College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, PR China.
College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, PR China; Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, PR China.
Ecotoxicol Environ Saf. 2022 Dec 1;247:114225. doi: 10.1016/j.ecoenv.2022.114225. Epub 2022 Oct 23.
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 researches 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 function of myocardial tissues with increased level of inducible nitric oxide synthase (iNOS), inflammatory factors (IL-6, IL-8, TNF-α and NF-κB), 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, HO), 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 eighteen 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 metabolism, 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.
代森锰锌是一种广泛用于保护作物和种子的二硫代氨基甲酸盐类农药。长期接触代森锰锌会对人类和动物的健康造成潜在危害。到目前为止，大多数关于代森锰锌的研究都集中在红细胞毒性、免疫系统、肾脏损伤和胫骨软骨发育不良上；然而，关于心脏毒性的数据较少。在这项研究中，我们研究了暴露于代森锰锌的肉鸡心脏的组织病理学变化、炎症因子、氧化应激指标和细胞凋亡标志物。研究结果表明，连续暴露于代森锰锌会导致心肌组织发生病理变化和功能异常，诱导型一氧化氮合酶（iNOS）、炎症因子（IL-6、IL-8、TNF-α 和 NF-κB）水平升高，抗炎因子（IL-10）水平降低。此外，代森锰锌显著上调了 cleaved-caspase 3 和 cleaved-PARP 的蛋白表达，引起了心肌细胞凋亡。同时，热休克蛋白（HSP60、HSP70、HSP90）的表达在代森锰锌处理组中明显下降。过氧化产物（MDA、HO）的过度积累、T-AOC 的减少以及抗氧化酶（T-SOD、GST 和 GPX）活性的降低也被观察到，所有这些都导致了氧化应激和 Nrf2 信号通路的激活，通过上调关键靶基因（HO-1 和 SODs）。通过非靶向代谢组学分析进一步鉴定了代森锰锌诱导的代谢物。相关性分析表明，有 18 种差异表达的代谢物与心脏损伤密切相关。重要的是，代森锰锌主要影响牛磺酸和羟乙磺酸代谢、嘧啶代谢以及甘油酯代谢。总的来说，我们的研究表明，代森锰锌可能通过干扰牛磺酸和羟乙磺酸代谢、嘧啶代谢和甘油酯代谢，进而通过触发 Nrf2 信号通路引起氧化应激，从而导致心脏毒性。这项研究可能为代森锰锌引起心脏毒性的分子机制提供新的证据，并为长期接触代森锰锌的动物和工人敲响警钟。
