Azoxystrobin (AZO) and Iprodione (IPR) fungicides are extensively used worldwide, and therefore, contaminate all environmental compartments. The toxicity and the mechanisms by which they affected immune cells are complex and remain unknown. This study investigated the impact of AZO and IPR on the in vitro function of mice peritoneal macrophages including lysosomal enzyme activity and tumor necrosis factor (TNF)α and nitric oxide (NO) production in response to lipopolysaccharide (LPS) stimulation, the proliferation of mice splenocytes stimulated by concanavalin (Con)A and LPS, and the production of the Th1cytokine interferon-gamma (IFNγ) and the Th2 cytokine interleukin (IL)-4 and IL-10 by ConA-activated splenocytes. This is the first report indicating that AZO and IPR fungicides dose-dependently inhibited mice macrophage lysosomal enzyme activity and LPS-stimulated production of TNFα and NO. Mitogen-induced proliferation of mice splenocytes was also suppressed by AZO and IPR in a dose-dependent manner. More pronounced impact was observed on ConA-induced response. The production of IFNγ by ConA-stimulated splenocytes was dose-dependently inhibited; however, the production of IL-4 and IL-10 increased in the same conditions. These results suggested that AZO and IPR polarized Th1/Th2 cytokine balance towards Th2 response. Overall, marked immunosuppressive effects were observed for AZO. The immunomodulatory effects caused by AZO and IPR were partially reversed by the pharmacological antioxidant N-acetylcysteine (NAC), suggesting that both fungicides exerted their actions through, at least in part, oxidative stress-dependent mechanism. Collectively, our data showed that AZO and IPR fungicides exerted potent immunomodulatory effects in vitro with eventually strong consequences on immune response and immunologically based diseases.

中文翻译：

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N-乙酰半胱氨酸降低嘧菌酯和异菌脲类杀菌剂对小鼠体外诱导的免疫毒性作用

嘧菌酯 (AZO) 和异菌脲 (IPR) 杀菌剂在世界范围内广泛使用，因此会污染所有环境隔间。它们影响免疫细胞的毒性和机制很复杂，仍然未知。本研究调查了 AZO 和 IPR 对小鼠腹腔巨噬细胞体外功能的影响，包括溶酶体酶活性和肿瘤坏死因子 (TNF)α 以及响应脂多糖 (LPS) 刺激的一氧化氮 (NO) 的产生、小鼠的增殖由刀豆蛋白 (Con)A 和 LPS 刺激的脾细胞，以及由 ConA 激活的脾细胞产生 Th1 细胞因子干扰素-γ (IFNγ) 和 Th2 细胞因子白细胞介素 (IL)-4 和 IL-10。这是首次报告表明 AZO 和 IPR 杀菌剂剂量依赖性地抑制小鼠巨噬细胞溶酶体酶活性和 LPS 刺激的 TNFα 和 NO 的产生。AZO 和 IPR 也以剂量依赖性方式抑制了丝裂原诱导的小鼠脾细胞增殖。观察到对 ConA 诱导的反应有更明显的影响。ConA 刺激的脾细胞产生 IFNγ 受到剂量依赖性抑制；然而，在相同条件下，IL-4 和 IL-10 的产生增加。这些结果表明 AZO 和 IPR 使 Th1/Th2 细胞因子平衡朝向 Th2 反应。总体而言，观察到 AZO 具有显着的免疫抑制作用。AZO 和 IPR 引起的免疫调节作用被药理抗氧化剂 N-乙酰半胱氨酸 (NAC) 部分逆转，表明这两种杀菌剂至少部分通过氧化应激依赖性机制发挥作用。总的来说，我们的数据表明 AZO 和 IPR 杀菌剂在体外发挥了强大的免疫调节作用，最终对免疫反应和基于免疫的疾病产生了强烈的影响。