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Using Human-Derived Neural Cells as an In Vitro Model for Developmental Neurotoxicity Following Exposure to Pesticides
Citation:
Smith, M., Matt Henderson, S. Wallace, A. Majumder, M. Amosu, X. Bian, K. Lu, AND S. Stice. Using Human-Derived Neural Cells as an In Vitro Model for Developmental Neurotoxicity Following Exposure to Pesticides. Presented at SOT 2015, San Diego, CA, March 22 - 26, 2015.
Impact/Purpose:
Presented at the Society of Toxicology 2015 in San Diego, CA.
Description:
Agricultural, industrial and commercial use of pesticides continues to increase with an estimated annual usage nearing a billion lbs/year. Many of these compounds target the nervous system of nuisance animals and due to their lack of selectivity, casue adverse effects in non-target species. Several classes of pesticides such as the organophosphates, carbamates and organochlorines are known to elicit neurotoxic effects in mammals. however, current testing and safety requirements do not require developmental neurotoxicity (DNT) tests for these chemicals. Understanding the consequence of pesticide exposure on fetal brain development specifically during critical windowns of susceptibility is necessary to accurately predict risk. Thus, there is a critical need for predictive in vitro models to aid in DNT screening and chemical prioritization. The objective of this study was to develop a metabolomics-based DNT assay that includes stages of neural development using proenitor (hNP) and post-mitotic neuronal cells (hN2) to delineate the adverse outcome pathways (AOP) associated with pesticide exposure. Assays were initially developed and validated with known neurotoxic chemicals. In this study, cells were exposed to varying doses of chlorpyrifos, aldicarb, and lindane for 48 hours. Following exposure, media and cells were separated and biological reactions were quenched prior to extraction, derivatization, and analysis by GC-MS. Metabolomic profiling and subsequent multivariate analysis demonstrated separation for each pesticide class and dose dependent responses were observed at concentrations lower than those eliciting effects in cytotoxicity assays. Understanding the biochemical metabolites associated with these responses and mapping them to critical pathways of DNT will aid in predicting the risks due to pesticide exposures.
