Grantee Research Project Results
2024 Progress Report: Wildfire Smoke Mixtures Toxicity Testing
EPA Grant Number: R840458Title: Wildfire Smoke Mixtures Toxicity Testing
Investigators: Rager, Julia , Reif, David , Jaspers, Ilona , Rebuli, Meghan E , Kim, Yong Ho
Institution: University of North Carolina at Chapel Hill , North Carolina State University
EPA Project Officer: Aja, Hayley
Project Period: October 1, 2022 through May 9, 2025
Project Period Covered by this Report: October 1, 2023 through September 30,2024
Project Amount: $599,999
RFA: Development of Innovative Approaches to Assess the Toxicity of Chemical Mixtures Request for Applications (RFA) (2022) RFA Text | Recipients Lists
Research Category: Health Effects , Endocrine Disruptors , New Approach Methods (NAMs) , Early Career Awards , Human Health , Air , Safer Chemicals , Mixtures , Chemical Safety for Sustainability , Wildfires , CSS
Objective:
This proposal hypothesizes that individual chemicals in wildfire smoke induce in vitro responses that group according to biological pathways, informing mixtures-based joint toxicities that overlap with in vivo pulmonary responses and disease outcomes. This hypothesis will be tested through three objectives: (1) Establish qualitative membership of wildfire mixture components into pathway groupings through in vitro transcriptomic screening; (2) Quantify joint toxicities across pathway groupings and compare to whole biomass smoke mixture effects through in silico modeling; and (3) Relate in vitro wildfire chemical-induced signatures to similarly exposed mice and human pulmonary disease tissues to evaluate events along adverse outcome pathways (AOPs).
Progress Summary:
Accomplishments over the past year span all objectives. Regarding Objective 1, extracted RNA was shipped for sequencing and the resulting hitcount data was cleaned and QA/QC’d. These sequencing data were analyzed for differential gene expression and gene set pathway enrichment across all 14 exposure scenarios and all dose groups within each exposure scenario (e.g. 70 conditions compared to their respective vehicle-matched control). Code was written to automate these analyses and facilitate data processing transparency. Regarding Objective 3, human transcriptomic signatures of canonical pulmonary disease processes were obtained from publicly available databases. In silico analyses were developed to relate these human transcriptomic data with our existing transcriptomic data from mice exposed to wildfire biomass smoke and identify human pulmonary diseases whose altered gene signatures overlap most closely with gene alterations induced by lab-simulated exposures to wildfire biomass smoke. These analyses were refined, sensitivity tested, and described within a manuscript that is under development and near submission.
Future Activities:
Future activies regarding Objectives 1 and 2 include performing gene set pathway enrichment analyses using other gene sets and sopware (e.g. QIAGEN’s Ingenuity Pathway Analysis) in addition to developing analysis pipelines for benchmark dose modeling and other in silico modeling methods that will quantify joint toxicities across pathway groupings and compare to whole biomass smoke mixture effects. Regarding Objective 3, a manuscript is being prepared that describes our in silico analysis relating transcriptomic signatures of human pulmonary disease with those of mice exposed to wildfire biomass smoke and is near submission.
Journal Articles:
No journal articles submitted with this report: View all 8 publications for this projectSupplemental Keywords:
In vitro, Joint Toxicity, Mixtures, Wildfire, Risk assessmentRelevant Websites:
Rager Lab Script for Wildfire Variable Toxicity: Identifying Biomass Smoke Exposure Groupings through Transcriptomic Similarity Scoring Exit
Progress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.