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

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 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 gained about transcriptional and proteomic networks, and the metabolic pathways perturbed by pesticides. 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 the disease. Using the Comparative Toxicogenomics 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 transcripts are already 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 to pesticide-related increases in PD risk. This review collates information on transcriptome responses to PD-associated pesticides to develop a mechanistic framework for quantifying PD risk with exposures.

Piperine-Coated Gold Nanoparticles Alleviate Paraquat-Induced Neurotoxicity in Drosophila melanogaster

“…In this context, the widely used herbicide paraquat (PQ) has been shown to exhibit neurotoxic effects that closely mimic the parkinsonian phenotype. , Different epidemiological studies have shown that chronic exposure to PQ increases the risk of PD. , PQ is known to induce elevated oxidative stress and has been shown to cause degeneration of DA-ergic neurons in the SN region of the brain . The link between PQ exposure and risk of PD has been further cemented by various studies conducted in cellular and animal models. − Not only have such studies provided important insight in deciphering the etiology of PD, but also such a PQ-induced PD phenotype mimicking animal model serves as an efficient tool to study the potential of novel therapeutic compounds.…”

Environmental Impact on the Epigenetic Mechanisms Underlying Parkinson’s Disease Pathogenesis: A Narrative Review

“…For instance, given the differentially methylated promoter of the TNF- α gene in PD [ 23 ], the role of cigarette smoking in this relationship should be further explored. Additionally, smoking seems to affect histone acetylation and de-acetylation, and affect the expression of miRNAs in non-nerve tissues [ 82 , 83 , 84 , 85 ]. Thus, DNA methylation and possibly other epigenetic modifications might mediate the effects of smoking in PD.…”

COVID-19, an opportunity to reevaluate the correlation between long-term effects of anthropogenic pollutants on viral epidemic/pandemic events and prevalence

“…Chronic organochlorine, organophosphate, paraquat and pyrethroid exposures have been linked to Parkinson's disease and other neurodegenerative diseases through mitochondrial dysfunction, oxidative stress, and apoptosis via cell signaling pathways (Cao et al, 2019). Some pesticides have been reported as potential risk factors of chronic erectile dysfunctions (Polsky et al, 2007), probably via NADPH oxidase/ROS production and reduced bioavailability of NO (Jin and Burnett, 2008).…”