A pesticide and iPSC dopaminergic neuron screen identifies and classifies Parkinson-relevant pesticides

Abstract

Parkinson’s disease (PD) is a complex neurodegenerative disease with etiology rooted in genetic vulnerability and environmental factors. Here we combine quantitative epidemiologic study of pesticide exposures and PD with toxicity screening in dopaminergic neurons derived from PD patient induced pluripotent stem cells (iPSCs) to identify Parkinson’s-relevant pesticides. Agricultural records enable investigation of 288 specific pesticides and PD risk in a comprehensive, pesticide-wide association study. We associate long-term exposure to 53 pesticides with PD and identify co-exposure profiles. We then employ a live-cell imaging screening paradigm exposing dopaminergic neurons to 39 PD-associated pesticides. We find that 10 pesticides are directly toxic to these neurons. Further, we analyze pesticides typically used in combinations in cotton farming, demonstrating that co-exposures result in greater toxicity than any single pesticide. We find trifluralin is a driver of toxicity to dopaminergic neurons and leads to mitochondrial dysfunction. Our paradigm may prove useful to mechanistically dissect pesticide exposures implicated in PD risk and guide agricultural policy.

Genetic variation and pesticide exposure influence blood DNA methylation signatures in females with early-stage Parkinson’s disease

“…In the specific context of pesticides, impacts of common genetic variation ( GSTP1 , ABCB1 ) and PD-associated mutations ( LRRK2 G2019S) on response to herbicide, organochlorine, and paraquat exposure have been identified in both human and model organism studies 77 – 80 . While we identified different SNPs associated with pesticide exposure in this study, it is still possible they may have influenced response to exposure, which could be resolved with more precise accounting of exposure and supported by experimental studies 73 . On the whole, the lack of association between SNPs explaining DNAm at PD-associated CMRs in TERRE and SNPs associated with genetic risk for PD in populations of European ancestry suggested that SNP genotype may impact DNAm levels at the given CMRs independently of PD status (for instance, if PD cases and controls had different genotypes by chance), and/or that genotype and PD could both be associated with additional unmeasured factors, such as population-specific G × G or G × E interactions 29 , 76 .…”

Parkinson’s Disease Is Predominantly an Environmental Disease

“…Due to cumulative or possibly even synergistic effects, such cocktails may contribute to a much higher risk of developing PD. A recent study in California suggests that co-exposure to multiple pesticides is associated with much greater damage to dopaminergic neurons than exposure to any single compound [ 62 ], yet current regulatory actions only consider the neurotoxicity of isolated compounds.…”

Parkinson’s Disease in Sub-Saharan Africa: Pesticides as a Double-Edged Sword

“…Most presently known PD linked pesticides have been banned in many areas of the world, particularly in high income regions, yet some of these pesticides continue to be used in SSA. Table 1 also shows organochlorines linked to PD [ 5, 25 ] which have been banned in many countries including SSA but still being used in the United States. Despite documented adverse effects on the ecosystem and carcinogenic risks, hazardous pesticides persist in SSA for lack of affordable and safer alternatives to control famine and epidemics.…”