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Identifying key events that drive neurotoxicity in larval zebrafish with transcriptomic concentration response modeling
Citation:
Howey, X., T. Tal, S. Gaballah, C. Wood, L. Bertotto, AND L. Wehmas. Identifying key events that drive neurotoxicity in larval zebrafish with transcriptomic concentration response modeling. Presented at Developmental Neurotoxicity Journal Club Meeting, RTP, NC, April 08, 2020. https://doi.org/10.23645/epacomptox.19172375
Impact/Purpose:
Presentation to the Developmental Neurotoxicity Journal Club April 2020. Gene expression data from short-term animal studies can inform chemical toxicity outcomes and shows promise in enhancing traditional chemical risk assessments especially for data poor chemicals. This work supports ongoing efforts to test PFAS, identify conserved effects of structurally similar PFAS, and communicate potential toxicity effects relative to real-world exposure levels.
Description:
Gene expression data from short-term in vivo studies shows efficacy in quantifying concentration-dependent effects that inform toxicity outcomes, particularly for chemicals with limited toxicity data such as Per- and Polyfluoroalkyl Substances (PFAS). Here, zebrafish were exposed to 4.4-44.8 µM potassium perfluorohexane-1-sulfonate (PFHxS), 0.28-5.0 µM perfluorooctane sulfonic acid (PFOS), 0.25-5.0 µM Heptachlor (control for developmental neurotoxicity; DNT) or 0.4% DMSO daily from 0-5 days post fertilization (dpf). Automated behavioral assessments on 6 dpf revealed hyperactivity for all compounds at non-teratogenic concentrations. To identify key events that drive DNT, zebrafish were exposed to 7.87-25.1 μM PFHxS, 0.88-2.8 μM PFOS, 0.49-1.57 μM Heptachlor, or 0.4% DMSO. RNA was isolated from head tissue collected at 4 and 5 dpf, before the onset of hyperactivity, for sequencing (NextSeq 500). Differentially expressed genes were identified using Gene Specific Analysis (Partek Flow) and mapped to human orthologs for analyses (IPA). PPAR was predicted as a major regulator for all chemicals. Enrichment in neurologic-related pathways, including axonal guidance signaling and dopamine feedback, was also identified. Dose estimates from transcriptomic benchmark dose modeling (BMDT, BMDExpress 2.0) identified median BMDT values of 18 μM (PFHxS), 2 μM (PFOS), and 1 μM (Hetachlor) at 4 dpf and 10 μM (PFHxS), 1 μM (PFOS), and 1 μM (Heptachlor) at 5 dpf. Median BMDT values were comparable to in vivo lowest observed effect concentration (LOEC) values for hyperactivity: 14 μM PFHxS, 0.88 μM PFOS, or 0.88 μM Heptachlor. This approach demonstrates that transcriptomic points of departure can be linked to hyperactivity (i.e. a functional DNT toxicity outcome) in larval zebrafish to ultimately inform mode of action delineation and enhance chemical risk assessments. This abstract does not necessarily reflect EPA policy.
URLs/Downloads:
DOI: Identifying key events that drive neurotoxicity in larval zebrafish with transcriptomic concentration response modeling
Identifying key events that drive neurotoxicity in larval zebrafish with transcriptomic concentration response modeling (PDF, 12 pp, 1043 KB, about PDF)