Delineating mechanisms underlying azole-induced developmental toxicity using single cell transcriptomic approaches, genome editing tools, and alternative models

使用单细胞转录组学方法、基因组编辑工具和替代模型描述唑类诱导的发育毒性的机制

基本信息

项目摘要

Summary (Parent Grant) Azoles are antifungal agents widely-used in clinical applications and agriculture. Despite evident exposures in humans, the developmental health risks associated with azole exposures during pregnancy remains undefined. In vertebrate models, azoles cause developmental toxicity, including a spectrum of congenital malformations. While the mechanisms are unresolved, azoles induce changes in the embryo that resemble excess bioavailability of all-trans retinoic acid (RA) due to similarities in adverse morphological and molecular phenotypes. In a spatiotemporal-dependent manner, RA regulates the transcription of hundreds of genes, several with known essential functions for embryonic development. Many environmental chemicals are suspected to cause developmental toxicity by disrupting RA signaling at different points in the pathway. As we transition towards alternative, animal-free approaches for developmental toxicity testing, delineating toxicological mechanisms associated with perturbations in key signaling pathways such as RA is warranted to establish appropriate in vitro and in silico testing models for identifying chemical hazards. In this project, we propose to leverage alternative models for developmental toxicity testing: rat whole embryo culture (WEC; Aim 1), zebrafish (Zf; Aim 2) embryo, and human embryonic stem cell (hESC; Aim 3) models and innovative molecular tools (e.g., single-cell RNA sequencing, CRISPR-Cas9), to investigate mechanisms linked with azole-induced developmental toxicity during a predefined susceptible window in embryogenesis (early organogenesis). We will determine conserved molecular, cellular, and morphological changes due to azole exposure and functional targets with roles in cell proliferation, differentiation and patterning. Results will be used to delineate an adverse outcome pathway (AOP) of azole-induced developmental toxicity. Finally, our study will be one of the first investigations to implement single-cell transcriptomics and multi-gene editing to link chemical exposures to adverse developmental outcomes on molecular, cellular and organism levels.
摘要(家长补助金)

项目成果

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Joshua Frederick Robinson其他文献

Joshua Frederick Robinson的其他文献

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{{ truncateString('Joshua Frederick Robinson', 18)}}的其他基金

Delineating mechanisms underlying azole-induced developmental toxicity using single cell transcriptomic approaches, genome editing tools, and alternative models
使用单细胞转录组学方法、基因组编辑工具和替代模型描述唑类诱导的发育毒性的机制
  • 批准号:
    10337968
  • 财政年份:
    2022
  • 资助金额:
    $ 5.8万
  • 项目类别:
Delineating mechanisms underlying azole-induced developmental toxicity using single cell transcriptomic approaches, genome editing tools, and alternative models
使用单细胞转录组学方法、基因组编辑工具和替代模型描述唑类诱导的发育毒性的机制
  • 批准号:
    10584486
  • 财政年份:
    2022
  • 资助金额:
    $ 5.8万
  • 项目类别:
Polybrominated Diphenyl Ether Effects on Human Neuronal Development
多溴二苯醚对人类神经元发育的影响
  • 批准号:
    8678771
  • 财政年份:
    2014
  • 资助金额:
    $ 5.8万
  • 项目类别:

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