Final Report: Human Neural Stem Cell Metabolomic, Cellular and Organ Level Adverse Outcome Pathway Relationships for Endocrine Active Compounds

EPA Grant Number: R835551
Title: Human Neural Stem Cell Metabolomic, Cellular and Organ Level Adverse Outcome Pathway Relationships for Endocrine Active Compounds
Investigators: Stice, Steve , Lu, Kun , Smith, Mary Alice , Zhao, Qun
Institution: University of Georgia
EPA Project Officer: Lasat, Mitch
Project Period: September 1, 2013 through August 31, 2016 (Extended to August 31, 2017)
Project Amount: $799,938
RFA: Development and Use of Adverse Outcome Pathways that Predict Adverse Developmental Neurotoxicity (2012) RFA Text |  Recipients Lists
Research Category: Health , Human Health , Safer Chemicals

Objective:

Our overall objective was to determine the effects of endocrine active compounds (EACs) on events and adverse outcome pathways, spanning key temporal windows of human neural development. We used human neural cells for metabolomics, cell function (viability and neurite outgrowth), and in vivo chick embryo central nervous system assays to reach this objective and provide information on EACs mode of actions.

Summary/Accomplishments (Outputs/Outcomes):

In current human DNT systems, chemical neurotoxicities have been assessed mostly by neuron-only models or undefined ratios of neurons-to-rodent astrocytes. A defined human multicellular system provides an interactive tissue-like environment with active modulation and presentation of toxicants to neurons, adding significant power to predictive in vitro DNT assays. We established a scalable, tunable and defined human PSC-derived astrocyte and neuron CNS co-culture system and identified the role of astrocyte-specific P450 acting to protect neurons from CPF toxicity.

Using MetaboAnalystâ„¢ for pathway analysis, major pathways affected in human neurons directly exposed to chlorpyrifos were phenylalanine metabolism, fatty acid biosynthesis, and cyanoamino acid metabolism. When neurons were exposed to conditioned media from liver cells treated with chlorpyrifos, the major pathways affected were valine, isoleucine, and leucine biosynthesis and degradation, as well as aminoacyl-tRNA biosynthesis. In summary, chlorpyrifos affects amino acid and fatty acid metabolism in developing neuronal cells.

A next-generation SPIO contrast agent Molday ION Rhodamine B (MIRB) allows for multimodal stem cell tracking with fluorescent microscopy and magnetic resonance imaging (MRI). MRI was employed to investigate anatomical and functional changes of developing neural systems of normal chick embryos, which now can be used as a benchmark for comparison with those embryos affected by endocrine active compounds, toxins and viruses.


Journal Articles on this Report : 7 Displayed | Download in RIS Format

Other project views: All 32 publications 7 publications in selected types All 7 journal articles
Type Citation Project Document Sources
Journal Article Bisesi Jr. JH, Merten J, Liu K, Parks AN, Afrooz AR, Glenn JB, Klaine SJ, Kane AS, Saleh NB, Ferguson PL, Sabo-Attwood T. Tracking and quantification of single-walled carbon nanotubes in fish using near infrared fluorescence. Environmental Science & Technology 2014;48(3):1973-1983. R835551 (Final)
RD835580 (2014)
RD835580 (2015)
RD835580 (2016)
RD835580 (2017)
  • Abstract from PubMed
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  • Journal Article Goodfellow FT, Simchick GA, Mortensen LJ, Stice SL, Zhao Q. Tracking and quantification of magetically labeled stem cells using magnetic resonance imaging. Advanced Functional Materials 2016;26(22):3899-3915. R835551 (2015)
    R835551 (2016)
    R835551 (Final)
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  • Journal Article Goodfellow FT, Tesla B, Simchick G, Zhao Q, Hodge T, Brindley MA, Stice SL. Zika virus induced mortality and microcephaly in chicken embryos. Stem Cells and Development 2016;25(22):1691-1697. R835551 (2016)
    R835551 (Final)
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  • Journal Article Wu X, Majumder A, Webb R, Stice SL. High content imaging quantification of multiple in vitro human neurogenesis events after neurotoxin exposure. BMC Pharmacology and Toxicology 2016;17(1):62. R835551 (2016)
    R835551 (Final)
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  • Journal Article Willard KA, Demakovsky L, Tesla B, Goodfellow FT, Stice SL, Murdock CC, Brindley MA. Zika virus exhibits lineage-specific phenotypes in cell culture, in Aedes aegypti mosquitoes, and in an embryo model. Viruses 2017;9(12):E383 (19 pp.). R835551 (Final)
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  • Journal Article Wu X, Yang X, Majumder A, Swetenburg R, Goodfellow FT, Bartlett MG, Stice SL. From the cover: Astrocytes are protective against chlorpyrifos developmental neurotoxicity in human pluripotent stem cell-derived astrocyte-neuron cocultures. Toxicological Sciences 2017;157(2):410-420. R835551 (Final)
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  • Journal Article Yang X, Wu X, Brown KA, Le T, Stice SL, Bartlett MG. Determination of chlorpyrifos and its metabolites in cells and culture media by liquid chromatography-electrospray ionization tandem mass spectrometry. Journal of Chromatography B 2017;1063:112-117. R835551 (Final)
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  • Progress and Final Reports:

    Original Abstract
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