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Access Type
WSU Access
Date of Award
January 2025
Degree Type
Dissertation
Degree Name
Ph.D.
Department
Pharmacology
First Advisor
Izabela Podgorski
Abstract
Per- and polyfluoroalkyl substances (PFAS) are a large and chemically diverse class of synthetic compounds used in industrial applications and consumer products for their water- and stain-resistant properties. Due to their environmental persistence and resistance to degradation, PFAS have become widespread contaminants, accumulating in soil, water, and human tissues, including bone and bone marrow. Epidemiological studies have linked PFAS exposure to a range of adverse health outcomes, including endocrine disruption, metabolic dysfunction, immune modulation, and increased risk of chronic diseases such as osteoporosis and cancer. Despite growing concern, the mechanisms by which PFAS compromise skeletal health and influence tumor progression remain poorly defined. Here, we investigate the mechanisms by which PFAS disrupt bone homeostasis and potentially drive prostate cancer progression, integrating in vitro, in vivo, and clinical analyses. Firstly, we concluded that PFAS exposure, particularly to PFHxS, promotes bone marrow adipogenesis via PPARγ activation, shifting mesenchymal stem cell (MSC) differentiation toward adipocytes and reducing bone mineral density (BMD) in mice. High-fat diets synergize with PFHxS to amplify marrow adiposity, underscoring diet-exposure interactions. Second, we found that both legacy (PFOS, PFOA) and alternative PFAS (GenX) enhance osteoclastogenesis via PPARα, with GenX emerging as a potent inducer of osteoclast differentiation and bone resorption. In vivo exposure reduces trabecular bone volume and alters mineral composition (e.g., chromium depletion), linking PFAS to structural and metabolic defects.Thirdly, our data suggest that PFAS reprogram immune-metabolic crosstalk in the bone tumor microenvironment. PFHxS-exposed bone marrow adipocytes upregulate lipid metabolism genes (CD36, FABP4) and stress markers (HO-1) in prostate cancer cells, enhancing tumor survival. Concurrently, PFAS polarize macrophages toward an immunosuppressive ARG1-high phenotype, potentially impairing T-cell function and fostering metastatic progression. Clinical data corroborate elevated ARG1 in metastatic prostate cancer tissues, aligning with our results demonstrating PFAS-driven macrophage polarization. Key findings reveal that PFAS compromise skeletal integrity through dual mechanisms: metabolic dysregulation (adipocyte expansion, lipid rewiring) and immune suppression (ARG1-mediated). These effects are exacerbated by dietary fat, highlighting gene-environment interactions. The work advances understanding of PFAS as environmental accelerants of bone loss and metastatic cancer, with implications for regulatory policies targeting PFAS exposure limits and therapeutic strategies (e.g., PPAR antagonists, FABP4 inhibitors). This dissertation underscores the urgent need for interdisciplinary approaches to mitigate the skeletal and oncological burdens of PFAS, informing public health interventions and environmental regulations.
Recommended Citation
Garmo, Laimar, "Mechanistic Insights Into Pfas-Mediated Disruption Of Bone Homeostasis: Impacts On Marrow Adiposity, Osteoclastogenesis, Macrophage Polarization And Prostate Cancer Progression" (2025). Wayne State University Dissertations. 4281.
https://digitalcommons.wayne.edu/oa_dissertations/4281