Abstract
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.
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Acknowledgements
This work was financially supported by the National Key Research and Development Program of China (2018YFC1603100), National Natural Science Foundation of China (NSFC81502811), Natural Science Foundation of Hubei Province (ZRMS2017000504) and Hubei Province Health and Family Planning Scientific Research Project (WJ2019M114). All authors read and approved the final manuscript. We would like to thank all the participants for their contribution to this study. We also like to thank Ms. Svetlana Gasimova (Department of Traumatology, BG Trauma center, Eberhard Karls University of Tübingen) for editing the manuscript. Meantime, we would also thank Ms. Lu Gao, Lecturer, (School of Art, Wuhan Bussiness University) for editing figures.
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Fig. S1 Cell viabilities of Hepa 1-6 cells exposed to 5, 10, 20, 30, 50, 100 nM DON for 0, 1, 3, 6, 9, 12, 24, 48 hours were measured by LDH detection. The cell viability at 0 h was regarded as 100% in each group. Three parallel samples for each time point. Data were presented as mean ± SD (JPG 335 kb)
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Fig. S2 Constructions of HO-1OE and HO-1shRNA AAV8 vectors. (a) HMOX1 sequence was inserted into pHBAAV-CMV-MCS-ZsGreen vector digested by KpnI and BamHI enzymes. (b) shRNA3 sequence was inserted into pHBAAV-U6-ZsGreen vector digested by BamHI and EcoRI enzymes. All vectors were labeled with green fluorescent protein genes and puromycin resistance genes. (JPG 2261 kb)
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Fig. S3 Constructions of HO-1OE and HO-1shRNA lentiviral vectors. (a) HMOX1 sequence was packaged into pHBLV-CMVIE-ZsGreen-Puro vector digested by BamHI and EcoRI enzymes. (b) Three different shRNAs were packaged into pHBLV-U6-Scramble-ZsGreen-Puro vector digested by BamHI and EcoRI enzymes to examine the most efficient shRNA. All vectors were labeled with green fluorescent protein genes and puromycin resistance genes. (JPG 2547 kb)
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Peng, Z., Liao, Y., Wang, X. et al. Heme oxygenase-1 regulates autophagy through carbon–oxygen to alleviate deoxynivalenol-induced hepatic damage. Arch Toxicol 94, 573–588 (2020). https://doi.org/10.1007/s00204-019-02649-6
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DOI: https://doi.org/10.1007/s00204-019-02649-6