Thiram induces myocardial oxidative damage and apoptosis in broilers via interfering their cardiac metabolism
Thiram induces myocardial oxidative damage and apoptosis in broilers via interfering their cardiac metabolism
复制标题
福美双通过干扰肉鸡的心脏代谢来诱导心肌氧化损伤和细胞凋亡。
DOI：
10.1016/j.ecoenv.2022.114225
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发表时间：
2022-10-23
影响因子：
6.8
通讯作者：
Li, Jiakui
中科院分区：
文献类型：
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作者：
Mo, Quan;Kulyar, Muhammad Fakhar-e-Alam;Li, Jiakui
福美双是一种二硫代氨基甲酸酯杀虫剂，广泛用作杀菌剂来保存农作物和种子。长期接触福美双会对人和动物的健康造成潜在危害。到目前为止，福美双的研究大多集中在红细胞毒性、免疫系统、肾脏损伤和胫骨软骨发育不良等方面，而关于心脏毒性的数据较少。在这项研究中，我们检测了暴露于福美双的肉鸡心脏的组织病理学、炎症因子、氧化应激指标和细胞凋亡标记物。结果表明，福美双可引起心肌组织病理改变和功能异常，诱导型一氧化氮合酶(INOS)、炎症因子(IL-6、IL-8、肿瘤坏死因子-α和核因子-kappaB)水平升高，抗炎因子(IL-10)水平下降。此外，福美双还可显著上调Caspase3、PARP的蛋白表达，并诱导心肌细胞凋亡。同时，福美双治疗组热休克蛋白(HSP60、HSP70、HSP90)的表达明显减少。过氧化产物(MDA、H_2O_2)过量积累，T-AOC降低，抗氧化酶(T-SOD、GST和GPX)活性降低，导致氧化应激，并通过上调关键靶基因(HO-1和SODS)激活Nrf2信号通路。通过非靶向代谢组学分析进一步鉴定福美双诱导的代谢物。相关分析揭示了与心脏损伤密切相关的18种差异表达的代谢物。重要的是，福美双主要影响牛磺酸和次牛磺酸代谢、嘧啶代谢以及甘油代谢。综上所述，我们的研究表明福美双可能通过干扰牛磺酸和次牛磺酸代谢、嘧啶代谢和甘油脂代谢而导致心脏毒性，后者通过触发Nrf2信号通路而进一步诱导氧化应激。本研究可能为福美双心脏毒性的分子机制提供新的证据，并为长期接触福美双的动物和工作者敲响警钟。
Thiram is a dithiocarbamate pesticide extensively used as a fungicide to preserve crops and seeds. Long-term exposure to thiram causes potential harm to the health of human beings and animals. So far, most of the re-searches on thiram focused on erythrocyte toxicity, immune system, kidney damage, and tibial dyschondroplasia; however, there is less data on cardiac toxicity. In this study, we examined cardiac histopathology, inflammatory factors, oxidative stress indicators, and apoptosis markers in the heart of broilers that were exposed to thiram. According to our findings, the continuous exposure to thiram caused pathological changes and abnormal func-tion of myocardial tissues with increased level of inducible nitric oxide synthase (iNOS), inflammatory factors (IL-6, IL-8, TNF-alpha and NF-kappa B), and decreased level of anti-inflammatory factor (IL-10). In addition, thiram significantly upregulated the protein expression of cleaved-caspase 3, cleaved-PARP, and caused cardiomyocyte apoptosis. Meanwhile, the expression of heat shock proteins (HSP60, HSP70, HSP90) markedly decreased in the thiram-treated groups. An excessive accumulation of peroxidation products (MDA, H2O2), a decrease in T-AOC, and antioxidant activity enzymes (T-SOD, GST and GPX) were also noticed, all of which led to oxidative stress and activation of Nrf2 signal pathway by up-regulating key target genes (HO-1 and SODs). Thiram-induced metabolites were further identified via non-targeted metabonomic analysis. Correlation analysis revealed eigh-teen differentially expressed metabolites, closely related to cardiac injury. Importantly, thiram primarily affected the taurine and hypotaurine metabolism, pyrimidine metabolism as well as glycerol metabolism. Collectively, our study suggests that thiram could cause cardiotoxicity by interfering with taurine and hypotaurine meta-bolism, pyrimidine metabolism, and glycerolipid metabolism, which further induce oxidative stress via triggering Nrf2 signal pathway. This study may provide new evidence for the molecular mechanism of cardiotoxicity caused by thiram and resonate the alarm for animals and workers who have been exposed to thiram for a long time.