Recovery from chronic PFAS exposure can reverse chemotherapy resistance and mitochondrial alterations in ovarian cancer cells
Per- and polyfluoroalkyl substances (PFAS) are environmental contaminants of global concern that have been associated with a variety of adverse health outcomes, including diminished chemotherapy response. Previous studies in moderately chemosensitive ovarian cancer cells (OVCAR-3) have shown that the induction of chemoresistance from PFAS exposure is duration-dependent, with longer, more human-relevant exposure durations leading to worse outcomes. Mitochondrial content was also altered following chronic PFAS exposure, suggesting mitochondria as contributors to PFAS-induced chemoresistance. Here, chemotherapy response following chronic PFAS exposure in a chemoresistant human ovarian cancer cell line, OVCAR-8, was evaluated. Compared to OVCAR-3 cells, chemotherapy response was unaffected by chronic PFAS exposure in OVCAR-8 cells. As individuals gain awareness of sources of PFAS exposure, and associated harmful effects, actions can be taken to limit exposure using water filtration systems and/or safer alternatives to PFAS-containing consumer goods. Thus, we also explored the ability of PFAS-sensitive OVCAR-3 cells to recover from chronic exposure. Following 6 passages of chronic PFAS exposure, cells were "outgrown" in the absence of PFAS for 7 additional passages and proliferation, chemotherapy response, and mitochondria-related alterations were assessed. Compared to chronically-exposed cells, outgrown cells displayed heightened sensitivity to chemotherapy along with decreased superoxide production and mitochondrial content. Proliferation remained significantly elevated compared to controls, suggesting that not all PFAS-induced effects are abrogated by a recovery period. Together, these findings suggest that ovarian cancer cells differ in their PFAS sensitivities and that mitochondria-related alterations resulting from chronic PFAS exposure can be reversed following a "recovery period", potentially resensitizing cancer cells to chemotherapy.
Journal
Toxicology LettersTL;DR
Institutions
Authors
Funding
Center for Environmental Health and Susceptibility, University of North Carolina at Chapel Hill FundingAdministrative CoreFondation Sanofi Espoir FundingOffice of Research and Innovation, Drexel University FundingNational Institutes of Health FundingTargeting Fluid Stress-induced Chemoresistance in a 3D Carcinomatosis Perfusion Model Using Mechanism-based Photo-immunoconjugate Nanoparticles