You are here:
Investigating Specific Mechanisms of Toxicity Using Zebrafish Developmental Assays and In Vitro High-Throughput Transcriptomics Analysis
Citation:
Knapp, B., R. Judson, L. Taylor, Nancy C. Baker, B. Chambers, AND S. Padilla. Investigating Specific Mechanisms of Toxicity Using Zebrafish Developmental Assays and In Vitro High-Throughput Transcriptomics Analysis. Carolina Society of Environmental Toxicology and Chemistry (CSETAC) 2022 Annual Meeting, RTP (may be virtual), NC, April 06 - 08, 2022. https://doi.org/10.23645/epacomptox.19583917
Impact/Purpose:
Presentation to the Carolina Society of Environmental Toxicology and Chemistry (CSETAC) 2022 Annual Meeting April 2022. Zebrafish are a popular model organism because they share many developmental pathways with humans. Zebrafish developmental toxicity assays can indicate whether a chemical causes malformations or lethality; however, they do not indicate the specific mechanisms that lead to toxicity. Transcriptomics analysis might fill this gap by providing information about gene-level responses to chemical perturbations. The current study aims to uncover the mechanisms by which chemicals cause zebrafish embryo toxicity by comparing zebrafish developmental data to high-throughput transcriptomics analyses using three human cell lines. We believe this type of analysis can generate testable hypotheses regarding pathways leading to developmental defects for specific chemicals.
Description:
Zebrafish are a popular model organism because they share many developmental pathways with humans. Zebrafish developmental toxicity assays can indicate whether a chemical causes malformations (e.g., heart defects) or lethality; however, they do not indicate the specific mechanisms that lead to toxicity. Transcriptomics analysis might fill this gap by providing information about gene-level responses to chemical perturbations. The current study aims to uncover the mechanisms by which chemicals cause zebrafish embryo toxicity by comparing zebrafish developmental data to high-throughput transcriptomics analyses using three human cell lines: hepatic (HepaRG), breast cancer (MCF7), and bone osteosarcoma epithelium (U2OS). We hypothesize that (1) embryo toxicity can be caused by specific modes of action (e.g., receptor-mediated toxicity) or by non-specific cell stress (e.g., oxidative stress); (2) chemicals should cause similar molecular responses in zebrafish and in human cells; and (3) chemicals triggering embryo toxicity through specific mechanisms should have potencies lower than expected from zebrafish toxicity caused by non-specific cell stress. For each chemical, we generated potential specific mechanisms of action by using a combination of target-based analyses using the transcriptomics data and the literature. Transcriptomics is run in concentration-response mode and data are analyzed at the target gene pathway level. Literature information is gathered in a semi-automated way using EPA’s literature database of MeSH terms (EPA LitDB) and AbstractR, which quantify the level of literature support for chemical-gene target associations. For each combination of cell type, chemical, and target pathway, measures of activity (hitcall) and potency (benchmark dose) are derived. Chemical activity is then categorized into specific mechanisms/potencies and non-specific cell stress, and then compared with the potencies in zebrafish data. We believe this type of analysis can generate testable hypotheses regarding pathways leading to developmental defects for specific chemicals. This work does not reflect the official policy of the US EPA.
URLs/Downloads:
DOI: Investigating Specific Mechanisms of Toxicity Using Zebrafish Developmental Assays and In Vitro High-Throughput Transcriptomics Analysis
BK FINAL CSETAC POSTER 3.24.2022.PDF (PDF, NA pp, 561.129 KB, about PDF)