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Author ORCID Identifier

https://orcid.org/0009-0000-1938-4356

Date Available

4-10-2026

Year of Publication

2026

Document Type

Master's Thesis

Degree Name

Master of Science (MS)

College

Medicine

Department/School/Program

Toxicology and Cancer Biology

Faculty

Kate Zaytseva

Abstract

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants widely detected in drinking water and food sources, resulting in chronic human exposure. Among these compounds, hexafluoropropylene oxide dimer acid (HFPO-DA), commonly known as GenX, has been introduced as a short-chain replacement for legacy PFAS such as perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA). Although GenX is believed to be a safer alternative, emerging research suggests it can still affect human health.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer-related death in the United States, highlighting the need to better understand environmental factors that may contribute to CRC risk. Published and ongoing work from our laboratory have demonstrated that PFOS can promote proliferative signaling and lipid metabolic dysregulation in normal intestinal epithelium, adenoma and CRC models through activation of receptor tyrosine kinase pathways and dysregulation of lipid metabolism, including activation of lipogenic transcription factor sterol regulatory element-binding protein 1 (SREBP1) and upregulation of fatty acid synthase (FASN).

The objective of this study was to determine whether GenX exposure similarly alters signaling pathways associated with colorectal carcinogenesis. Human CRC cell lines (HT29 and Caco-2) were exposed to GenX under chronic, time-dependent, and physiologically relevant exposure conditions. Cellular proliferation was assessed using a PrestoBlue assay, while protein signaling pathways were evaluated using Western blot analysis and gene expression changes were measured using quantitative RT-PCR. Chronic exposure to GenX increased proliferative capacity in HT29 cells and elevated expression of proliferation-associated proteins. GenX exposure also enhanced activation of receptor tyrosine kinases, including Epidermal growth factor receptor (EGFR) and Tropomyosin receptor kinase B (TRKB), along with downstream Extracellular Signal-Regulated Kinase (ERK) signaling and increased expression of lipid metabolic regulators including SREBP1 and its target genes FASN and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). Time-course experiments indicated that receptor activation occurred rapidly following GenX exposure and preceded activation of SREBP1 signaling. Notably, environmentally relevant nanogram-per-milliliter concentrations of GenX induced receptor activation in Caco-2 cells, suggesting that low-level exposure may influence colorectal cancer–related signaling pathways.

Collectively, these findings support a model in which GenX exposure promotes receptor tyrosine kinase signaling and lipid metabolic reprogramming that may contribute to colorectal cancer cell proliferation. These results provide new mechanistic insight into how emerging PFAS contaminants may influence colorectal carcinogenesis and highlight the need for future studies investigating PFAS exposure in more physiologically relevant models

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2026.42

Archival?

Archival

Funding Information

This study was supported by the University of Kentucky's Superfund Research Center (Project 1), and a National Cancer Institute R01 Grant (no.: CA208343)

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