Neurotoxicity of zearalenone's metabolites and beauvericin mycotoxins via apoptosis and cell cycle disruption

Cell cycle progression and programmed cell death are imposed by pathological stimuli of extrinsic or intrinsic including the exposure to neurotoxins, oxidative stress and DNA damage. All can cause abrupt or delayed cell death, inactivate normal cell survival or cell death networks. Nevertheless, the mechanisms of the neuronal cell death are unresolved. One of the cell deaths triggers which have been wildly studied, correspond to mycotoxins produced by Fusarium species, which have been demonstrated cytotoxicity and neurotoxicity through impairing cell proliferation, gene expression and induction of oxidative stress. The aim of present study was to analyze the cell cycle progression and cell death pathway by flow cytometry in undifferentiated SH-SY5Y neuronal cells exposed to alpha-zearalenol (alpha-ZEL), beta-zearalenol (beta-ZEL) and beauvericin (BEA) over 24 h and 48 h individually and combined at the following concentration ranges: from 1.56 to 12.5 mu M for alpha-ZEL and beta-ZEL, from 0.39 to 2.5 mu M for BEA, from 1.87 to 25 mu M for binary combinations and from 3.43 to 27.5 mu M for tertiary combination. Al-terations in cell cycle were observed remarkably for beta-ZEL at the highest concentration in all treatments where engaged (beta-ZEL, beta-ZEL + BEA and beta-ZEL + alpha-ZEL), for both 24 h and 48 h. by activating the cell proliferation in G0/G1 phase (up to 43.6 %) and causing delays or arrests in S and G2/M phases (up to 19.6 %). Tertiary mixtures revealed increases of cell proliferation in subG0 phase by 4-folds versus control. Similarly, for cell death among individual treatments beta-ZEL showed a significant growth in early apoptotic cells population at the highest concentration assayed as well as for all combination treatments where beta-ZEL was involved, in both early apoptotic and apoptotic/necrotic cell death pathways.

Automated summary

This study analyzed the effects of different concentrations of alpha-zearalenol, beta-zearalenol, and beauvericin on cell cycle progression and cell death pathways in neuronal cells. The highest concentration of beta-zearalenol caused alterations in cell cycle progression and an increase in early apoptotic cells. Combination treatments involving beta-zearalenol also showed significant changes in cell death pathways.