Molecular mechanisms of pesticide-induced neurotoxicity: Relevance to Parkinson's disease

Abstract

Pesticides are widely used in agricultural and other settings, resulting in continued human exposure. Pesticide toxicity has been clearly demonstrated to alter a variety of neurological functions. Particularly, there is strong evidence suggesting that pesticide exposure predisposes to neurodegenerative diseases. Epidemiological data have suggested a relationship between pesticide exposure and brain neurodegeneration. However, an increasing debate has aroused regarding this issue. Paraquat is a highly toxic quaternary nitrogen herbicide which has been largely studied as a model for Parkinson's disease providing valuable insight into the molecular mechanisms involved in the toxic effects of pesticides and their role in the progression of neurodegenerative diseases. In this work, we review the molecular mechanisms involved in the neurotoxic action of pesticides, with emphasis on the mechanisms associated with the induction of neuronal cell death by paraquat as a model for Parkinsonian neurodegeneration.

Figure 1. Redox cycling by paraquat

Paraquat is a highly toxic quarternary nitrogen herbicide which has been shown capable to redox cycle in some cell types. Dication paraquat (PQ²⁺) is reduced to PQ⁺ by an NADPH-cytochrome P450 reductase. In the presence of O₂, PQ²⁺ is oxidized with the concomitant production of superoxide anion (•O₂⁻). SOD dismutates •O₂⁻ to H₂O₂ which is further metabolized by GPX. •O₂⁻ also reacts •NO leading to the formation of ONOO⁻. Overexpression of SOD and GPX protects against paraquat-induced toxicity [107]. However, PQ²⁺ can redox cycle again, leading to a continuous generation of ROS and oxidative stress, and depleting the intracellular pools of GSH and NADPH (required for GSSG recycling to GSH by GR). Accumulation of H₂O₂ is reduced further to •OH⁻ through Fenton type reactions.

Figure 2. Molecular mechanisms involved in paraquat-induced neurotoxicity

The mechanisms by which paraquat enters the cell are still unknown. However, it is clear that paraquat can promote the generation of ROS in the cytoplasm by three distinct mechanisms including: 1) redox cycling, 2) inhibition of mitochondrial electron transport chain, and/or 3) induction/activation of ROS generating enzymes such as NADPH-oxidases. Paraquat has also been shown to induce neuronal oxidative stress through the activation of glial cells. Accumulation of ROS leads to oxidative stress observed by the oxidative modification of lipids, proteins and nucleic acids which mediate the activation of cell death signaling cascades. Neuron loss in PD is mostly associated with apoptosis, and paraquat-induced apoptosis has been demonstrated to involve mainly intrinsic pathways. Oxidative stress can directly induce the activation of the mitochondrial pathway of apoptosis. However, paraquat-induced oxidative stress has also been suggested to trigger the activation of ASK1/JNK signaling cascade through the induction of endoplasmic reticulum stress and the activation of IRE1, and also by the direct oxidation of Trx. Activation of SAPKs such as JNK has been demonstrated to regulate the activation/induction of pro-apoptotic Bcl-2 family members, which can further trigger the mitochondrial pathway of apoptosis by inducing cytochrome C (Cyt C) release and the activation of caspases.