Integrative Studies to Define Drivers of Nanomaterial Toxicity

描述(申请人提供)：纳米毒理学是研究由于纳米材料的独特性质而可能导致的未知和潜在的不可预见的后果，这些独特的性质可能会导致对生命系统的不利影响。目前，与纳米材料接触相关的风险方面存在着巨大的毒理学数据缺口，由于缺乏信息，可能预测纳米材料与生物系统相互作用的主要特征尚未确定。因此，迫切需要快速测试战略，以确定导致毒性的纳米材料的具体特征，以便减少暴露的风险，并确定可用于预测纳米材料危险的结构-性能关系，而不是经验数据。这项拟议的研究利用了一种综合的方法，通过利用纳米材料的表征和使用信息学的毒性数据，从战略上确定目标结构-活性关系。目标是确定支配纳米材料-生物相互作用的主要特征，并确定纳米材料毒性的关键驱动因素。它们的总体目标是确定大小、形状和表面化学对毒性的吸收、效应和机制的相对影响。在拟议的研究完成后，我们预计：i)通过提供关于纳米材料表征、命运和生物影响的原始数据，填补关键的信息空白；ii)为快速确定纳米材料的特征和测试生物影响提供有效的分析方法；iii)确定导致暴露在与环境相关的纳米材料浓度下的斑马鱼有毒结果的分子事件链；以及iv)提供一个公正的信息平台，以确定哪些纳米材料特征或特征组合修饰了有毒潜力。这些信息将产生积极的影响，通过减少对每一种纳米材料配方进行经验测试的需要，提供关于可以修改以将固有的纳米材料毒性降至最低的结构元素的信息，增加社区资源来传播关于纳米材料的重要信息，最后为风险评估人员提供新的工具，以保护人类和环境免受潜在的有害暴露，从而促进纳米医学、纳米毒理学和纳米技术领域的发展。

DESCRIPTION (provided by applicant): Nanotoxicology is the study of the unknown and potentially unforeseen consequences that may result from nanomaterial exposure due to the unique properties that may cause them to adversely impact living systems. Currently, vast toxicological data gaps exist regarding the risks associated with nanomaterial exposure, and the principal characteristics that may be predictive of nanomaterial interactions with biological systems have yet to be identified due of this lack of information. Thus, rapid testing strategies are immediately necessary to identify the specific features of nanomaterial that result in toxicity in order to mitigate risks from exposure and define structure-property relationships that can be used to predict nanomaterial hazard in lieu of empirical data. The proposed research utilizes an integrative approach to strategically target structure-activity relationships by leveraging nanomaterial characterization and toxicity data using informatics. The goal is to identify the principal features that govern nanomaterial- biological interactions and define key drivers for nanomaterial toxicity. The overall objective of the ONES is to determine the relative influence that size, shape and surface chemistry have on uptake, effects and mechanism of toxicity. Upon completion of the proposed studies, we expect to: i) fill critical information gaps by providing primary data on nanomaterial characterization, fate and biological impact, ii) provide validated assays for rapidly determining nanomaterial characteristics and testing for biological impact, iii) identify the chain of molecular events that lead to a toxic outcome in zebrafish exposed to environmentally relevant nanomaterial concentrations, and iv) deliver an unbiased information platform to delineate which nanomaterial features, or combination of features, modify toxic potential. Such information will have a positive impact and advance the fields of nanomedicine, nanotoxicology, and nanotechnology by reducing the need to empirically test every nanomaterial formulation, providing information on the structural elements that can be modified to minimize inherent nanomaterial toxicity, enhancing community resources for dissemination of important information on nanomaterial, and finally providing new tools for risk assessors to protect humans and the environment from potentially harmful exposures.