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Abstract
Common disorders, including diabetes and Parkinson’s disease, are caused by a combination of environmental factors and genetic susceptibility. However, defining the mechanisms underlying gene-environment interactions has been challenging due to the lack of a suitable experimental platform. Using pancreatic β-like cells derived from human pluripotent stem cells (hPSCs), we discovered that a commonly used pesticide, propargite, induces pancreatic β-cell death, a pathological hallmark of diabetes. Screening a panel of diverse hPSC-derived cell types we extended this observation to a similar susceptibility in midbrain dopamine neurons, a cell type affected in Parkinson’s disease. We assessed gene-environment interactions using isogenic hPSC lines for genetic variants associated with diabetes and Parkinson’s disease. We found GSTT1−/− pancreatic β-like cells and dopamine neurons were both hypersensitive to propargite-induced cell death. Our study identifies an environmental chemical that contributes to human β-cell and dopamine neuron loss and validates a novel hPSC-based platform for determining gene-environment interactions.
Highlights
Common disorders, including diabetes and Parkinson’s disease, are caused by a combination of environmental factors and genetic susceptibility
To perform the chemical screen, H1 human embryonic stem cells (hESCs) were differentiated toward INS+ cell fate following our previously reported stepwise differentiation protocol: generating first SOX17+/FOXA2+ definitive endoderm, followed by PDX1+/NKX6.1+ pancreatic progenitors and PDX1+/INS+ cells (Fig. 1a and Supplementary Fig. 1a)[18]
The Phase I Toxicity Forecaster (ToxCast) library provided by the U.S Environmental Protection Agency (EPA) was used, which represents ~2000 compounds, including pesticides, industrial and consumer products
Summary
A HTS to identify chemicals that target human β-cells. We first sought to systematically explore the effects of environmental chemicals on human pancreatic β-cell survival using hESCderived insulin-expressing (INS+) β-like cells. Lower survival rates were accompanied by significantly higher levels of DNA damage in the cells as determined by the percentages of γH2AX+ INS+ /INS+ cells (Fig. 3g, h) Together, these results indicate that GSTT1 gene deletion increases the susceptibility of INS+ cells to propargite-induced cell death. We determined whether propargite is toxic to other cell types by treating a range of different hESC-derived lineages with 1.6 μM of propargite, including CD29+/CD73+ mesenchymal stem cells, CTNT+ cardiomyocytes, A1AT+ hepatocytes, HuC/D+ neurons and primary BJ-fibroblasts (Supplementary Fig. 4a–e). A significant increase of the percentage of γ-H2AX+/INS+ in INS+ cells of propargite-treated mice was observed, suggesting enhanced rates of propargite-induced DNA damage in mouse pancreatic βcells in vivo (Fig. 5b, c). To further confirm that the sensitivity of β-cells to propargite depends on genetic background, EndoC-βH1-Luc cells carrying sgGSTT1 were transplanted into the immunea
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