Author ORCID Identifier

https://orcid.org/0000-0002-1313-0627

Date Available

7-20-2025

Year of Publication

2025

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Medicine

Department/School/Program

Toxicology and Cancer Biology

Faculty

Dr. Yekaterina Zaytseva

Abstract

Commonly referred to as "forever chemicals," per- and polyfluoroalkyl substances (PFAS) have been linked to a number of detrimental health effects, including an elevated risk of cancer. One "long-chain" subtype of PFAS, perfluorooctanesulfonic acid (PFOS), has a long elimination half-life and a significant propensity for bioaccumulation. Because PFOS is commonly found in drinking water, the gastrointestinal system absorbs it at a high rate. Recent studies demonstrate that PFAS exposures promote intestinal inflammation and gut barrier dysfunction. However, how a long-term PFOS exposure affects colorectal cancer (CRC) progression is not known. Therefore, the purpose of this research is to understand how PFOS exposure is linked gastrointestinal (GI) inflammation, metabolism, immune responses, and carcinogenesis and delineate its effect of PFOS on CRC cell proliferation. In this study I have 1) reviewed relevant scientific literature associated with PFOS exposure and carcinogenesis; 2) delineated the effect of PFOS on colorectal cancer cell proliferation and chemotherapy response; 3) examined the effect PFOS-induced perturbations of immune response in mice. According to relevant scientific literature associated with PFOS exposure in inflammation and intestinal carcinogenesis there is a link between long-term PFOS exposure and lipid metabolism dysregulation, inflammation, microbiome dysfunction, and the etiology of colorectal cancer. However, improved study design is necessary to relate current PFOS literature to human exposure. Primary results of this research showed the chronic exposure to PFOS increased proliferation of colorectal cancer cells at the three-month time point and promoted alterations in genes that are associated with etiology of colorectal cancer. Cyclin D1 and pAkt, factors that are associated with cell division and proliferation, were upregulated following PFOS exposure in three month treated cell lines. Chronically PFOS-exposed colorectal cells also showed reduced levels of factors associated with apoptosis, such as cleaved PARP and Caspase 3. RNAseq analysis showed chronic PFOS exposure downregulated DEFA5, a potential tumor suppressor, and increased levels of genes associated with lipid metabolism, such as FASN and CD36, in colorectal cancer cells. We found that low expression of DEFA5 is associated with lower survival and worse colorectal cancer prognosis. Even though chronic PFOS exposure promoted colorectal cancer cell proliferation and growth, it did not have a substantial effect on chemotherapy response. In summary, findings from the current study suggest that chronic PFOS exposure has a colorectal cancer promoting effect. There is a need to better understand the relationship between PFOS and GI pathology and carcinogenesis, which will enable development of better approaches for interventions in populations exposed to high levels of PFAS, and in particular to PFOS.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2025.288

Funding Information

This study was supported by the P42ES007380 PFAS Grant and the P30ES026529 UK-CARES Grant.

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