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

在过去的二十年里，新烟碱类杀虫剂已成为世界五大化学类杀虫剂中最重要和增长最快的。顾名思义，这些化合物作为乙酰胆碱受体(NAChRs)烟碱亚类的激动剂，导致“过度刺激”，导致神经肌肉瘫痪。通常用作种子处理，它们也直接用于植物，并被用作包括狗和猫在内的家畜的“跳蚤粉”。尽管nAChRs是所有脊椎动物(以及无脊椎动物)生理的基础，但基于毒理学数据，新烟碱类化合物已被批准并广泛使用，这些数据表明，它们与昆虫nAChRs的亲和力比哺乳动物nAChRs高得多；与有机磷或甲基氨基甲酸酯等其他类别的杀虫剂相比，赋予了更大的“安全边际”。然而，这一结论几乎完全基于对目标物种产生致死性的相对效力(LD50)的比较。然而，对这些化合物对哺乳动物亚致死毒性的比较相对较少。关于这些化合物对脊椎动物的繁殖和免疫抑制的影响的数据有限，但几乎没有关于这些化合物对哺乳动物的神经发育毒性或低剂量暴露的长期影响的数据。缺乏对老鼠等物种的知识，这些物种会消耗经过处理的种子，进而成为高级哺乳动物(例如狐狸)或猛禽(猫头鹰、鹰等)的猎物。是我们目前对新烟碱使用的环境后果的理解中的一个主要差距，Gibbons等人最近的一篇综述中强调了这一点。(2015)这引发了关于这些化合物对脊椎动物野生动物影响的严重问题。 基于现有的数据报道和明显的数据差距，迫切需要进一步研究新烟碱类化合物在非靶标哺乳动物物种中的亚致死性和神经发育毒性。这项建议将调查低浓度的新烟碱类杀虫剂吡虫啉和甲氧西林对成年和幼年大鼠的nAChR介导的行为和中枢神经病理的影响；这既代表了易受影响的非目标种群，也代表了其他脊椎动物野生动物的替代物种。此外，我们将确定孕前接触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新烟碱类杀虫剂对小型哺乳动物影响的迫切需要的数据，并在必要时为未来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.