Life span-resolved nanotoxicology: neuronal targets and vulnerable age-groups in the nematode Caenorhabditis elegans

工程纳米材料的应用不断增长，它们不可避免地分布到环境中，以及作为食品添加剂的应用越来越多，这要求对相关暴露情景进行调查。因此，所提交的资助建议建议进行长期分析，例如线虫线虫的终生纳米毒理学研究。我们的初步工作表明，线虫的神经系统是纳米材料不良影响的敏感靶器官。纳米二氧化硅诱导淀粉样蛋白聚集，也影响肾上腺素能神经元。特定的神经元退化，多巴胺能神经传递受损，这反过来又促进了神经肌肉行为的缺陷，如产卵和向前运动。由于这些缺陷在老年人C中发生。我们假设某些纳米材料的毒性表现在由于淀粉样蛋白聚集和决定性神经元的退化而导致蠕虫的健康寿命缩短。因此，该项目建议对观察到的神经退化和神经行为缺陷之间的时间相互作用进行终身研究。因此，关于纳米颗粒诱导的神经变性的时间顺序和模式，表征了多巴胺能、多巴胺能和GABA能神经元的报告蠕虫。同时，将量化由相应（退化）神经元控制的行为表型的缺陷。全生命周期分析有助于确定对某些纳米材料特别敏感的年龄组，例如易受影响的年龄组。易受伤害的年龄组将被询问蛋白质稳态缺陷和淀粉样蛋白聚集增加。对蛋白质聚集、神经变性、神经适应性和健康寿命缩短之间相互作用的预定寿命分辨表征将缩小C. elegans，这对于开发具有成本效益和可靠的不同纳米材料筛选平台是有用的。此外，寿命分辨研究的概念不仅可能革新纳米毒理学，而且可能革新污染物及其组合的一般研究。elegans提交的资助提案旨在鉴定不促进神经系统缺陷并从而维持最大健康跨度的纳米颗粒（“欧洲安全纳米材料”）。

Continuously growing applications of engineered nanomaterials, their inevitable distribution into the environment as well as increasing application as food additives calls for the investigation of relevant exposition scenarios. Thus, the submitted grant proposal suggests long-term analyses, e.g. whole-life nanotoxicology in the nematode roundworm Caenorhabditis elegans.Our preliminary work shows that the nervous system of the nematode represents a sensitive target organ of adverse effects of nanomaterials. Nano silica induce global amyloid protein aggregation that also affects serotonergic neurons. Specific neurons degenerate and serotonergic neurotransmission is impaired which in turn promotes defects of neuromuscular behavior such as egg-laying and forward locomotion. Since these defects otherwise occur in aged adult C. elegans we hypothesize that the toxicity of certain nanomaterials manifests in a reduced health span of the worms due to amyloid protein aggregation and degeneration of decisive neurons.Thus, the project proposal suggests whole-life investigation of the temporal interactions between the observed neurodegeneration and neural behavior defects. Accordingly, reporter worms of serotonergic, dopaminergic and GABAergic neurons are characterized concerning the chronological sequence and patterns of nanoparticle-induced neurodegeneration. In parallel, defects of behavioral phenotypes will be quantified that are controlled by the respective (degenerated) neurons. Whole-life analyses enable the identification of age-groups that are especially sensitive, e.g. vulnerable, to certain nanomaterials. The vulnerable age-groups will be interrogated for defects of protein homeostasis and increased amyloid protein aggregation. The scheduled life span-resolved characterization of interactions between protein aggregation, neurodegeneration, neural fitness and reduced health span will narrow down biological effects in C. elegans that are useful to develop a cost-effective and reliable screening platform for different nanomaterials. Moreover, the concept of life span-resolved studies might not only innovate nanotoxicology, but investigations of pollutants and their combinations in general.By investigation of the nanotoxicity in aging C. elegans the submitted grant proposal aims to identify nanoparticles that do not promote defects of the neural system and thereby maintain a maximal health span ('eurosafe nanomaterials'.