Rotenone and Paraquat Linked to Parkinson’s Disease: Human Exposure Study Supports Years of Animal Studies

Abstract

A growing body of evidence suggests pesticides may play a role in Parkinson's disease (PD) in humans. Selfreported PD has been associ ated with lifetime use of pesticides, and animal studies have suggested that the pesticides paraquat and rotenone can cause oxidative stress and mitochondrial dysfunction, respectively-posited mechanisms of action in PD-as well as symptoms in rodents similar to human PD. Now, researchers have linked human exposure to paraquat and rotenone with PD [EHP 119(6):866-872; Tanner et al.]. Their study is the first analysis of pesticides classified by presumed mechanism of action rather than by intended use or chemical class.The researchers assessed lifetime use of pesticides as reported by participants in the Agricultural Health Study, a prospective study of private pesticide applicators (mostly farmers) and their spouses in Iowa and North Carolina. In the nested case-control study, neurologists specializing in movement disorders identified 110 people with PD and 358 controls without who were frequency matched by age, sex, and state.The researchers collected detailed information about use of 31 different pesticides as well as covariate information including lifelong smoking and family history of PD. Each pesticide was classified according to its mechanism of action as either an oxidative stressor or a mitochondrial complex I inhibitor. For participants with PD, the researchers considered pesticide use that occurred before their PD diagnosis. For controls, they considered pesticide use that occurred before the median age of PD diagnosis for cases in the corresponding age, sex, and statespecific groups.Among the mitochondrial complex I inhibitors studied, the researchers found the strongest association between PD and use of rotenone. Among oxidative stressors, they found the strongest association between PD and use of paraquat. Participants with PD were 2.5 times more likely than controls to have reported use of rotenone or paraquat.The results may have farreaching implications, considering the widespread use of these pesticides. Paraquat remains one of the most widely used herbicides worldwide, and rotenone was used ubiquitously before most uses were voluntarily stopped in the United States in 2007. Other agents associated with mitochondrial complex I inhibition, such as permethrin, remain in common use.The authors point out several limitations of the study, including the fact that participants reported exposure to many pesticides, and effects of other agents can't be excluded. However, the associations between PD and paraquat and rotenone remained after adjustment for overall pesticide use. It also was impossible to measure pesticide exposure, only estimate it retrospectively. Future investigations of combinations of pesticides and of other mechanistic groups will be important, as will mechanistic studies that model exposure conditions similar to those occurring in humans. Coal combustion and motor vehicle emissions create severe air pol lution in Beijing and other major Chinese cities. ...

Evidence of neuroprotective effects of saffron and crocin in a Drosophila model of parkinsonism

“…In animal models, ROT (a potent redox disruptor and mitochondrial complex-I inhibitor) has been demonstrated to cause dose-dependent ATP depletion, oxidative damage and mitochondrial dysfunctions (Sherer et al, 2003;Spivey 2011;Canon and Greenamyre, 2010). Evidence suggests that exposure of flies to chemical neurotoxins such as ROT, PQ and MPTP can result in PD like manifestations and pathology.…”

Standardized extract of Withania somnifera (Ashwagandha) markedly offsets rotenone-induced locomotor deficits, oxidative impairments and neurotoxicity in Drosophila melanogaster

“…Rotenone has been demonstrated to cause dose-dependent ATP depletion, oxidative damage and early mortality (Spivey 2011;Sherer et al 2003). Several evidences suggests that Table 2 The modulatory effect of Withania somnifera (WS, 0.05 %) on rotenone (500 μM) induced alteration in the activity levels of antioxidant and cholinergic functions in the whole body homogenates of adult male Drosophila melanogaster -methyl-4 phenyl-1,2,3,6-tetrahydropyridine) can result in PD like manifestations and pathology.…”

Rotenone exerts developmental neurotoxicity in a human brain spheroid model

“…At certain concentrations, rotenone has been shown to produce progressive neurodegeneration of dopaminergic and non-do-paminergic neurons, and also of other brain cell populations such as astrocytes (Betarbet et al, 2000; Sindhu et al, 2005; Zagoura et al, 2017). Rotenone has been suggested as one of the most important environmental risk factor for Parkinson’s Disease (PD) (Betarbet et al, 2000; Perier et al, 2003; Spivey, 2011; Tanner et al, 2011; Nandipati and Litvan, 2016). The major effect of rotenone is related to dopaminergic dysfunction, however, animal studies have found that rotenone may cause diffuse mitochondrial dysfunction in central non-dopaminergic and peripheral cells outside of the CNS (Fleming et al, 2004; Richter et al, 2007) and affect fish, chick and rat development (Khera et al, 1982; Spencer and Sing, 1982; Melo et al, 2015; Rao and Chauhan, 2004).…”