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Toxicity Screening with Zebrafish AssayEPA Grant Number: R835168
Title: Toxicity Screening with Zebrafish Assay
Investigators: Tanguay, Robert L.
Institution: Oregon State University
EPA Project Officer: Pascual, Pasky
Project Period: July 9, 2012 through July 9, 2015
Project Amount: $1,199,999
RFA: Developing High-Throughput Assays for Predictive Modeling of Reproductive and Developmental Toxicity Modulated Through the Endocrine System or Pertinent Pathways in Humans and Species Relevant to Ecological Risk Assessment (2011) RFA Text | Recipients Lists
Research Category: Computational Toxicology , Endocrine Disruptors , Health , Ecosystems , Safer Chemicals
Expose zebrafish embryos to at least 1,000 chemicals. 2) Study the morphology and behavior of the embryos to look for evidence of developmental toxicity. 3) When an adverse effect occurs, conduct whole-transcriptome RNA sequencing studies to observe gene expression patterns, identify the initial biochemical target, and begin to elucidate the toxicity pathway. 4) Conduct statistical modeling to compare the results of the zebrafish assay with the results of in vitro assays and other in vivo assays where they exist. 5) Share our data with EPA and the broader research community.
Hypotheses: 1) The zebrafish assay outperforms current cell-based assays by corresponding more closely with the results of rodent assays, at least for certain classes of chemicals. 2) Exposure known to impact the endocrine system in mice and humans will also modulate biological targets that perturb development in zebrafish.Approach:
We will conduct the first in vivo study of the complete set of Phase I and Phase II ToxCast chemicals and approximately 520 other chemicals, including mixtures of chemicals. (We are now testing half of the ToxCast chemicals in a current project under NIH funding and sharing our data with EPA.) We will apply the zebrafish assay not only as a screening platform but also as a discovery platform. We will report gene expression patterns, initial biochemical targets, and our understanding of the toxicity pathway for each chemical that causes an adverse effect.Expected Results:
The proposed toxicity screening will help EPA to prioritize chemicals for further testing, and it may also alert chemical manufacturers that some of their commercial products may be toxic. The proposed toxicity pathway studies will improve the research community’s ability to translate zebrafish results to other species. If high-throughput, low-cost zebrafish testing closely replicates the results of rodent testing, then zebrafish testing, in combination with other assays, may eliminate the need for rodent testing, at least for certain classes of chemicals. The proposed work will help to establish a base of knowledge that will lead to novel cell-based assays that can reliably predict chemical toxicity without in vivo testing.