Introduction: Chemical pesticides, especially those applied in agriculture, are suspected to be risk factors for neurodegenerative diseases such as Parkinson's disease. Epidemiological studies, however, report inconsistencies in rates of relative risk for those exposed to pesticides such as Rotenone, Maneb. and Paraquat (PQ). PQ is an herbicide used world-wide, except for the European Union. In addition to its herbicidal effects, PQ is highly toxic to mammalian lung, and in animals PQ has been shown to be neurotoxic. A major target of PQ neurotoxicity is the substantia nigra pars compacta (SNc), and this region's population of dopaminergic neurons. Degeneration of these cells with subsequent loss of dopamine in the caudate-putamen is the primary pathophysiological feature of idiopathic Parkinson's disease. Methods and Materials: We recently showed that differential susceptibility to PQ neurotoxicity in four inbred mouse strains from the family of BXD recombinant inbred strains is associated with the increase in iron concentration in the ventral midbrain - the area containing both the SNc and ventral tegmentum. In comparing the effect of PQ on gene expression in the ventral midbrain, one PQ-susceptible strain showed changes in more than 300 transcripts whereas one resistant strain showed changes in fewer than one dozen transcripts. Results: In the sensitive strain, the preponderance of genes with altered expression is iron binding protein genes; whereas in the resistant strain, the few altered genes are related to intermediate metabolisms. While we have shown the likely involvement of iron in PQ-related dopamine neurotoxicity, the question remains whether the relationship between iron and PQ is unique to PQ. We also studied genetic differences among 10 BXD recombinant inbred mouse strains to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a proneurotoxicant (the active agent is the metabolite, MPP+ produced in astrocytes) used to model the pathophysiology of Parkinson's disease. Again, we detected large genetic differences in neurotoxicity produced by this agent. In the strain most susceptible to MPTP toxicity we observed a significant increase in iron concentration in the ventral midbrain. Conclusion: Our research is not the first to show a relationship between PQ and iron in neurotoxicity. It is the first however, to show that individual differences in susceptibility to PQ and probably other neurotoxicants are related to genetic differences in toxicant-based influx of iron into the ventral midbrain, especially in the SNc.
Agriculture; Agricultural-chemicals; Agricultural-workers; Pesticides; Pesticides-and-agricultural-chemicals; Iron-compounds; Neurotoxicity; Neurotoxic-effects; Occupational-diseases; Risk-factors; Hematology; Herbicides; Cell-damage; Brain-disorders; Laboratory-animals; Laboratory-testing; Gene-mutation; Genes; Proteins; Genetic-factors; Chronic-degenerative-diseases; Metabolites