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

TitleA hPSC-based platform to discover gene-environment interactions that impact human β-cell and dopamine neuron survival.
Publication TypeJournal Article
Year of Publication2018
AuthorsZhou, T, Kim, TWan, Chong, CNok, Tan, L, Amin, S, Badieyan, ZSadat, Mukherjee, S, Ghazizadeh, Z, Zeng, H, Guo, M, Crespo, M, Zhang, T, Kenyon, R, Robinson, CL, Apostolou, E, Wang, H, Xiang, JZhaoying, Evans, T, Studer, L, Chen, S
JournalNat Commun
Volume9
Issue1
Pagination4815
Date Published2018 11 16
ISSN2041-1723
KeywordsAnimals, Cell Death, Cell Differentiation, Cyclohexanes, Diabetes Mellitus, Dopaminergic Neurons, Gene-Environment Interaction, Glutathione Transferase, Humans, Insulin-Secreting Cells, Mesencephalon, Mice, Models, Biological, Parkinson Disease, Pesticides, Pluripotent Stem Cells
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.

DOI10.1038/s41467-018-07201-1
Alternate JournalNat Commun
PubMed ID30446643
PubMed Central IDPMC6240096
Grant ListDP3 DK111907 / DK / NIDDK NIH HHS / United States
R01 AG054720 / AG / NIA NIH HHS / United States
U01 CA224326 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
DP2 DK098093 / DK / NIDDK NIH HHS / United States
R01 DK116075 / DK / NIDDK NIH HHS / United States