Abstract：
Although many organochlorine pesticides (OCPs) have been banned or restricted because of their persistence and linkage to neurodegenerative diseases, there is evidence of continued human exposure. In contrast, registered herbicides are reported to have a moderate to low level of toxicity; however, there is little information regarding their toxicity to humans or their combined effects with OCPs. This study aimed to characterize the mechanism of toxicity of banned OCP insecticides (aldrin, dieldrin, heptachlor, and lindane) and registered herbicides (trifluralin, triallate, and clopyralid) detected at a legacy contaminated pesticide manufacturing and packing site using SH-SY5Y cells. Cell viability, LDH release, production of reactive oxygen species (ROS), and caspase 3/7 activity were evaluated following 24 h of exposure to the biocides. In addition, RNASeq was conducted at sublethal concentrations to investigate potential mechanisms involved in cellular toxicity. Our findings suggested that aldrin and heptachlor were the most toxic, while dieldrin, lindane, trifluralin, and triallate exhibited moderate toxicity, and clopyralid was not toxic to SH-SY5Y cells. While aldrin and heptachlor induced their toxicity through damage to the cell membrane, the toxicity of dieldrin was partially attributed to necrosis and apoptosis. Moreover, toxic effects of lindane, trifluralin, and triallate, at least partially, were associated with ROS generation. Gene expression profiles suggested that decreased cell viability induced by most of the tested biocides was related to inhibited cell proliferation. The dysregulation of genes encoding for proteins with anti-apoptotic properties also supported the absence of caspase activation. Identified enriched terms showed that OCP toxicity in SH-SY5Y cells was mediated through pathways associated with the pathogenesis of neurodegenerative diseases. In conclusion, this study provides a basis for elucidating the molecular mechanisms of pesticide-induced neurotoxicity. Moreover, it introduced SH-SY5Y cells as a relevant in vitro model for investigating the neurotoxicity of pesticides in humans.
摘要：
尽管许多有机氯农药（OCPs）由于其持久性和与神经退行性疾病的联系而被禁止或限制，有证据表明人类持续暴露。相比之下,据报道，注册的除草剂具有中等至低水平的毒性；然而，关于它们对人类的毒性或与OCPs的联合作用的信息很少。本研究旨在表征禁用的OCP杀虫剂(艾氏剂，狄氏剂,七氯,和林丹)和注册除草剂(氟乐灵，triallate,和clopyralid）在使用SH-SY5Y细胞的传统污染农药生产和包装现场检测到。细胞活力，LDH释放,活性氧（ROS）的产生，和半胱天冬酶3/7活性在暴露于杀生物剂24小时后进行评估。此外,在亚致死浓度下进行RNASeq以研究参与细胞毒性的潜在机制。我们的发现表明艾氏剂和七氯毒性最大，而狄氏剂,林丹,氟乐灵,和triallate表现出中等毒性，氯吡啶对SH-SY5Y细胞无毒。艾氏剂和七草胺通过对细胞膜的损伤引起毒性，狄氏剂的毒性部分归因于坏死和细胞凋亡。此外，林丹的毒性作用,氟乐灵,三重，至少部分地,与ROS的产生有关。基因表达谱表明，大多数测试的杀生物剂诱导的细胞活力降低与抑制细胞增殖有关。失调基因的抗凋亡特性也支持不存在胱天蛋白酶激活。鉴定的富集术语表明，SH-SY5Y细胞中的OCP毒性是通过与神经退行性疾病的发病机理相关的途径介导的。总之,本研究为阐明农药致神经毒性的分子机制提供了基础。此外，它引入了SH-SY5Y细胞作为研究农药对人类神经毒性的相关体外模型。
