Suzanne E. Fenton

Select Per- and Polyfluoroalkyl Substances (PFAS) Induce Resistance to Carboplatin in Ovarian Cancer Cell Lines

Per- and polyfluoroalkyl substances (PFAS) are ubiquitous environmental contaminants associated with adverse reproductive outcomes including reproductive cancers in women. PFAS can alter normal ovarian function, but the effects of PFAS on ovarian cancer progression and therapy response remain understudied. Ovarian cancer is the most lethal gynecologic malignancy, and a major barrier to effective treatment is resistance to platinum-based chemotherapy. Platinum resistance may arise from exposure to external stimuli such as environmental contaminants. This study evaluated PFAS and PFAS mixture exposures to two human ovarian cancer cell lines to evaluate the ability of PFAS exposure to affect survival fraction following treatment with carboplatin. This is the first study to demonstrate that, at sub-cytotoxic concentrations, select PFAS and PFAS mixtures increased survival fraction in ovarian cancer cells following carboplatin treatment, indicative of platinum resistance. A concomitant increase in mitochondrial membrane potential, measured by the JC-1 fluorescent probe, was observed in PFAS-exposed and PFAS + carboplatin-treated cells, suggesting a potential role for altered mitochondrial function that requires further investigation.

Chronic PFAS Exposure Induces Chemotherapy Resistance by Promoting Mitochondria-Related Alterations in Ovarian Cancer Cells.

Resistance to chemotherapy is a major barrier to the effective treatment of ovarian cancer; however, the role of environmental exposures in the onset of chemoresistance remains elusive. Our previous work in ovarian cancer cells suggests that short-term perfluoroalkyl substances (PFAS) exposures induce chemoresistance, potentially by influencing mitochondrial parameters, but little is known about the effects of longer-term exposures, which are more human-relevant. Since mitochondria play critical roles in determining ovarian cancer chemotherapy response, it is also important to understand the role of environmental exposures in modulating mitochondrial function. This study explored how varying durations of PFAS exposure (2-35 days) affect mitochondrial parameters known to drive chemoresistance in human ovarian cancer cell lines. An ovarian cancer cell line (OVCAR-3) that was chronically exposed to PFAS (26-35 days) was generated. Compared to short-term PFAS exposure, chronic PFAS exposures significantly increased resistance to both carboplatin and doxorubicin. Chemotherapy resistance was accompanied by increased mitochondrial superoxide production, alterations in bioenergetics, and elevated mitochondrial content. These findings suggest that PFAS exposure induces chemotherapy resistance in ovarian cancer cells in a duration-dependent manner, worsened by human-relevant chronic exposures, and that mechanisms driving these effects are influenced by the modulation of mitochondrial parameters. Future studies should focus on targeting mechanisms underlying PFAS-induced chemotherapy resistance to improve survival outcomes.