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Human Pluripotent Stem Cell Based Developmental Toxicity Assays for Chemical Safety Screening and Systems Biology Data Generation
Published on: June 17, 2015
Morphology-based mammalian stem cell tests reveal potential developmental toxicity of donepezil
Caroline G Y Lau1, Yusuke Marikawa
1University of Hawaii John A. Burns School of Medicine, Honolulu, Hawaii.
Abstract:
Various compounds, including therapeutic drugs, can adversely impact the survival and development of embryos in the uterus. Identification of such development-interfering agents is a challenging task, although multi-angle approaches--including the use of in vitro toxicology studies involving embryonic stem cells--should alleviate some of the current difficulties. In the present study, we utilized the in vitro elongation of embryoid bodies (EBs) derived from mouse embryonal carcinoma stem cell line P19C5 as a model of early embryological events, specifically that of gastrulation and axial patterning. From our study, we identified donepezil, a medication indicated for the management of Alzheimer's disease, as a potential developmental toxicant. The extent of P19C5 EB axial elongation was diminished by donepezil in a dose-dependent manner. Although donepezil is a known inhibitor of acetylcholinesterase, interference of elongation was not mediated through this enzyme. Quantitative reverse-transcriptase PCR revealed that donepezil altered the expression pattern of a specific set of developmental regulator genes involved in patterning along the anterior-posterior body axis. When tested in mouse whole embryo culture, donepezil caused morphological abnormalities including impaired somitogenesis. Donepezil also diminished elongation morphogenesis of EBs generated from human embryonic stem cells. These results suggest that donepezil interferes with axial elongation morphogenesis of early embryos by altering the expression pattern of regulators of axial development.
Insights
Donepezil, an Alzheimer's drug, may harm early embryo development by disrupting axial elongation. This study used embryoid bodies to identify donepezil as a potential developmental toxicant affecting key gene expression.
Area of Science:
- Developmental toxicology
- Embryology
- Stem cell biology
Background:
- Therapeutic drugs can pose risks to embryonic development.
- Identifying developmental toxicants requires robust in vitro models.
- Embryonic stem cells offer a valuable tool for toxicological screening.
Purpose of the Study:
- To identify potential developmental toxicants using an in vitro embryoid body elongation model.
- To investigate the impact of donepezil on early embryonic patterning.
- To assess donepezil's effects on both mouse and human embryonic stem cell-derived embryoid bodies.
Main Methods:
- Utilized in vitro elongation of P19C5 mouse embryonal carcinoma stem cell-derived embryoid bodies (EBs) as a model for gastrulation and axial patterning.
- Administered donepezil to EBs in a dose-dependent manner.
- Performed quantitative reverse-transcriptase PCR to analyze gene expression.
- Evaluated donepezil's effects in mouse whole embryo culture and on human embryonic stem cell-derived EBs.
Main Results:
- Donepezil significantly inhibited P19C5 EB axial elongation in a dose-dependent manner.
- Donepezil altered the expression of developmental regulator genes involved in anterior-posterior axis patterning.
- Donepezil induced morphological abnormalities, including impaired somitogenesis, in whole mouse embryo cultures.
- Donepezil also impaired elongation morphogenesis in human embryonic stem cell-derived EBs.
Conclusions:
- Donepezil is identified as a potential developmental toxicant affecting early embryonic axial elongation.
- The mechanism of interference does not involve acetylcholinesterase inhibition.
- Donepezil disrupts embryonic development by altering the expression of key axial patterning regulators.
- These findings highlight the need for careful evaluation of drugs like donepezil for potential embryotoxicity.
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