Grantee Research Project Results
2024 Progress Report: 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: Chung, Serena
Project Period: October 1, 2022 through September 30, 2025 (Extended to March 31, 2026)
Project Period Covered by this Report: October 1, 2023 through September 30,2024
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: Children's Health , Health Effects , Computational Toxicology , Urban Air Toxics , Endocrine Disruptors , Heavy Metal Contamination of Soil/Water , New Approach Methods (NAMs) , Human Health , Safer Chemicals , Mixtures , PFAS Treatment , Chemical Safety for Sustainability , Non-Vertebrate Animal Testing , CSS
Objective:
This study aims to 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). 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.
Progress Summary:
Our recent publication on the “Neurotoxic effects of PFAS mixtures of perfluoroalkyl substances (PFAS) at environmental and human blood concentrations” (Environ. Sci. Technol., 2024.58(38):16774- 84) was selected as December 2024 Extramural Paper of the Month by NIEHS. Using a chemical-specific baseline toxicity assay, we predicted the toxicity of individual PFAS compounds and assessed the toxicity of PFAS mixtures through two cell-based assays: neurotoxicity and cytoxicity. Our findings indicate that exposure to PFAS mixtures present a greater health risk than with individual PFAS compounds at individual concentrations that are below cytotoxicity and neurotoxicity levels. We demonstrated that toxicity of PFAS mixtures follows concentration addition models, allowing for predictions based on single-compound data. In another recent paper from our team entitled “Investigating the Mechanism of Neurotoxic Effects of PFAS in Differentiated Neuronal Cells through Transcriptomics and Lipidomics Analysis” (ACS Chem. Neurosci., 2024. 15(24):4568-4579) we showed that exposure to various PFAS treatments in differentiated SH-SY5Y neuronal cells leads to alterations in lipid metabolism and to enrichment of key pathways vital for neuronal function and development. We investigated the role of the cellular transporter OAT10 (organic anion transporter) on cellular uptake of PFAS and observed that shorter chain PFHxA (perfluorohexanoic acid) is taken up at a higher level in OAT10 overexpressing SHSY5Y cells compared to control SH-SY5Y cells, while longer chain PFOA and PFDA are not affected; these findings suggest a preferential uptake of shorter chain PFAS by OAT10. Finally, our in vivo experiments using zebrafish have shown that exposure to 8:2 FTOH induces behavioral abnormalities in larval zebrafish. This latter study is on-going and we will report more detail in our next reporting year.
In another recent publication, we introduced “PFAS-Atlas”, an artificial intelligence-driven platform featuring a rule-based automatic classification system and machine learning-based grouping model (Sci. Total Environ., 2024. 921:171229). This platform will serve as a crucial resource for both PFAS research and regulatory efforts. Moreover, our informatics-driven approaches have provided deeper insights into the molecular properties and mechanisms underlying PFAS-related environmental and human toxicity (MRS Energy and Sustainability, 2024).
Future Activities:
Task 1.3. The mixtures of PFAS and non-PFAS run so far relied on mean blood concentrations. Next, we will run the same mixture design with chemicals and concentration ratios as detected in wastewater and surface water.
Task 2. We will continue establishing machine-learning tools that map the multivariate data on the structure and/or functionality of PFAS listed in the EPA Masterlist Database. We will use these data to link to in vitro and in vivo experiments being done in the other Research Tasks.
Task 3. We will continue our investigations on the role of cellular transporters on the uptake of PFAS and their different mixtures and assess the mechanisms of PFAS accumulation in cells. We will generate similar overexpression systems of fatty acid transport proteins and use these systems to investigate the role of these protein in uptake of PFAS and their mixtures.
Task 4. We will continue to examine the impacts of PFAS compounds on complex behaviors including learning and social interactions. In addition, we will initiate experiments to test interactions between PFAS compounds and genetic susceptibilities. In humans, FMR1 mutations are a leading cause of intellectual disability and are associated with autism spectrum disorder. We will expose FMR1 mutant and heterozygote embryos to PFAS compounds to determine whether animals with these genotypes are particularly vulnerable to PFAS exposure. Behavioral assays will include prey capture learning and social behaviors
Journal Articles on this Report : 2 Displayed | Download in RIS Format
| Other project views: | All 5 publications | 4 publications in selected types | All 4 journal articles |
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Fong A, McPherson A, Rossi M, Rajan K. Building a roadmap for safer and sustainable material chemistries: Addressing the PFAS problem through informatics and data-driven chemistry. MRS Energy & Sustainability. 2024 Nov:1-9. |
R840451 (2024) |
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Ríos-Bonilla KM, Aga DS, Lee J, König M, Qin W, Cristobal JR, Atilla-Gokcumen GE, Escher BI. Neurotoxic effects of mixtures of perfluoroalkyl substances (PFAS) at environmental and human blood concentrations. Environmental Science & Technology. 2024 Sept;58(38):16774-84. |
R840451 (2024) |
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Supplemental Keywords:
neurotoxicity, LC-MS/MS, PFAS mixtures, transporters, in vivo and in silico studiesRelevant Websites:
Research News: Study finds forever chemicals are more toxic as mixtures Exit
PFAS mixtures more harmful to health than exposure to a single compound
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.