Grantee Research Project Results
Assessment of neurotoxicity of mixtures of PFAS and other neuroactive organic pollutants through integrated in silico, in vitro cellular and in vivo models
EPA Grant Number: R840451Title: Assessment of neurotoxicity of mixtures of PFAS and other neuroactive organic pollutants through integrated in silico, in vitro cellular and in vivo models
Investigators: Aga, Diana S. , Atilla-Gokcumen, Ekin , Rajan, Krishna , Sirotkin, Howard
Institution: The State University of New York at Buffalo
EPA Project Officer: Aja, Hayley
Project Period: October 1, 2022 through May 12, 2025
Project Amount: $750,000
RFA: Development of Innovative Approaches to Assess the Toxicity of Chemical Mixtures Request for Applications (RFA) (2022) RFA Text | Recipients Lists
Research Category: CSS , Chemical Safety for Sustainability , Children's Health , Computational Toxicology , Endocrine Disruptors , Health Effects , Heavy Metal Contamination of Soil/Water , Human Health , Mixtures , New Approach Methods (NAMs) , Non-Vertebrate Animal Testing , PFAS Treatment , Safer Chemicals , Urban Air Toxics
Description:
This study will integrate in vitro and in silico high throughput testing (HTT) with in vivo tests using zebrafish model to evaluate the neurotoxicity of mixtures of per- and polyfluoroalkyl substances (PFAS), and their mixtures with other organic contaminants. The role of cellular transporters in the active transport of PFAS will be evaluated to study the bioactivity of PFAS and their mixtures. These approaches will assess the role of PFAS in the etiology of neurodevelopmental disorders, particularly in the development of autism spectrum disorder (ASD).
Objective:
The objectives of the study are to: (1) derive information on the effects of PFAS and their mixtures on cellular key events leading to neurotoxicity; (2) develop machine learning toxicity prediction tools to map the multivariate data on the structure and/or functionality of PFAS and other organic contaminants, (3) investigate the role of cellular transporters in PFAS uptake and localization, and (4) validate results from in vitro and in silico approaches using zebrafish model to assess impacts of PFAS on neurodevelopment, and on the development of complex behaviors.
We hypothesize that PFAS uptake is facilitated by transporters, and that exposure to mixtures of PFAS during embryogenesis disrupts brain development and contributes to the etiology of ASD and related neurodevelopmental disorders. We also hypothesize that although individual components may be too low to cause any effect at environmentally realistic concentrations mixtures of PFAS will act in a concentration additive manner such that PFAS mixtures are likely to be active.
Approach:
We propose a tiered workflow combining experimental and computational approaches to investigate neurotoxic effects of individual PFAS, equipotent mixtures of PFAS, and mixtures of PFAS with other neuroactive organic contaminants. We will apply an imaging-based HTT using the differentiated SHSY5Y or LHUMES cell lines to assess cell uptake, viability, mitochondrial dysfunction, and disturbances of neuronal networks. A uniform manifold approximation and projection deep learning model will be developed to predict chemical mixture toxicity. Finally, zebrafish larvae will be used to assess PFAS effects on brain development and on social interactions using a sensitized genetic background consisting of mutations in genes that are associated with ASD.
Expected Results:
Overall, these studies will provide multiple end point results of exposure to PFAS mixtures; experimental data can be used to generate in silico models to predict general biological activity, such as neurotoxicity, of PFAS mixtures. By investigating the particular mechanisms underlying known effects, we will have a better understanding of the effects of individual PFAS and how they interact in mixtures. A series of presentations, fact sheets, and peer-reviewed manuscripts will detail the scientific findings of each tested hypothesis, which will be disseminated to the scientific community and stakeholders. The data generated will enable the application of adverse outcome pathway framework for PFAS neurological outcomes.
Publications and Presentations:
Publications have been submitted on this project: View all 5 publications for this projectJournal Articles:
Journal Articles have been submitted on this project: View all 4 journal articles for this projectSupplemental Keywords:
antidepressants, LC/MS/MS, binary mixtures, CD36 transporterProgress and Final Reports:
The 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.