Investigating the impacts of per- and polyfluoroalkyl substances (PFAS) on biological systems by complementary in vivo, in vitro, and in silico approaches

Khazaee, Manoochehr (2022) Investigating the impacts of per- and polyfluoroalkyl substances (PFAS) on biological systems by complementary in vivo, in vitro, and in silico approaches. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Per-and polyfluoroalkyl substances (PFAS) are synthetic industrial compounds that have been widely used in many commercial and consumer applications due to their unique physicochemical characteristics. Recent studies have identified more than 4700 PFAS that have been produced or registered since the late 1940s. The toxicity of many of these chemicals remain understudied despite their widespread use and detection in organisms and environmental media over the past several decades. Therefore, as part of efforts to fill such gaps and to tackle PFAS management issues, this work investigates the toxicokinetics and toxicodynamics of legacy and emerging PFAS at different levels of biological organization via complementary in vivo, in vitro, and in silico approaches. First, we present a validated in silico approach for the prediction of perfluorooctanoic acid toxicokinetics in zebrafish. Our results showed that parameters related to physiology, PFAS-protein interactions, and passive diffusion are largely missing for zebrafish and estimates need further refinement. Considering protein interactions, the structural similarity of most PFAS to lipids, particularly fatty acids, has raised concerns about links between PFAS exposure and lipid dysfunction. For example, both PFAS and fatty acids bind to peroxisome proliferator-activated nuclear receptors (PPARs). We therefore next evaluated the binding affinity of several PFAS of different chain lengths to fatty acid binding proteins and PPAR-α, -δ, and -γ via complementary in silico and in vitro techniques. Results indicated strong binding between short chain PFAS (with 6 or fewer carbons) and PPAR-α and δ, which may have implications for the assumed safety of shorter-chain PFAS. Finally, the impacts of PFAS on gut microbiome composition and genes involved in fatty acid metabolism and the nervous system were investigated via in vivo experiments. Our findings highlighted that emerging PFAS adversely impacted murine gut taxa having important roles in short chain fatty acid production, including butyrate. In addition, perfluorooctane sulfonate exposure altered the expression of genes in zebrafish in ways that vary with both exposure concentration and sex. Overall, this work provided new insight into both the toxicokinetics and toxicodynamics of PFAS.

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Details

Item Type:	University of Pittsburgh ETD
Status:	Unpublished
Creators/Authors:	Creators Email Pitt Username ORCID Khazaee, Manoochehr mak382@pitt.edu
ETD Committee:	Title Member Email Address Pitt Username ORCID Committee Chair Ng, Carla carla.ng@pitt.edu Committee Member Bilec, Melissa mbilec@pitt.edu Committee Member Wendell, Stacy Gelhaus gstacy@pitt.edu Committee Member Haig, Sarah SJHAIG@pitt.edu
Date:	10 June 2022
Date Type:	Publication
Defense Date:	17 February 2022
Approval Date:	10 June 2022
Submission Date:	11 April 2022
Access Restriction:	No restriction; Release the ETD for access worldwide immediately.
Number of Pages:	250
Institution:	University of Pittsburgh
Schools and Programs:	Swanson School of Engineering > Civil and Environmental Engineering
Degree:	PhD - Doctor of Philosophy
Thesis Type:	Doctoral Dissertation
Refereed:	Yes
Uncontrolled Keywords:	Per-and polyfluoroalkyl substances, toxicokinetics, toxicodynamics, PFAS-protein interactions, fatty acid binding proteins, gut microbiome, zebrafish
Related URLs:	Evaluating parameter availability for physiologically based pharmacokinetic (PBPK) modeling of perfluorooctanoic acid (PFOA) in zebrafish Perfluoroalkyl Acid Binding with Peroxisome Proliferator-Activated Receptors α, γ, and δ, and Fatty Acid Binding Proteins by Equilibrium Dialysis with a Comparison of Methods Impacts of Sex and Exposure Duration on Gene Expression in Zebrafish Following Perfluorooctane Sulfonate Exposure
Date Deposited:	10 Jun 2022 19:20
Last Modified:	10 Jun 2022 19:20
URI:	http://d-scholarship.pitt.edu/id/eprint/42592

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• Investigating the impacts of per- and polyfluoroalkyl substances (PFAS) on biological systems by complementary in vivo, in vitro, and in silico approaches. (deposited 10 Jun 2022 19:20) [Currently Displayed]

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