Shifting paradigms to emerging toxins in freshwater cyanobacterial blooms

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PROJECT SUMMARY Cyanobacterial harmful algal blooms (cyanoHABs) and the toxic compounds produced during these events have become a persistent problem in freshwater systems and have affected local populations by contaminating drinking water and placing a significant burden on local economies due to diminished recreational activity. Microcystins, generally the dominant class of toxins in cyanoHABs, primarily affect the liver (hepatotoxin), but have been described to also affect the kidney, the reproductive system, and the brain. Cyanobacteria in these bloom events are known to produce a suite of hepatotoxins in addition to the microcystins such as the cylindrospermopsins, and alkaloid neurotoxins such as saxitoxin and anatoxin. Preliminary results from the Bertin Laboratory and collaborative industry partners in the proposed project, Biosortia Pharmaceuticals, have shown exquisitely potent cytotoxins exist in environmental collections of cyanobacterial biomass harvested from inland lakes and water bodies. A suite of these emerging compounds (steroidal lactones) departs significantly from the types of toxic compounds typically associated with these bloom events (peptidic and alkaloidal toxins). These newly discovered compounds are significantly more potent than microcystin-LR and have never been previously described from cyanoHAB events. Thus, there is a significant and unmet need to understand the production of these compounds and other cytotoxic metabolites during cyanoHABs and to develop detection, isolation, and toxicological evaluation tools that can be utilized by natural resource management agencies and inform public health policy makers. Furthermore, preliminary results indicate that there are new microcystins in cyanoHABs that are significantly more cytotoxic than any of the 130 known microcystin congeners. The rationale of this research project is that there needs to be a full accounting of the toxic chemical space present in cyanoHABs. Furthermore, the diversity of multiple toxic compounds requires new evaluation tools to determine the most potent cyanotoxins, their mode of action, and their potential toxicity on the liver and how that relates to systemic injury. Project goals will consist of the identification and isolation of emerging toxic compounds using metabolomics approaches, microbial community analysis, and the structure elucidation of emerging toxins (Aim 1). Furthermore, the toxin composition of cyanoHABs will be investigated in a time course study to provide temporal resolution with respect to toxic metabolite composition (Aim 1). Next, a toxicological assessment will be used that integrates in silico, in vitro, and proteomic studies to determine toxicity and the mechanism of action of toxins (Aim 2). Instrumentation and expertise are in place for project success. This project will result in the isolation and characterization of emerging toxins and significantly departs from the current status quo of focusing on microcystins. Additionally, this work will develop an understanding of the mechanistic toxicity of these novel emerging metabolites to potential liver injury, which can be an early mediator of systemic disease.