Deoxynivalenol (DON) cannot be totally removed due to its stable chemical characteristics and chronic exposure to low doses of DON causes significant toxic effects in humans and animals. However, the potential hazard of such low-dose exposure in target organs still remains not completely understood, especially in liver, which is mainly responsible for detoxification of DON. In the present study, we demonstrated for the first time that estimated human daily DON exposure (25 μg/kg bw) for 30 and 90 days caused low-grade inflammatory infiltration around hepatic centrilobular veins, elevated systemic IL-1β, IL-6 and TNF-α and impaired liver function evidenced by increased serum ALT activity. At the molecular level, expressions of autophagy-related proteins as well as Cleaved Caspase-3 and Cleaved Caspase-7 were upregulated during DON exposure, which indicated the activation of autophagy and apoptosis. Importantly, AAV-mediated liver-specific overexpression of HO-1 reversed DON-induced liver damages, upregulated autophagy and attenuated apoptosis in liver, while AAV-mediated HO-1 silence aggravated DON-induced liver damages, inhibited autophagy and increased apoptosis. Furthermore, in vitro experiments demonstrated that lentivirus-mediated HO-1 overexpression in Hepa 1-6 cells prolonged the duration of autophagy and delayed the onset of apoptosis. HO-1 silence in Hepa 1-6 cells inhibited activation of autophagy and accelerated occurrence of apoptosis, and these could be recovered by CO pre-treatment. Therefore, we suppose that HO-1 might be a potential research target to protect human and animal from liver injuries induced by low dose of DON exposure.

中文翻译：

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血红素加氧酶-1通过碳氧调节自噬，以减轻脱氧雪腐酚对肝的损害。

脱氧雪腐烯（DON）由于其稳定的化学特性而不能完全去除，长期暴露于低剂量的DON中会对人和动物产生明显的毒性作用。然而，仍未完全了解靶器官中这种低剂量暴露的潜在危害，尤其是在肝脏中，这是造成DON排毒的主要原因。在本研究中，我们首次证明了估计的人类每天DON暴露量（25μg/ kg bw）在30天和90天时引起肝小叶静脉周围的轻度炎症浸润，全身性IL-1β，IL-6和血清ALT活性升高可证明TNF-α和肝功能受损。在分子水平上，DON暴露过程中自噬相关蛋白以及Cleaved Caspase-3和Cleaved Caspase-7的表达上调，这表明自噬和细胞凋亡的激活。重要的是，AAV介导的HO-1的肝脏特异性过表达逆转了DON诱导的肝损伤，上调了自噬并减弱了肝脏的细胞凋亡，而AAV介导的HO-1沉默加剧了DON诱导的肝损伤，抑制了自噬并增加了细胞凋亡。此外，体外实验表明，慢病毒介导的HO-1在Hepa 1-6细胞中的过表达延长了自噬的持续时间并延迟了细胞凋亡的发生。Hepa 1-6细胞中的HO-1沉默抑制了自噬的激活并加速了细胞凋亡的发生，这些可以通过CO预处理来恢复。因此，我们认为HO-1可能是保护人类和动物免受低剂量DON暴露所致肝损伤的潜在研究目标。