Toxic freshwaters cyanobacteria represent a serious environmental and health problem. While previous research focused exclusively on microcystins, recent reports document toxic effects of other cyanotoxins. Also our pilot study showed microcystin-independent potential to inhibit gap-junctional intercellular communication (GJIC), which is an established biomarker of non-genotoxic tumor promotion. The hypothesis assumes production of unidentified cyanobacterial metabolites with tumor promoting potencies. Our studies will employ the rat liver stem-like WBF344 cells (an established model for studies of tumor promoters). We will investigate the effects of cyanobacterial samples on GJIC, activations of mitogen-activated protein kinases ERK1/2 and cellular proliferation. Using fractionation followed by HPLC and MALDI-TOF MS we will characterize physico-chemical properties of bioactive metabolites. Further, we will study detailed mechanisms using chemicalinhibitors of signaling pathways and siRNA. The research outcomes of the project will be (1) the first insight into the mechanisms of tumor promotional potencies of new cyanotoxins, (2) the data on interactive effects with other tumor promoters, and (3) chemical characterization of these bioactive compounds. The project challenges the hypothesis on microcystins as major toxic agents of cyanobacteria and it will provide valuable results for re-assessment of health risks of freshwater cyanobacterial water blooms.

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