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S13-2 Identifying chemical agents that cause neurodegeneration in humans: insights gained from studying gene-environment interactions in parkinson’s disease
  1. Beate Ritz1,
  2. Kimberly Paul1,
  3. Xin Cui1,
  4. Zeyan Liew1,
  5. Myles Cockburn2,
  6. Janet Sinsheimer1,
  7. Jeff Bronstein1
  1. 1University of California Los Angeles, USA
  2. 2University of Southern California, USA

Abstract

Epidemiologic, animal and cell based studies showed that pesticide exposures –occupational and non-occupational - increase the risk of developing Parkinson’s disease (PD). Yet, human studies have mostly relied on recall of chemical agents and exposures and were unable to investigate specific agents or mechanisms of action of toxicants. Human genetic variations that increase vulnerability to the neurotoxic effects of environmental agents can help us identify vulnerable populations and biologic mechanisms of neurodegeneration.

Here, we will summarise lessons learned from more than a decade of research in California where we conducted the largest case-controls study of long-term human pesticide exposures in PD to date. We will present results for specific exposures derived from a unique geographic information system that incorporates land use maps and agricultural pesticide application records for California to assess pesticide exposures. We employed this tool to assess ambient exposures at residential and work place addresses in addition to creating a job exposure matrix for occupational pesticide use. We present results for specific pesticides as well as interactions between pesticides and genetic variants in metabolism genes and pathways that influence neurotoxic action and increase susceptibility or resilience to such environmental toxins. Specifically, we estimated increased risks for PD with exposures to combinations of paraquat and maneb, for ziram, organophosphate and dithiocarbamate pesticides and aldehydedehydrogenase inhibiting pesticides that interact with biologic pathways involved in the disease. This approach allowed us to identify important mechanism through which environmental toxicants contribute to neurodegeneration – even at long-term but low dose exposures – and to identify genetically vulnerable individuals.

Funding This work was funded in part by the National Institute of Environmental Health Sciences (grants P01ES016732, R01ES010544, 5R21ES16446-2, U54ES012078, T32ES015457), the National Institute of Neurologic Disorders and Stroke (grant NS038367), the Veterans Administration Healthcare System (SW PADRECC), the Michael J. Fox Foundation, the Levine Foundation, and the Parkinson Alliance.

COI (yes/no) declaration: None

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