Role of Oxidative Stress and Protein Transporters in Glyphosate and Mancozeb Neur

氧化应激和蛋白质转运蛋白在草甘膦和代森锰锌神经中的作用

• 批准号: 8232627
• 负责人: VANESSA A FITSANAKIS
• 金额: $ 30万
• 依托单位: KING UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-10 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8232627
• 关键词: Address; Affect; Agriculture; Agrochemicals; Animal Model; Antioxidants; Biochemical; Biological Models; Brain region; Bromides; Caenorhabditis elegans; Cell Death; Cell Survival; Cells; Chemicals; Communities; Complex; Data; Diagnosis; Dose; Environment; Esters; Ethylenes; Etiology; Exposure to; GABA transporter; General Population; Generations; Genetic; Genetic Predisposition to Disease; Glean; Glutathione; Goals; Green Fluorescent Proteins; Health; Heat shock proteins; Herbicides; Hydrogen Peroxide; Hydroxyl Radical; Individual; Industrial fungicide; Industry; Intracellular Transport; Knock-out; Lead; Life; Link; Maneb; Manganese; Marketing; Metals; Mission; Mitochondria; Monitor; National Institute of Environmental Health Sciences; Nematoda; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurotoxins; Neurotransmitters; Onset of illness; Organelles; Organism; Oxidative Stress; Parkinson Disease; Patients; Pesticides; Play; Population; Procedures; Production; Proteins; Public Health; RNA Interference; Reactive Oxygen Species; Reporter; Reporting; Research Design; Respiration; Role; Roundup; Students; Superoxide Dismutase; Superoxides; Techniques; Testing; Touchdown; Toxic Environmental Substances; Toxic effect; United States; Work; Zinc; base; catalase; design; divalent metal; dopamine transporter; glyphosate; human disease; in vivo; in vivo Model; inhibitor/antagonist; interest; knock-down; mancozeb; mitochondrial dysfunction; neurotoxic; neurotoxicity; novel; pesticide exposure; pesticide poisoning; programs; serotonin transporter; stress protein; tetramethylrhodamine; toxicant; uptake

DESCRIPTION (provided by applicant): In accordance with the mission of the NIEHS, understanding how environment influences human disease etiology and progression, this project will examine the contribution of two high-usage pesticides to general neurotoxicity as well as Parkinson's disease (PD). Numerous reports suggest a link between PD and agricultural environments and/or pesticide usage. Other data indicate that exposure to manganese (Mn) also may be linked to disease onset. Interestingly, many agrochemicals, as well as Mn, impair mitochondrial respiration, resulting in an insufficient quantity of energy production required for cells survival. Furthermore, mitochondrial dysfunction is present in various cell populations in PD patients. The long-term goal of this project is to understand the mechanisms through which pesticides may contribute to cell death in brain regions associate with to PD. Using the nematode Caenorhabditis elegans (C. elegans), the following hypothesis will be tested: Exposure to the popular pesticides Mancozeb (MZ) and TouchDown (TD) leads to neuronal degeneration via mitochondrial inhibition and/or increased oxidative stress. Additionally, it is hypothesized that these pesticides may enter vulnerable neuron through uptake by specific neurotransmitter transporters. These hypotheses will be tested through three specific aims: (1) to establish which mitochondrial complexes are inhibited; (2) to discover the specific reactive oxygen species (ROS) increased following exposure to MZ and/or TD; and (3) to determine if MZ and TD enter neurons through individual neurotransmitter or metal transporters. In order to monitor neurodegeneration, C. elegans with neuronal populations tagged with green fluorescent protein (GFP) will be exposed to varying concentrations of MZ or TD. This will be followed by treatment with various chemical reporters to determine whether mitochondrial function is compromised. Subsequent studies will involve pretreatment of worms with specific neurotransmitter transporter antagonists to determine if assess whether degeneration is decreased following subsequent exposure to MZ or TD. Results from these novel studies will further our understanding of neurotoxic effects related to pesticide exposure. Additionally, this work will provide evidence related to mechanisms involved in intracellular transport of glyphosate-containing herbicides (i.e., TD, RoundUP), or manganese-containing fungicides (i.e., MZ, maneb). It is anticipated that these data will further our understanding not only of general pesticide neurotoxicity, but also of mechanisms through which environmental toxicants may contribute the etiology of idiopathic PD. PUBLIC HEALTH RELEVANCE: These studies are particularly timely and relevant to public health because of the link between Parkinson's disease (PD), the second most-common neurodegenerative disease in the United States, and pesticide exposure. Use of glyphosate-containing herbicides (i.e., RoundUp and TouchDown) is increasing exponentially in the general public and the agricultural community, while Mancozeb, a manganese-containing fungicide, is gaining increased market shares. These pesticides are suspected mitochondrial inhibitors, an observation commonly documented in various cell populations in PD patients.

