AUTHOR=Cao Fangjie , Souders II Christopher L. , Perez-Rodriguez Veronica , Martyniuk Christopher J. 

TITLE=Elucidating Conserved Transcriptional Networks Underlying Pesticide Exposure and Parkinson's Disease: A Focus on Chemicals of Epidemiological Relevance

JOURNAL=Frontiers in Genetics

VOLUME=Volume 9 - 2018

YEAR=2019

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2018.00701

DOI=10.3389/fgene.2018.00701

ISSN=1664-8021

ABSTRACT=While a number of genetic mutations are associated with Parkinson’s disease (PD), it is also widely acknowledged that the environment plays a significant role in the etiology of the neurodegenerative diseases. Epidemiological evidence suggests that occupational exposure to pesticides (e.g. dieldrin, paraquat, rotenone, maneb, and ziram) is associated with a higher risk of developing PD in susceptible populations. Within dopaminergic neurons, environmental chemicals can have an array of adverse effects resulting in cell death, such as aberrant redox cycling and oxidative damage, mitochondrial dysfunction, unfolded protein response, ubiquitin-proteome system dysfunction, neuroinflammation, and metabolic disruption. More recently, our understanding of how pesticides affect cells of the central nervous system has been strengthened by computational biology. New insight has been generated about transcriptional and proteomic networks, and the metabolic pathways affected by pesticids. These networks and cell signaling pathways constitute potential therapeutic targets for intervention to slow or mitigate neurodegenerative diseases. Here we review the epidemiological evidence that supports a role for specific pesticides in the etiology of PD and identify molecular profiles amongst these pesticides that may contribute to PD. Using the Comparative Toxicogenomic Database, these transcripts were compared to those regulated by the PD-associated neurotoxicant MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). While many are established as those related to PD (alpha-synuclein, caspases, leucine rich repeat kinase 2, and parkin2), lesser studied targets have emerged as “pesticide/PD-associated transcripts” (e.g. phosphatidylinositol glycan anchor biosynthesis class C (Pigc), allograft inflammatory factor 1 (Aif1), TIMP metallopeptidase inhibitor 3, and DNA damage inducible transcript 4). We also compared pesticide-regulated genes to a recent meta-analysis of genome-wide association studies in PD which revealed new genetic mutant alleles; the pesticides under review regulated the expression of many of these genes (e.g. ELOVL fatty acid elongase 7, ATPase H+ transporting V0 subunit a1, and bridging integrator 3). The significance is that these proteins may contribute as mechanisms to pesticides and increased PD risk. This review collates information on transcriptome responses following pesticide induced-PD to develop a framework for mechanisms that lead to higher PD risk with pesticide exposures.