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.