Toxicology Letters

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.

Estrogen receptor α mediates alternariol-induced apoptosis and modulation of the invasiveness of ovarian cancer cells

Mycotoxins are secondary metabolites of fungi that may affect both human and animal health. Some of them possess estrogenic activity, due to direct binding to estrogen receptors (ERs) and hence disturb the hormonal balance of the organism. Alternariol (AOH) was previously reported as genotoxic, estrogenic and immunomodulatory agent. However, detailed mechanism of its action has not been fully elucidated. Estrogen receptor α (ERα) was previously reported to modulate the proliferation and invasiveness of ovarian cancer cells. Thus, we decided to verify whether estrogenic-like mycotoxin may affect ovarian cancer cells via ERα. The results showed that AOH induces apoptosis and oxidative stress and that these effects are partially modulated by ERα. Moreover, AOH decreases the invasion and migration of ovarian cancer cells and promotes changes in the expression of genes and proteins that are associated with the invasiveness of cancer i.e. MMP9, SNAIL1/2, ZEB1/2, VIM, CDH1 and CDH2. In conclusion, we postulate that AOH might significantly affect the viability and invasiveness of ovarian cancer cells via modulation of ERα and therefore possibly act as an endocrine disruptive agent in ovarian cancer cells.

Bisphenols S and F drive ovarian granulosa cell tumor invasion via a metabolic switch

Alterations in the metabolism of cancer cells are crucial for tumor growth and progression. However, the mechanism whereby environmental pollutants such as bisphenols F (BPF) and S (BPS) affect glucose metabolism through the glycolytic pathway, and therefore influence tumor progression, are unclear. Both bisphenols are endocrine-disrupting molecules that are used in plastics. As a consequence of their widespread use, these compounds have been detected in various human body fluids. Thus, hormone-sensitive cancers, such as ovarian cancers, are exposed to these compounds. In the present study, we aimed to determine the effects of the concentrations of BPS and BPF found in body fluids on the cell viability, glucose uptake, glycolysis, oxygen consumption, and invasion by the adult ovarian granulosa cell tumor (AGCT) cell line. We found that BPS and BPF increased the glucose uptake, hexokinase activity, proliferation, and invasion of the cells at environmentally relevant concentrations. Furthermore, we identified an inhibition of glycolysis in parallel with an increase in oxygen consumption, suggesting a BPS/BPF-induced switch from aerobic glycolysis to mitochondrial respiration. In summary, these findings demonstrate a new mechanism through which BPS and BPF promote ovarian granulosa cell tumor progression by increasing energy production through mitochondrial respiration. Thus, both bisphenols induced a metabolic switch that appears to be a stimulus for AGCT progression.

Extended sub-chronic exposure to heavy metal mixture induced multidrug resistance against chemotherapy agents in ovarian cancer cells

Recent scientific findings suggest that persistent, minimal quantity exposure to heavy metals combinations can instigate negative reactions across various cell types, tissues, and organs. However, the interplay between heavy metals present in blood and cancerous cells remains largely unclear. We aimed to examine the capability of a Pb, Cd, and Co at very low concentrations blend to trigger multidrug resistance against chemotherapeutic remedies such as cisplatin, 5-fluorouracil, and doxorubicin in the NIH-Ovcar3 human ovarian cancer cell line. Additionally, we sought to dissect the molecular mechanisms bolstering this resistance. Our results illustrate that consistent administration of the heavy metal mixture at extraordinarily low concentrations fosters pronounced chemotherapy resistance in Ovcar3 cells via cross resistance. This resistance endured and was propagated through ensuing cell generations. We observed that ATP-binding cassette (ABC) membrane transporters, specifically P-gp/ABCB1, BRCP/ABCG2, and ABCC1-type cellular detoxification functions, were markedly overexpressed, playing a crucial role in multidrug resistance. This finding supports the molecular evidence of the acquired multidrug resistance phenotype and provides preliminary insights into the potential resistance mechanism. We also found decreased mortality rates in the resistant ovarian cancer cells, with the mitochondrial apoptosis pathway activating at a reduced rate post-chemotherapy relative to the non-resistant control cells. Furthermore, multidrug-resistant cells exhibited increased motility and enhanced wound-healing abilities, hinting at a higher metastatic potential. These findings suggest that analysing P-gp, BRCP, and ABCC1 multidrug resistance gene expression and/or protein levels within biopsy samples from ovarian cancer patients at risk of heavy metal exposure could prove advantageous in determining chemotherapy dosage and prolonging patient lifespan.