Shifting paradigms to emerging toxins in freshwater cyanobacterial blooms

淡水蓝藻水华中新出现的毒素的范式转变

• 批准号: 10912318
• 负责人: Matthew John Bertin
• 金额: $ 19.74万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10912318
• 关键词: Accounting; Acute; Acute Liver Failure; Affect; Alkaloids; Amino Acids; Anatoxins; Animals; Arginine; Artificial Membranes; Biological Assay; Biological Availability; Biomass; Biomimetics; Brain; Cell Membrane Permeability; Chemicals; Chronic; Collection; Communities; Complex; Cyanobacterium; Cyanotoxin; Cytotoxin; Data; Detection; Environment; Environmental Health; Evaluation; Event; Exposure to; Fatty Liver; Fresh Water; Genetic; Goals; Harvest; Health; Hepatocyte; Hepatotoxicity; Human; Image; In Vitro; Individual; Injury; Invertebrates; Kidney; Knowledge; Laboratories; Lactones; Leucine; Liver; Mediator; Membrane; Methods; Microbe; Microcystis; Mission; Molecular; Monitor; Natural Resources; Neurotoxins; New England; Peptides; Permeability; Pharmacologic Substance; Phosphoric Monoester Hydrolases; Poison; Policy Maker; Population; Production; Proteomics; Public Health; Recreation; Regulation; Reproductive system; Research; Research Project Grants; Resources; Rhode Island; Risk; Rodent; Role; Sampling; Saxitoxin; Screening procedure; Site; Structure; System; Systemic disease; Taxonomy; Testing; Time; Toxic effect; Toxicology; Toxin; Tyrosine; United States; United States National Institutes of Health; Vertebrates; Water; Work; Writing; acute hepatotoxicity; bioaccumulation; climate change; contaminated drinking water; cyanobacterial toxin; cyanoginosin LR; cylindrospermopsin; cytotoxic; drinking water; exposed human population; harmful algal blooms; hepatotoxin; in silico; in vivo; industry partner; innovation; insight; instrumentation; liver injury; local economy; member; metabolome; metabolomics; microbial community; microcystin; non-alcoholic fatty liver disease; novel; success; temporal measurement; tool; vector

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.

项目摘要 这些事件期间产生的蓝细菌有害藻类花朵（氰基栖息）和有毒化合物具有 成为淡水系统中的持续问题，并通过污染来影响当地人口 由于休闲活动减少，饮用水并给当地经济体带来了重大负担。 微囊蛋白，通常是氰基hab中主要的毒素类别，主要影响肝脏（肝毒素），但 已经描述了还影响肾脏，生殖系统和大脑。这些中的蓝细菌 已知开花事件除了微囊蛋白（例如 棒状腺蛋白和生物碱神经毒素，例如saxitoxin和anatoxin。伯丁的初步结果 拟议项目的实验室和合作行业合作伙伴Biosortia Pharmaceuticals已显示 从内陆收获的蓝细菌生物量的环境收集中，存在明显有效的细胞毒素 湖泊和水体。这些新兴化合物（类固醇内酯）的一套套件显着从 通常与这些花朵事件（肽和生物碱毒素）相关的有毒化合物的类型。这些 新发现的化合物比Microcystin-lr更有效，并且从未有过 从蓝绿色事件中描述。因此，有很大且未满足的需要了解 这些化合物和其他细胞毒性代谢产物在氰基hab期间，并开发检测，分离和 自然资源管理机构可以使用并通知公众的毒理学评估工具 卫生政策制定者。此外，初步结果表明氰基hab中有新的微囊蛋白 比130个已知的微囊蛋白植物中的任何一个都要高得多。理由 研究项目是，需要对氰基栖息地中存在的有毒化学空间进行全面考虑。 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多 有效的蓝毒素，它们的作用方式及其对肝脏的潜在毒性以及与全身关系的关系 受伤。项目目标将包括使用和隔离新兴的有毒化合物 代谢组学方法，微生物社区分析以及新兴毒素的结构阐明（目标 1）。此外，将在时间课程中研究氰基hab的毒素组成以提供 关于有毒代谢产物组成的时间分辨率（AIM 1）。接下来，毒理学评估将 用于整合硅，体外和蛋白质组学研究以确定毒性和作用机理 毒素（目标2）。仪器和专业知识已成为项目成功。这个项目将导致 新兴毒素的隔离和表征，并显着脱离了关注的现状 在微囊蛋白上。此外，这项工作将对这些新颖的机械毒性有所了解 新兴的代谢产物可能是潜在的肝损伤，这可能是全身性疾病的早期介体。