The PEG study has provided important and groundbreaking results on pesticide and pesticide-gene interactions in Parkinson's disease (PD) in humans, and now offers the unique opportunity to extent its aims to identify epigenetic signatures of exposure and disease in PD. Many pesticide exposures are low dose and chronic or episodic and occur on a background of other exposures and risk factors that affect the susceptibility to PD. By the time disease occurs, most of these exposures - those agents without long-term storage in the body - are not detectable with existing biomarkers even though they may have caused damage to neurons and brain and altered the epigenome of many cell types and tissues. We refer to this as leaving a 'biological signature'evoked by exposures which we hypothesize to still be present when disease is diagnosed. Here we propose to use a powerful new tool and systems biology analytic methods to identify signatures for toxic exposures that evoke long-term biologic responses. Although DNA methylation is arguably the best understood and most widely studied epigenetic mechanism, little is known about which specific epigenetic markers (CpGs) correlate with toxic exposures and what role these epigenetic changes play in PD. While biomarker studies of neurodegenerative diseases in the elderly have met with some success, the development of epigenome wide technologies combined with analytic tools to integrate these data promises to facilitate a more comprehensive assessment of environmental stress factors tied to disrupted gene regulatory processes. Using the latest version of the well-validated Ilumina Infinium DNA methylation array, this proposal will generate high-resolution genome wide DNA methylation profiles which will then be integrated with existing clinical, genetic, and biomarker data using state of the art statistical methodologies. The relatively large sample size (720 subjects) of this pilot study provides sufficient statistical power to explore the role of exposure-related epigenomic changes in PD and to explore whether and how current and/or ongoing environmental exposures (i.e., those occurring after the onset of disease) alter PD disease trajectory. The PEG study is uniquely positioned to study whether chronic environmental stress factors influence epigenome and whether clinically useful biomarkers in the elderly and PD patients can be found that predict disease onset and progression. The two PIs have broad expertise conducting interdisciplinary research spanning the fields of epidemiology, environmental health, human genetics, bioinformatics, biostatistics, and neuroscience. This expertise and experience is a necessary prerequisite for the successful execution of both a hypothesis driven and hypothesis generating investigation that applies Illumina DNA methylation technology on existing biospecimens to investigate the effect of environmental exposures on epigenetic determinants of Parkinson's disease.
This R21 proposal will generate crucial epigenetic data for studying the role of toxic environmental exposures in Parkinson's disease. If successful, we will identify epigenetic biomarkers of exposure and disease that can be employed more widely in other studies of pesticide health effects. The study promises to further our understanding of how environmental toxins impact neuronal and brain health. Therefore, it could ultimately improve prevention efforts, advance therapeutic developments, and inform public policy on pesticide regulation.