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, 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 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.

福美双是一种二硫代氨基甲酸盐类杀虫剂，广泛用作杀菌剂以保护农作物和种子。长期接触福美双会对人类和动物的健康造成潜在危害。迄今为止，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；然而，关于心脏毒性的数据较少。在这项研究中，我们检查了暴露于福美双的肉鸡心脏的心脏组织病理学、炎症因子、氧化应激指标和细胞凋亡标志物。根据我们的研究结果，持续暴露于福美双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）水平升高和抗炎因子 (IL-10) 水平降低。此外，福美双显着上调cleaved-caspase 3、cleaved-PARP的蛋白表达，并引起心肌细胞凋亡。同时，福美双治疗组热休克蛋白（HSP60、HSP70、HSP90）的表达显着降低。过氧化产物（MDA、H₂氧₂), T-AOC 减少, 抗氧化活性酶 (T-SOD, GST 和 GPX) 也被注意到, 所有这些都通过上调关键靶基因 (HO-1) 导致氧化应激和 Nrf2 信号通路的激活和 SOD）。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。相关性分析揭示了 18 种差异表达的代谢物，与心脏损伤密切相关。重要的是，福美双主要影响牛磺酸和亚牛磺酸代谢、嘧啶代谢以及甘油代谢。总的来说，我们的研究表明，福美双可通过干扰牛磺酸和亚牛磺酸代谢、嘧啶代谢和甘油脂代谢而引起心脏毒性，从而通过触发 Nrf2 信号通路进一步诱导氧化应激。