Department of Pharmacodynamics, University of Florida, College of Pharmacy, Gainesville, Florida 32610, USA.
Department of Environmental and Global Health, University of Florida, College of Public Health and Health Professions, Gainesville, Florida 32610, USA.
Toxicol Sci. 2021 Aug 3;182(2):260-274. doi: 10.1093/toxsci/kfab064.
Organochlorine pesticides (OCPs) are persistent pollutants linked to diverse adverse health outcomes. Environmental exposure to OCPs has been suggested to negatively impact the immune system but their effects on cellular antiviral responses remain unknown. Transcriptomic analysis of N27 rat dopaminergic neuronal cells unexpectedly detected high level expression of genes in the interferon (IFN)-related antiviral response pathways including the IFN-induced protein with tetratricopeptide repeats 1 and 2 (Ifit1/2) and the MX Dynamin Like GTPases Mx1 and Mx2. Interestingly, treatment of N27 cells with dieldrin markedly downregulated the expression of many of these genes. Dieldrin exterted a similar effect in inhibiting IFIT2 and MX1 gene expression in human SH-SY5Y neuronal cells induced by an RNA viral mimic, polyinosinic: polycytidylic acid (poly I:C) and IFIT2/3 gene expression in human pulmonary epithelial cells exposed to human influenza H1N1 virus. Mechanistically, dieldrin induced a rapid rise in levels of intracellular reactive oxygen species (iROS) and a decrease in intracellular glutathione (GSH) levels in SH-SY5Y cells. Treatment with N-acetylcysteine, an antioxidant and GSH biosynthesis precursor, effectively blocked both dieldrin-induced increases in iROS and its inhibition of poly I:C-induced upregulation of IFIT and MX gene expression, suggesting a role for intracellular oxidative status in dieldrin's modulation of antiviral gene expression. This study demonstrates that dieldrin modulates key genes of the cellular innate immune responses that are normally involved in the host's cellular defense against viral infections. Our findings have potential relevance to understanding the organismal effects of environmentally persistent organochlorine contaminants on the mammalian cellular immune system.
有机氯农药（OCPs）是与多种不良健康后果相关的持久性污染物。环境暴露于 OCPs 被认为会对免疫系统产生负面影响，但它们对细胞抗病毒反应的影响尚不清楚。对 N27 大鼠多巴胺能神经元细胞的转录组分析出人意料地检测到干扰素（IFN）相关抗病毒反应途径中的基因高水平表达，包括干扰素诱导的四肽重复蛋白 1 和 2（Ifit1/2）和 MX 动力蛋白样 GTPases Mx1 和 Mx2。有趣的是，狄氏剂处理 N27 细胞显著下调了许多这些基因的表达。狄氏剂在抑制 RNA 病毒模拟物多聚肌苷酸：多聚胞苷酸（poly I:C）诱导的人类 SH-SY5Y 神经元细胞中 IFIT2 和 MX1 基因表达以及人类流感 H1N1 病毒暴露的人肺上皮细胞中 IFIT2/3 基因表达方面发挥了类似作用。从机制上讲，狄氏剂诱导 SH-SY5Y 细胞内活性氧（iROS）水平迅速升高和细胞内谷胱甘肽（GSH）水平降低。抗氧化剂和 GSH 生物合成前体 N-乙酰半胱氨酸的处理有效阻断了狄氏剂诱导的 iROS 增加及其对 poly I:C 诱导的 IFIT 和 MX 基因表达上调的抑制作用，表明细胞内氧化状态在狄氏剂调节抗病毒基因表达中起作用。本研究表明，狄氏剂调节细胞固有免疫反应的关键基因，这些基因通常参与宿主对病毒感染的细胞防御。我们的发现可能与理解环境持久性有机氯污染物对哺乳动物细胞免疫系统的机体影响有关。
