Date of Award
2024
Degree Type
Dissertation
Degree Name
Doctor of Philosophy in Pharmaceutical Sciences
Specialization
Pharmacology and Toxicology
Department
Biomedical and Pharmaceutical Sciences
First Advisor
Angela Slitt
Abstract
Per- and polyfluoroalkyl substances (PFAS) are persistent chemicals used in many industries, known for their resilience and resistance to degradation. The extended half-lives of PFAS in the human body result in bioaccumulation, with serum half-lives for perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), and perfluorohexane sulfonic acid (PFHxS) estimated at 3.4, 4.6, and 7.1 years, respectively. PFAS primarily accumulate in the liver, hypothesized due to their resemblance to fatty acids and their binding with liver fatty acid-binding proteins (LFABP), affecting lipid metabolism and leading to liver toxicity. Although extensive research has been performed on long-chain PFAS over the past decade, and despite the increasing industrial production and use of short-chain PFAS, there has been a significant lack of studies addressing their health effects upon exposure, and alteration of short-chain PFAS in the environment. Given the extensive spectrum of toxic effects exerted by PFAS, proteomics emerges as a valuable approach for investigating the underlying mechanisms and pathways involved in PFAS-induced toxicity. This thesis uses animal models to explore the role of FABPs on distribution and hepatotoxicity of the PFOS. Moreover, using proteomics technique, HFD and PFAS adverse effects on pups’ lung development in vivo and the adipogenicity potential of PFAS in vitro were studied. In manuscript 1, we investigated PFOS distribution and retention in wild-type, LFABP-deficient, and IFABP-deficient mice. The study showed that LFABP doesn’t plays a significant role in PFOS preferential distribution to the liver. In manuscript 2 we studied the impact of LFABP deficiency on lipid profiles and liver toxicity in mice exposed to PFOS. LFABP-deficient mice displayed altered lipid profiles and activated lipid metabolism regulators, and a possible protective effect against PFOS-induced liver toxicity. In manuscript 3 we explored the adipogenic potential of ten different PFAS compounds in vitro. 3T3-L1 cells were used to assess changes in protein expression, identifying pathways related to adipogenesis and associated health risks. Manuscript 4 focused on the effects of maternal PFAS exposure on neonatal lung development in mice. Pregnant mice received PFAS compounds with varying diets, showing that maternal exposure to PFAS could impact lung proteomics in offspring, potentially exacerbated by high-fat diets. Overall, these studies highlight the adverse health effects of PFAS emphasizing the urgent need for regulation and ultimately ban these chemicals from being used in consumer goods and industrial settings.
Recommended Citation
Modaresi, Seyed Mohamad Sadegh, "MECHANISTIC AND TOXICOKINETIC ANALYSIS OF PERFLUOROALKYL SUBSTANCES: PROTEOMICS APPROACH AND THE ROLE OF FATTY ACID BINDING (FABP)" (2024). Open Access Dissertations. Paper 1663.
https://digitalcommons.uri.edu/oa_diss/1663