Propargite, an environmental chemical, interacts with GWAS identified diabetes genes to impact human pancreatic ß-cell death [PTPN2 knockout]

This paper describes the first time a high-content environmental chemicals screen using pancreatic ß-like cells derived from human pluripotent stem cells (hPSCs), and discovered that a commonly used pesticide, propargite, induces pancreatic ß-cell DNA damage and necrosis. More interestingly, we found out the genetic background of ß-like cells affects their response to propargite-induced toxicity, based on isogenic hPSC platform, including for variants GWAS identified associated with T1D, since isogenic GSTT1-/- and PTPN2-/- pancreatic ß-like cells are hypersensitive to propargite-induced ß-cell death both in vitro and in vivo. In summary, our study identified an environmental chemical that contributes to the loss of ß-cells and provides an innovative platform for using hPSC-derived cells to explore gene-environment interactions that impact diabetes disease progression. Overall design: RNA-seq was used to compare the gene expression for two wildtype hESC (PTPN2+/+-1 and PTPN2+/+-2) and two PTPN2 knockout hESC (PTPN2-/--1 and PTPN2-/--2) derived INS-GFP+ cells.