Alehashem M, Alcaraz A J, Hogan N, Weber L, Siciliano S D, Hecker M
Toxicology Centre, University of Saskatchewan, Saskatoon, SK S7N 5B4, Canada.
Toxicology Centre, University of Saskatchewan, Saskatoon, SK S7N 5B4, Canada; Department of Animal Science, University of Saskatchewan, Saskatoon, SK, Canada.
Sci Total Environ. 2024 Jul 10;933:173041. doi: 10.1016/j.scitotenv.2024.173041. Epub 2024 May 8.
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.
尽管许多有机氯农药（OCPs）因其持久性以及与神经退行性疾病的关联而被禁止或限制使用，但仍有证据表明人类持续暴露于这些农药中。相比之下，据报道登记在册的除草剂毒性为中度至低度；然而，关于它们对人类的毒性或与有机氯农药的联合效应的信息却很少。本研究旨在利用SH-SY5Y细胞，阐明在一个遗留污染的农药生产和包装场地检测到的禁用有机氯农药杀虫剂（艾氏剂、狄氏剂、七氯和林丹）和登记在册的除草剂（氟乐灵、燕麦敌和氯吡嘧磺隆）的毒性机制。在接触这些杀生物剂24小时后，评估细胞活力、乳酸脱氢酶（LDH）释放、活性氧（ROS）生成以及半胱天冬酶3/7活性。此外，在亚致死浓度下进行RNA测序，以研究细胞毒性所涉及的潜在机制。我们的研究结果表明，艾氏剂和七氯毒性最强，而狄氏剂、林丹、氟乐灵和燕麦敌表现出中度毒性，氯吡嘧磺隆对SH-SY5Y细胞无毒。虽然艾氏剂和七氯通过损害细胞膜诱导毒性，但狄氏剂的毒性部分归因于坏死和凋亡。此外，林丹、氟乐灵和燕麦敌的毒性作用至少部分与ROS生成有关。基因表达谱表明，大多数受试杀生物剂诱导的细胞活力下降与细胞增殖受抑制有关。编码具有抗凋亡特性蛋白质的基因失调也支持了半胱天冬酶未被激活。确定的富集术语表明，SH-SY5Y细胞中有机氯农药的毒性是通过与神经退行性疾病发病机制相关的途径介导的。总之，本研究为阐明农药诱导神经毒性的分子机制提供了依据。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。
