Title | A hPSC-based platform to discover gene-environment interactions that impact human β-cell and dopamine neuron survival. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Zhou, 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 |
Journal | Nat Commun |
Volume | 9 |
Issue | 1 |
Pagination | 4815 |
Date Published | 2018 11 16 |
ISSN | 2041-1723 |
Keywords | Animals, 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. |
DOI | 10.1038/s41467-018-07201-1 |
Alternate Journal | Nat Commun |
PubMed ID | 30446643 |
PubMed Central ID | PMC6240096 |
Grant List | DP3 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 |