Environmental toxicology of neonicotinoid pesticides: effects on central nervous system function in small mammals

在过去的二十年中，类烟碱已成为全球五大化学杀虫剂中最重要和增长最快的一类。 顾名思义，这些化合物作为乙酰胆碱受体（nAchR）烟碱亚类的激动剂，导致“过度刺激”，导致神经肌肉麻痹。 它们通常用作种子处理剂，也直接应用于植物，并用作包括狗和猫在内的家畜的“跳蚤粉”。 尽管nAChR是所有脊椎动物物种（以及无脊椎动物）生理学的基础，但基于毒理学数据，类烟碱已被批准并广泛使用，该毒理学数据表明它们与昆虫nAChR的结合亲和力显著高于哺乳动物nAChR;赋予比其他类别的杀虫剂（如有机磷酸酯或氨基甲酸甲酯）更大的“安全边际”。 然而，该结论几乎完全基于在靶种属中产生致死性（LD 50）的相对效价比较。 然而，这些化合物在哺乳动物中的亚致死毒性的比较相对较少。 关于这些化合物对脊椎动物生殖和免疫抑制的影响，数据有限，但关于这些化合物对哺乳动物的神经发育毒性或低剂量接触的长期影响，几乎没有数据。 缺乏对诸如大鼠和小鼠之类的物种的知识，这些物种会消耗经处理的种子，进而成为高阶哺乳动物（如狐狸）或鸟类物种（如猛禽（猫头鹰、鹰等））的猎物。是我们目前对类烟碱使用的环境后果的理解中的一个主要空白，并且在Gibbons等人（2015）最近的一篇综述中强调了这一点，该综述对这些化合物对脊椎动物野生动物的影响提出了严重的问题。根据现有的数据报告和明显的数据缺口，迫切需要进一步研究类尼古丁在非靶哺乳动物种属中的亚致死和神经发育毒性。本提案将研究低浓度的烟碱类杀虫剂吡虫啉和噻虫嗪对成年和幼年大鼠nAChR介导的行为和CNS神经病理学的影响;代表易感的非目标人群和其他脊椎动物野生动物的替代物种。 此外，我们将确定妊娠前暴露于这些化合物是否会导致后代出现缺陷。拟议的研究将提供关于类烟碱农药对小型哺乳动物影响的急需数据，并在必要时为今后的实地研究奠定基础。

Over the last two decades the neonicotinoids have become the most important and fastest growing of the five major chemical classes of insecticides worldwide. As the name suggests, these compounds act as agonists at the nicotinic subclass of acetylcholine receptors (nAchRs) resulting in “over-stimulation” that leads to neuromuscular paralysis. Commonly used as seed treatments they are also applied directly to plants and are used as “flea powders” for domestic animals including dogs and cats. Although nAChRs are fundamental to the physiology of all vertebrate species (as well as invertebrates) the neonicotinoids have been approved and used widely based on toxicological data indicating that they bind with substantially higher affinity to insect nAChRs than mammalian nAChRs; conferring a larger “margin of safety” than other classes of insecticides such as organophosphates or methylcarbamates. This conclusion, however, is based almost exclusively on comparisons of the relative potency to produce lethality (LD50 ) in the target species. Comparisons of sublethal toxicity of these compounds in mammals, however, are comparatively sparse. There is some limited data of effects on reproduction and immunosuppression in vertebrates but almost no available data on either the neurodevelopmental toxicity of these compounds in mammals or the long-term effects of low dose exposure. This lack of knowledge in species such as rats and mice that would consume treated seed and in turn become prey for higher-order mammals (e.g. foxes) or avian species such as raptors (owls, hawks, etc.) is a major gap in our current understanding of the environmental consequences of neonicotinoid use, and was highlighted in a recent review by Gibbons et al. (2015) that raises serious questions about the effects of these compounds on vertebrate wildlife.***Based on both existing data reports and obvious data gaps, there is an urgent need to further investigate the sublethal and neurodevelopmental toxicity of neonicotinoids in non-target mammalian species. This proposal will investigate the effects of low concentrations of the neonicotinoid pesticides imidacloprid and thiamethoxam on nAChR-mediated behaviour and CNS neuropathology in both adult and juvenile rats; representing both a susceptible non-target population and a surrogate species for other vertebrate wildlife. Further we will determine if pre-gestational exposure to these compounds produces deficits in the resulting offspring.******The studies proposed will provide much needed data on the effects of neonicotinoid pesticides on small mammals and form a foundation for future field studies if warranted.**