环境浓度丁虫腈通过扰动铁代谢平衡诱导肝毒性及对映体选择性

Flufiprole, an efficient and low toxicity chiral phenyl pyrazole derivatives insecticides which is the substitution of fipronil, has been classified as the high-toxic pesticide succedaneums and promoted products in China. However, as the widely use of flufiprole, investigations regarding the potential flufiprole-induced risk of ecological safety and population health are still limited, additionally, it’s becoming more complicated due to the enantioselectivity of flufiprole. In particular, low-dose exposure of flufiprole-incurred toxicities and the underlying mechanisms remain unknown. Liver, as the major target organ subjected to various pesticides, is also an important metabolic organ, which could be injured once the iron metabolism disordered. Hence, after the separation of flufiprole enantiomers through HPLC, in vitro and in vivo studies will be carried out to discuss the iron homeostasis dysregulation-mediated hepatotoxicity induced by flufiprole at environmental concentration, and the relevant molecular mechanisms, which aims at uncover the mechanism responsible for the hepatotoxicity induced by low-dose flufiprole, and the enantioselectivity of flufiprole. Overall, our study may be of significance for understanding of novel-pesticide-induced health risks from a new angel of dysregulated iron metabolism, and more importantly, provide theoretical basis for selecting the environment friendly enantiomer of flufiprole.

丁虫腈是取代氟虫腈的高效、低毒手性苯基吡唑类杀虫剂，已被我国列为高毒农药替代及推广产品，使用量逐年递增。随着其广泛应用，对进入环境中的丁虫腈引发的潜在健康风险的研究很有限，由于手性特征又增加了丁虫腈风险和机制研究的复杂性，特别是对于低剂量丁虫腈暴露引起的毒性效应和致毒分子机制研究几乎是空白。肝脏作为农药暴露的主要靶器官，也是重要的代谢器官，而铁代谢失衡是肝毒性产生的重要原因。本项目拟利用实验小鼠和肝细胞为实验模型，在通过HPLC技术获得对映体纯丁虫腈标样的基础上，研究环境浓度下丁虫腈通过干扰肝细胞铁代谢诱导肝脏毒性及其分子机制。旨在揭示低剂量丁虫腈暴露的肝毒性机制及其对映体选择性。本研究将为这类新农药的健康风险评价提供新思路及全面的毒理学数据，为筛选丁虫腈环境友好的对映体构型提供重要的理论依据。

丁虫腈是取代氟虫腈的高效、低毒手性苯基吡唑类杀虫剂，已被我国列为高毒农药替代及推广产品，使用量逐年递增。随着其广泛应用，对进入环境中的丁虫腈引发的潜在健康风险的研究很有限，由于手性特征又增加了丁虫腈风险和机制研究的复杂性，特别是对于低剂量丁虫腈暴露引起的毒性效应和致毒分子机制研究几乎是空白。肝脏作为农药暴露的主要靶器官，也是重要的代谢器官，而铁代谢失衡是肝毒性产生的重要原因。因此，本项目选取正常肝细胞和SD大鼠为模型，在通过高效液相色谱获得对映体纯丁虫腈标样的基础上，研究丁虫腈通过干扰机体铁代谢诱导肝毒性及其分子机制，结果显示丁虫腈及其对映体均诱发肝细胞及大鼠机体铁代谢紊乱，并伴随着炎症反应的产生；同时肝细胞及肝组织铁代谢相关基因出现明显的异常表达，且具有显著的对映体选择性差异（S>R）；此外，丁虫腈进入环境水体后，主要的降解产物为氟虫腈，因此，本项目还对氟虫腈进行了水生生物的对映体选择性神经毒性评估：所有氟虫腈构型中，R型对斑马鱼幼体诱发最显著的类焦虑行为，且该现象与神经发育相关基因的异常DNA甲基化高度相关。以上结果揭示了丁虫腈通过干扰关键基因的表达诱导机体铁代谢紊乱，从而诱发对映体选择性肝毒性；氟虫腈通过差异性调控神经相关基因的DNA甲基化诱导该基因的异常表达，进而诱导其对斑马鱼幼体的对映体选择性神经毒性效应。本研究为此类农药的健康风险评估提供新思路及全面的毒理学数据，为筛选环境友好的手性农药对映体构型提供重要的理论依据。