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Conjugated linolenic acids (CLnAs) are emerging as promising agents to trigger ferroptosis, a cell death driven by excessive lipid peroxidation, in cancer cells. Given the aggressive nature and treatment resistance of malignant melanoma, exploring CLnAs as therapeutic agents may offer a novel strategy to overcome these challenges. Here, we investigated the toxicity of four CLnA isomers on human (A375, WM266.4) and zebrafish (ZMEL1) melanoma cell lines. We observed a dose-dependent reduction in cell viability across all three tested cell lines. While human melanoma cells were more sensitive to CLnAs than ZMEL1 cells, treatment with ferroptosis inhibitors mitigated cell death in all models, confirming ferroptosis as the consistent primary mechanism of cell death. In addition, chemical inhibitors of ACSL4 and GPX4 modulated CLnA toxicity, further substantiating the ferroptotic mechanism by highlighting the role of these key regulators. Furthermore, fatty acid analysis revealed that CLnAs were effectively incorporated into phospholipids, generating substrates for lethal lipid peroxidation. At the transcriptional level, CLnA treatment significantly upregulated the pro-ferroptotic gene acsl4a in ZMEL1 cells. Overall, our study identifies specific CLnAs as potent ferroptosis inducers in both human and zebrafish melanoma cells and underscores the translational relevance of the zebrafish model based on a shared ferroptotic mechanism.

Recent studies suggest that environmental pollutants play a role in the continuous increase of the worldwide prevalence of obesity. To our knowledge, there is only one study investigating the impacts of methylmercury, a common and more toxic form of mercury, mainly present in fish and shellfish, on adipose tissue. It shows that methylmercury can cause changes in the structure and function of 3T3-L1 preadipocytes. In this context, we decided to study the effects of methylmercury on primary cultured adipocytes of rainbow trout. This species is a well-known model to study the impact of pollution. In addition, fish adipose tissue metabolism is close to the one of humans. Using an in vitro model allows us to focus on adipocyte differentiation and lipid metabolism. Preadipocytes were obtained after isolating precursor cells from perivisceral adipose tissue by enzymatic digestion. Cells were cultured at 19°C until confluence before being incubated for 6 days in growth medium supplemented or not with a hormonal cocktail (insulin, dexamethasone, ciglitizone) enriched with 0, 0.3, 1.7 or 3.8 mM of methylmercury and lipid mixture. Cytotoxicity was evaluated every two days via LDH assay. At day 6, quantification of total mercury in cells was performed with Direct Mercury Analyser-80. Phospholipid and neutral lipid fractions were analyzed by gas chromatography and expression of adipocyte-related genes was evaluated by RT-PCR. Three biological replicates were carried out. No cytotoxicity was observed during the methylmercury treatment. Methylmercury was partially accumulated but in a dose-dependent manner. At day 6, all fatty acids (FA) from neutral lipid fraction significantly increased at the highest methylmercury concentration. However, the rate of increase was different for each FA. In particular, n-3 polyunsaturated FA were preferentially accumulated. The total amount of phospholipids was not impacted by methylmercury but a decrease of n-6 polyunsaturated FA was observed. Surprisingly, methylmercury decreased the expression of three adipocyte markers, FA transport protein 1 and glycerol-3-phosphate dehydrogenase in presence or absence of hormonal cocktail, and CCAAT/enhancer binding protein delta in presence of hormonal cocktail. On the other hand, methylmercury increased the expression of FA synthase and perilipin. As a conclusion, methylmercury appears to be a candidate obesogen as it increased the cellular lipid content in primary cultured trout adipocytes. Additional genes involved in adipogenesis, FA de novo synthesis and FA intracellular transport are being investigated. Further experiments currently conducted in our lab should allow us to better clarify the mechanisms involved.