新烟碱类杀虫剂对斑马鱼胚胎发育的温度特异性多尺度毒性效应与机制

New emerging chemicals such as neonicotinoid insecticides have become one of the most threat to the environment (e.g., biodiversity and integrity) and human due to their widely use in the last two decades. Temperature variations caused by global climate change also have profound implications on chemical toxicity to individual aquatic organisms which will in turn exacerbate their impact to the biological community, leading to high uncertainties for their toxicity evaluation and risk assessment and management. Therefore, this project firstly intends to investigate the multi-scale temperature-dependent toxicities of neonicotinoids to the embryonic development of zebrafish (Danio rerio) through laboratory standard fish embryo tests. Multiple endpoints include molecular/cellular/organ responses (e.g., oxidative stress, osmoregulation, energy metabolism, neurotoxicity and other stress factors such as heat shock protein and metallothionein), and apical endpoints related to developmental toxicity. Subsequently, computational predictive models based on quantitative structure-activity relationships and chemical toxicity distributions (QSAR-CTD) will be developed through examining relationships among physicochemical parameters of neonicotinoids, temperature and the multiscale toxic responses. In addition, endpoint-based extrapolation models will also be established through comparing temperature-dependent CTDs using pairwise datasets of corresponding molecular/cellular/organ response and apical developmental toxicity, and endpoint-based extrapolation factors will also be derived (if any). The completion of this project will enhance our understanding of the temperature-dependent toxicity of neonicotinoids and potential mechanisms to zebrafish embryo development through multiscale endpoints analyses. Findings will also decrease uncertainty of future risk assessment through development of temperature-adjusted computational predictive models (e.g., QSAR-CTD and endpoint-based extrapolation models). This project will also provide an example for toxicity identification and/or risk assessment for classes of chemicals (e.g., synthetic compounds) in the environment with limited toxicity information.

化学品（新烟碱类杀虫剂）的无序使用为生态环境带来严重威胁，环境因子如温度的变化亦增加了对化学品毒性鉴别和风险防控的不确定性。本项目拟通过胚胎毒性测试技术，探讨温度变化对新烟碱诱导的斑马鱼胚胎发育多尺度毒性效应的影响；测试终点包括细胞/组织/器官层次（氧化应激、渗透调节、能量代谢、神经调节和应激因子）和宏观尺度发育毒性等响应。其次，通过预测毒理学技术，系统分析新烟碱理化特性、温度和毒性效应之间的关系，建立定量构效关系-化合物毒性分布（QSAR-CTD）预测模型和毒性效应外推模型，推导温度特异性风险阈值和毒性效应外推因子。项目的实施将从多角度、综合评定新烟碱类杀虫剂潜在的温度特异性多尺度毒性效应与机制；QSAR-CTD模型和毒性效应外推模型的构建，将校正温度对生态风险的影响，降低风险评估的不确定性。本项目也为环境中其他数据相对匮乏、结构类似的合成化合物的毒性鉴定和风险评估提供方法支持。

新烟碱类杀虫剂的大量使用及其于环境中的大量赋存，对环境和人体健康造成严重威胁。本项目在验证了斑马鱼胚胎毒性测试可有效评估化合物如新烟碱的生态效应的基础上，揭示了温度和新烟碱对斑马鱼胚胎发育的多尺度毒性效应，并验证了新烟碱的急性毒性（致死）和亚致死（AChE抑制、GST激活）随着温度的升高/降低而增强，呈“倒三角”关系，而环氧虫啶、噻虫啉和哌虫啶对AChE的抑制效应随着温度的升高而增强，呈“线性”关系；初步构建了新烟碱经温度校正的定量结构活性相关-化合物分布（QSAR-CTD）模型，推导了基于胚胎发育、氧化损伤和神经毒性的温度特异性风险阈值；基于全球淡水环境暴露和毒性测试信息，耦合概率风险评价模型，推导了全球淡水河流最大暴露水平，构建了不同类别新烟碱的急性与慢性水质基准建议值和急性-慢性比；多层次风险评价结果表明：目前新烟碱的暴露水平具有较高的慢性风险（特别是啶虫脒和噻虫啉）。最后，通过生物医学等的交叉学科手段，本项目进一步对新烟碱及其代谢物能否穿越血脑屏障进入人体脑脊液进行了探索，并首次于人体脑脊液检测出其残留。本项目为将来对新烟碱的毒理学、健康与风险评估研究提供了理论基础和方法支撑。

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