Shifting paradigms to emerging toxins in freshwater cyanobacterial blooms

项目总结 在这些事件中产生的蓝细菌有害藻华(氰化氢)和有毒化合物 成为淡水系统中的一个持久问题，并通过污染影响了当地人口 由于娱乐活动减少，饮用水供应减少，给当地经济造成很大负担。 微囊藻毒素通常是氰化氢的主要毒素类别，主要影响肝脏(肝毒素)，但 已经被描述为也会影响肾脏、生殖系统和大脑。这些中的蓝藻 众所周知，水华事件除了产生微囊藻毒素外，还会产生一系列肝毒素，如 圆柱状精液蛋白，以及生物碱神经毒素，如岩藻毒素和类毒素。贝尔坦的初步结果 在拟议项目Biosortia PharmPharmticals中，实验室和协作行业合作伙伴已经展示了 从内陆采集的蓝藻生物量的环境收集中存在着极强的细胞毒素 湖泊和水体。一系列这些新出现的化合物(类固醇内酯)显著偏离了 通常与这些水华事件有关的有毒化合物的类型(多肽和生物碱毒素)。这些 新发现的化合物比微囊藻毒素-LR的效力要强得多，而且以前从未 从氰化HAB事件中描述。因此，有一个重大的和未得到满足的需要，以了解生产 这些化合物和其他细胞毒性代谢物在氰化氢和发展检测，分离和 可供自然资源管理机构使用并告知公众的毒理学评估工具 卫生政策制定者。此外，初步结果表明，在氰基Habs中存在新的微囊藻毒素。 它们的细胞毒性比已知的130种微囊藻毒素中的任何一种都要强得多。这样做的理由是 研究项目是，需要对氰化氢中存在的有毒化学空间进行全面核算。 此外，多种有毒化合物的多样性需要新的评估工具来确定最 强有力的氰基毒素，它们的作用方式，它们对肝脏的潜在毒性，以及这与全身毒性的关系 受伤。项目目标将包括识别和分离新出现的有毒化合物 代谢组学方法、微生物群落分析和新出现的毒素的结构阐明(目的 1)。此外，将在时间进程研究中调查氰化氢的毒素组成，以提供 关于有毒代谢物成分的时间分辨率(目标1)。接下来，毒理学评估将 在计算机、体外和蛋白质组学研究中用于确定毒性和作用机制 毒素(目标2)。为了项目的成功，仪器设备和专业知识已经到位。这一项目将导致 新出现的毒素的分离和鉴定，与目前关注的现状有很大不同 关于微囊藻毒素。此外，这项工作将加深对这些新药的机械毒性的理解。 新出现的代谢物可能导致潜在的肝脏损伤，这可能是系统性疾病的早期介体。

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.