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 has 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 possible 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 actions of pesticides, with a particular emphasis on the mechanisms associated with the induction neuronal cell death by paraquat as a model for Parkinsonian neurodegeneration.

Herbicides and the Risk of Neurodegenerative Disease

“…Specifically, atrazine prevents electron transfer at complex II in the chloroplast (Gysin & Knuesli, 1960). Thus, the mechanism of toxicity is similar to the mechanism whereby dopaminergic neurons are killed in the paraquat model of PD (Franco et al, 2010).…”

Epigenetic Landscape of Parkinson's Disease: Emerging Role in Disease Mechanisms and Therapeutic Modalities

“…In addition to MPTP, other environmental toxins, such as pesticides and industrial agents [59,60], have been associated with increased risk for developing PD, although a definitive causal role continues to be debated [61]. Emerging evidence indicates that chronic environmental exposure can alter gene expression via epigenetic mechanisms and can be a key risk factor in the pathogenesis of late-onset neurodegenerative diseases.…”

Molecular Mechanisms of Pesticide Toxicity

“…Oxidative stress arises if detoxification systems and antioxidants are compromised or if ROS production is excessive, resulting in DNA, protein, and lipid oxidation (Fig. 3) ( Franco et al, 2009( Franco et al, , 2010Ryter et al, 2007). Oxidative damage to DNA leads to the formation of lesions such as 8-oxo-deoxyguanosine, 8-oxo-deoxyadenosine, and deoxythymidine glycol which are selectively excised from DNA by DNA glycosylases.…”

“…4). However, the exact mechanisms mediating cytochrome C release are still controversial (Franco et al, 2010). Distinct mitochondrial components and mitochondrial released proteins such as apoptosis inducing factor (AIF), endonuclease G (EndoG), adenine nucleotide translocase (ANT), cyclophilin D, Bit1, p53-regulated Apoptosis Inducing Protein 1 (p53AIP), gene associated with retinoic-interferon-induced mortality 19 (GRIM-19), death associated protein 3 (DAP3), Nerve Growthfactor IB (Nur77/TR3/NGFB-1), HtrA serine peptidase 2 (HtrA2)/ second mitochondria-derived activator of caspases (Omi and Smac)/Diablo have been proposed to participate in the mitochondrial pathway to apoptosis (Ekert & Vaux, 2005).…”

“…Neurodegenerative diseases are most commonly associated with selective neuron loss by apoptosis. Paraquat-induced neural cell death has been demonstrated to involve primarily the activation of apoptosis (Franco et al, 2010). In PD, cell death by apoptosis has been proposed to result from mitochondrial dysfunction, leading to an increase in oxidative stress and a decline in ATP production.…”