A hPSC-based platform to discover gene-environment interactions that impact human β-cell and dopamine neuron survival

Nat Commun. 2018 Nov 16;9(1):4815. doi: 10.1038/s41467-018-07201-1.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Death / drug effects
  • Cell Death / genetics
  • Cell Differentiation
  • Cyclohexanes / toxicity*
  • Diabetes Mellitus / chemically induced*
  • Diabetes Mellitus / genetics
  • Diabetes Mellitus / pathology
  • Dopaminergic Neurons / cytology
  • Dopaminergic Neurons / drug effects*
  • Dopaminergic Neurons / enzymology
  • Gene-Environment Interaction*
  • Glutathione Transferase / deficiency
  • Glutathione Transferase / genetics
  • Humans
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / enzymology
  • Mesencephalon / cytology
  • Mesencephalon / drug effects
  • Mesencephalon / enzymology
  • Mice
  • Models, Biological
  • Parkinson Disease / etiology
  • Parkinson Disease / genetics
  • Parkinson Disease / pathology
  • Pesticides / toxicity*
  • Pluripotent Stem Cells / cytology
  • Pluripotent Stem Cells / enzymology


  • Cyclohexanes
  • Pesticides
  • Omite
  • glutathione S-transferase T1
  • Glutathione Transferase