The Bipyridyl Herbicide Paraquat Produces Oxidative Stress-Mediated Toxicity in Human Neuroblastoma SH-SY5Y Cells: Relevance to the Dopaminergic Pathogenesis

Abstract

Paraquat (PQ) is a cationic nonselective bipyridyl herbicide widely used to control weeds and grasses in agriculture. Epidemiologic studies indicate that exposure to pesticides can be a risk factor in the incidence of Parkinson's disease (PD). A strong correlation has been reported between exposure to paraquat and PD incidence in Canada, Taiwan, and the United States. This correlation is supported by animal studies showing that paraquat produces toxicity in dopaminergic neurons of the rat and mouse brain. However, it is unclear how paraquat triggers toxicity in dopaminergic neurons. Based on the prooxidant properties of paraquat, it was hypothesized that paraquat may induce oxidative stress-mediated toxicity in dopaminergic neurons. To explore this possibility, dopaminergic SH-SY5Y cells were treated with paraquat, and several biomarkers of oxidativestress were measured. First, a specific dopamine transporter inhibitor GBR12909 significantly protected SY5Y cells against the toxicity of paraquat, indicating that paraquat exerts its toxicity by a mechanism involving the dopamine transporter (DAT). Second, paraquat increased intracellular levels of reactive oxygen species (ROS), but decreased the levels of glutathione. Third, paraquat inhibited glutathione peroxidase activity, but did not affect glutathione reductase activity. On the other hand, paraquat increased GST activity by 24 h, after which GST activity returned to the control value at 48 h. Fourth, paraquat dissipated mitochondrial transmembrane potential (MTP). Fifth, paraquat produced increases of malondialdehyde (MDA) and protein carbonyls, as well as DNA fragmentation, indicating oxidative damage to major cellular components. Sixth, paraquat increased the protein level of heme oxygenase-1 (HO-1). Taken together, these findings verify our hypothesis that paraquat produces oxidative stress-mediated toxicity in SH-SY5Y cells. Thus, current findings suggest that paraquat may induce the pathogenesis of dopaminergic neurons through oxidative stress.

Oxidative and Inflammatory Pathways in Parkinson’s Disease

“…PQ is a cationic non-selective herbicide used to control weeds and grasses in agriculture fields such as cotton [13,25,36]. Unfortunately, the waste greenery from cotton is fed to beef cattle [13].…”

Increased Reactive Oxygen Species Production in the Brain After Repeated Low-Dose Pesticide Paraquat Exposure in Rats. A Comparison with Peripheral Tissues

“…Up to date there have been many publications revealing the processes involved in the generation of ROS by PQ but most of them were performed in vitro on cell cultures [16][17][18][19][20][21][22][23] or ex vivo on isolated microsomes or mitochondria from different organs [15,24,25]. Very few reports have proven ROS generation in vivo after intraperitoneal PQ administration, especially in the brain structures.…”

Neural Repair Strategies for Parkinson's Disease: Insights from Primate Models

“…and reports of human contamination (34,122) have reNonhuman primate models of PD, particularly the 6-searchers looking to determine the appropriateness of OHDA and MPTP models, have played a significant PQ and maneb toxicity as a model for PD.…”