描述（由申请人提供）：根据 NIEHS 的使命，了解环境如何影响人类疾病的病因和进展，该项目将研究两种高用量农药对一般神经毒性以及帕金森病 (PD) 的影响。许多报告表明局部放电与农业环境和/或农药使用之间存在联系。其他数据表明，接触锰 (Mn) 也可能与疾病的发生有关。有趣的是，许多农用化学品以及锰都会损害线粒体呼吸，导致细胞生存所需的能量产生不足。此外，PD患者的多种细胞群中都存在线粒体功能障碍。该项目的长期目标是了解农药可能导致与帕金森病相关的大脑区域细胞死亡的机制。使用线虫秀丽隐杆线虫 (C. elegans)，将测试以下假设：接触流行的杀虫剂代森锰锌 (MZ) 和 TouchDown (TD) 通过线粒体抑制和/或氧化应激增加导致神经元变性。此外，据推测，这些农药可能通过特定的神经递质转运蛋白的摄取进入脆弱的神经元。 这些假设将通过三个具体目标进行检验：（1）确定哪些线粒体复合物受到抑制； (2) 发现暴露于 MZ 和/或 TD 后特定的活性氧 (ROS) 增加； (3) 确定 MZ 和 TD 是否通过单独的神经递质或金属转运蛋白进入神经元。为了监测神经变性，将带有绿色荧光蛋白 (GFP) 标记的神经元群的线虫暴露于不同浓度的 MZ 或 TD。随后将用各种化学报告基因进行处理，以确定线粒体功能是否受到损害。后续研究将涉及用特定神经递质转运蛋白拮抗剂对线虫进行预处理，以确定随后暴露于 MZ 或 TD 后是否会减少变性。这些新研究的结果将进一步加深我们对与农药接触相关的神经毒性作用的理解。此外，这项工作还将提供与含草甘膦除草剂（即 TD、RoundUP）或含锰杀菌剂（即 MZ、代森锰）细胞内转运机制相关的证据。预计这些数据不仅将进一步加深我们对一般农药神经毒性的理解，而且还将进一步了解环境毒物可能导致特发性帕金森病病因的机制。 公共健康相关性：这些研究特别及时且与公共健康相关，因为帕金森病（PD）是美国第二常见的神经退行性疾病，与农药接触之间存在联系。公众和农业界对含草甘膦除草剂（即 RoundUp 和 TouchDown）的使用呈指数级增长，而含锰杀菌剂代森锰锌的市场份额也不断增加。这些杀虫剂被怀疑是线粒体抑制剂，这是在帕金森病患者的各种细胞群中常见的观察结果。

项目成果

Chronic exposure to a glyphosate-containing pesticide leads to mitochondrial dysfunction and increased reactive oxygen species production in Caenorhabditis elegans.

• DOI: 10.1016/j.etap.2017.11.005
• 发表时间: 2018-01
• 期刊: Environmental toxicology and pharmacology
• 影响因子: 4.3
• 作者: Bailey DC;Todt CE;Burchfield SL;Pressley AS;Denney RD;Snapp IB;Negga R;Traynor WL;Fitsanakis VA
• 通讯作者: Fitsanakis VA

Acute exposure to a Mn/Zn ethylene-bis-dithiocarbamate fungicide leads to mitochondrial dysfunction and increased reactive oxygen species production in Caenorhabditis elegans.

急性接触锰/锌亚乙基双二硫代氨基甲酸酯杀菌剂会导致线虫线粒体功能障碍和活性氧产生增加。

• DOI: 10.1016/j.neuro.2016.09.011
• 发表时间: 2016
• 期刊: Neurotoxicology
• 影响因子: 3.4
• 作者: Todt,CallieE;Bailey,DeniseC;Pressley,AirealS;Orfield,SarahE;Denney,RachelD;Snapp,IsaacB;Negga,Rekek;Bailey,AndrewC;Montgomery,KaraM;Traynor,WendyL;Fitsanakis,VanessaA
• 通讯作者: Fitsanakis,VanessaA

Transport of a manganese/zinc ethylene-bis-dithiocarbamate fungicide may involve pre-synaptic dopaminergic transporters.

亚乙基双二硫代氨基甲酸锰/锌杀真菌剂的转运可能涉及突触前多巴胺能转运蛋白。

• DOI: 10.1016/j.ntt.2018.05.004
• 发表时间: 2018
• 期刊: Neurotoxicology and teratology
• 影响因子: 2.9
• 作者: Montgomery,Kara;Corona,Caleb;Frye,Rebekah;Barnett,Reid;Bailey,Andrew;Fitsanakis,VanessaA
• 通讯作者: Fitsanakis,VanessaA