Reversing Zearalenone\nToxicity: The Role of Hydroxytyrosol\nin Zebrafish

Zearalenone (ZEA) is a widely distributed mycotoxin that\npresents\na substantial worldwide health risk to animals. Several natural compounds\nhave shown promise in mitigating the detrimental impacts of ZEA. This\nstudy examined the detoxification potential of previously identified\ncompounds by utilizing zebrafish embryos as a model organism. Hydroxytyrosol\nstands out among these natural compounds. Our findings indicate that\nhydroxytyrosol effectively mitigated mortality, hatching delay, and\nphenotypic abnormalities induced by ZEA in the assessed embryos. Furthermore,\nhydroxytyrosol restored the frequency and intensity of tail coiling\n(TC) while decreasing the expression of heat shock proteins (HSPs)\nin the zebrafish embryos. Extended incubation with hydroxytyrosol\ndemonstrated protective effects on zebrafish growth and morphology,\nmuscle birefringence, and touch-evoked escape behavior. Subsequent\ninvestigations indicated that hydroxytyrosol reversed the expression\nof proapoptotic targets (e.g., <i>bax</i> and <i>caspase</i>8) and cell cycle regulators (e.g., <i>p</i>21, <i>gadd</i>45<i>a</i>, and <i>rbl</i>2), thereby\nmitigating apoptosis and G2 cell cycle arrest induced by ZEA in zebrafish\nembryos. Additionally, hydroxytyrosol decreased staining for senescence\nassociated-β-galactosidase (SA-β-Gal). Notably, p53/FoxO\npathway plays an important role in detoxification mechanisms. Overall,\nthese novel findings highlight the potential of hydroxytyrosol to\nreverse ZEA-induced toxicity in multiple aspects. The mitigating effect\nof hydroxytyrosol on ZEA toxicity may have been underestimated.