recent studies suggest that these toxicants contribute to elevated intracellular dopamine levels, increased oxidative stress, and ultimately dopaminergic cell death, a hallmark of PD. The primary objective of this proposal is to rapidly advance the career of the candidate in this field through a combination of didactic learning, mentored research, and multi-disciplinary proposal development. The candidate, Kurt D. Pennell, is an Associate Professor of Environmental Engineering in the School of Civil & Environmental Engineering at the Georgia Institute of Technology. The career development plan, which includes coursework in bioinformatics, advanced spectroscopy and neurotoxicology, builds upon his training in science and engineering, research on contaminant transport and remediation in subsurface systems, analytical skills, and on-going sabbatical in the Department of Neurology at Emory University. The proposed activities will be carried out at Georgia Tech and Emory, where the candidate holds the title of visiting Associate Professor. The underlying hypothesis of the proposed research is that biomarkers of oxidative stress and metabolomic profiles can be correlated to chronic toxicant exposures and neurodegenerative disease. Under the mentorship of Dean P. Jones, Professor and Director of the Emory Clinical Biomarkers Laboratory, the specific aims of the research project are to: 1) Quantify the accumulation and distribution of chlorinated organic compounds in postmortem human tissue and exposed C57BL/6 mice, 2) Assess metabolic disruption and oxidative stress using established HPLC methods and H1-nuclear magnetic resonance (NMR) spectroscopy, and 3) Develop and evaluate a high-throughput, quantitative metabolomic profiling method based on coupled ion exchange liquid chromatography and Fourier Transform Ion Cyclotron Resonance Mass Spectrometry (FT-ICR MS). Dr. Pennell's career goals are to establish an active research program in environmental metabolomics, play an integral role in multi-disciplinary research teams investigating chronic exposures to environmental toxicants, and to be a leader in fostering linkages between environmental engineering and biomedical sciences. Relevance: The proposal is relevant to public health because it will advance our understanding of the relationship between chronic exposure to environmental toxicants and neurodegenerative disease, provide quantitative methods to rapidly screen for oxidative stress and adverse metabolic profiles, and offer the possibility for early detection and intervention.