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|Title:||Common pesticides and the development of Parkinson's disease|
|Abstract:||Parkinson’s disease (PD) is an age-related neurodegenerative disorder, characterised by progressive degeneration of dopaminergic neurons in the substantia nigra, with the formation of α-synuclein rich, intracytoplasmic Lewy bodies. Several genetic and environmental factors, including pesticides are linked with sporadic PD. The aim of this study was to investigate the effect of selected pesticides on dopaminergic neuroblastoma SH-SY5Y cells and differentiated human neural precursor cells. Several parameters of toxicity were successfully measured including cell-viability in SH-SY5Y cells and estimation of sub-cytotoxic doses which were used to study the effects of signalling inhibitors, measurement of mitochondrial transmembrane potential, reactive oxygen species formation, inhibitory activity towards mitochondrial complex I/II, protein expression after acute and chronic toxin treatment and changes in gene expression. Twenty nine commonly used pesticides were screened for potential PD involvement, using cell viability and Alamar Blue reduction assay in SH-SY5Y cells. Most chemicals showed low toxicity using this system. Chemicals known (MPTP or MPP+) or thought to be involved with PD (e.g. paraquat) showed significant toxicity at the highest chosen dose i.e. 1mM (MPTP/MPP+ caused 20-30% reduction in cell-viability at 1mM whereas paraquat caused 60-70% reduction at 1mM). Significant toxicity was observed at concentrations as low as 0.01mM (60-70% reduction in cell-viability after maneb and mancozeb exposure) and 0.1mM (60%, 50%, 80% and 40% reduction in cell-viability after diquat, epoxiconazole, fluroxypyr-ester and mecoprop-methyl ester treatment respectively). Toxin exposure of human midbrain neurones (hNPCs) derived from embryonic neural stem cells showed that hNPCs were more vulnerable at 0.01mM and 0.1mM than SH-SY5Y cells (except maneb, mancozeb and fluroxypyr ester). Pharmacological inhibition of apoptosis showed a marginal but insignificant reduction in toxicity for most chemicals whereas macroautophagy inhibition had no effect. The absence of any effect of caspase inhibitors, with the exception of diquat, may indicate caspase independent induction of cell death markers like PARP-1 suggesting that toxin treatment seems to cause caspase independent cell death involving RIP. This was shown by using Necrostatin-1, a RIP1 and necroptosis inhibitor, which significantly increased viability (greater than 90% recovery vs. untreated cells) in diquat (0.1mM), mancozeb (0.05mM) and maneb (0.05mM) treated cells. Other results suggested possible involvement of chaperone-mediated autophagy (CMA) with diquat, maneb and mancozeb toxicity which showed increased lysosomal accumulation. Mitochondrial energetics were not affected after acute and chronic toxin exposure which did not affect the mitochondrial complex I or II activities. Coincidentally, cells exposed chronically to diquat appeared to down-regulate expression of autophagic and apoptotic response genes. It can be concluded that these agrochemicals exert their toxicity through distinct mechanisms including indirect energy depletion and direct damage to cell components and show significant toxicity possibly due to ROS generation causing necroptosis and CMA induction.|
|Appears in Collections:||Institute of Cellular Medicine|
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|Nisar 11.pdf||Thesis||5.39 MB||Adobe PDF||View/Open|
|dspacelicence.pdf||Licence||43.82 kB||Adobe PDF||View/Open|
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