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.
Parkinson's disease (PD) is a complex, multi-factorial neurodegenerative disease, known to involve genetic, aging-related components, but also to be highly sensitive to environmental factors. In particular, ample evidence links pesticides to PD etiology. Here, establishing a field-to-bench paradigm, we have combined record-based exposure assessment in a population-based epidemiologic study of PD with testing in dopaminergic neurons produced from iPSCs to further identify and classify PD-relevant pesticides. First, agricultural pesticide-application records in California enabled us to investigate exposure to nearly 300 specific pesticides and PD risk in a comprehensive, pesticide-wide association study (PWAS). We implicated long-term exposure to 53 pesticide active ingredients in PD risk and identified their relevant co-exposure profiles. Second, to identify which of these pesticides might contribute to PD through direct effects on dopaminergic neurons, we employed a live-cell imaging screening paradigm in which neurons, definitively identified with a tyrosine hydroxylase reporter, were exposed to 43 of the high-risk pesticides. Using detailed morphometric measures, we found 10 pesticides were directly toxic to these neurons. Further, we analyzed pesticides typically used in combinations in cotton farming. Among these "cotton cluster" pesticides, co-exposures resulted in markedly greater toxicity than any single pesticide. Trifluralin was a pivotal driver of toxicity to dopaminergic neurons and led to marked mitochondrial dysfunction. Our field-to-bench paradigm may prove useful to mechanistically dissect pesticide exposure implicated in PD risk, and guide agricultural policy in the future.
Polymeric scaffolds aid in creating an environment for cell proliferation and differentiation in tissue engineering applications by acting as temporary artificial extracellular matrices (ECMs) for cells to form functional tissue. Many studies have reported that cell behavior can be significantly affected by the physical and chemical properties of a given scaffold. Therefore, the mechanical and structural properties of these scaffolds must be characterized. Polymeric solutions, such as polycaprolactone (PCL), have been electrospun into nanofiber mats to be used as cell scaffolds. Polycaprolactone (PCL) is a biocompatible polymer and is commonly used in tissue engineering applications; however, PCL is hydrophobic, which makes it difficult for cells to adhere to the mat. Coating the PCL-based mats with collagen, a naturally occurring protein with hydrophilic properties, may improve cell adhesion to the scaffold. The collagen coating may also alter the mechanical properties of the nanofiber mats. In this study, the effect of collagen coating on cell adhesion and proliferation are investigated using alamarBlue tests. Additionally, the mechanical and surface properties of PCL-based nanofiber mats are investigated using a Nanosurf C3000 atomic force microscope (AFM). One batch of PCL mats were coated with collagen, while the uncoated mats were used as controls. The cell behavior and material property values obtained from the uncoated PCL and collagen-coated PCL mats were analyzed and compared. The results of this study suggest that collagen does significantly influence the cell proliferation and material properties of PCL-based mats and that further studies should be conducted to better understand the effects of the nanoscale properties of the PCL-based mats on cell adhesion.
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