National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, Hubei, 430070, China; MAO Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei, 430070, China.
Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, 28040, Madrid, Spain.
Food Chem Toxicol. 2021 Dec;158:112629. doi: 10.1016/j.fct.2021.112629. Epub 2021 Oct 19.
DON is commonly found in foods and feeds; it presents health risks, especially an increase of growth inhibition in humans, particularly infants and young children. However, there are relatively few research studies devoted to the mechanism of DON-mediated growth retardation. Interestingly, our results showed that DON does not cause any significant production of ROS but results in a persistent and significant release of NO with iNOS increasing activity, mitochondrial ultrastructural changes and decreasing ΔΨm. Moreover, the significant decreases in GH production and secretion induced by DON were dose-dependent, accompanied by an increase of caspase 3, 8 and 9, IL-11, IL-lβ and GHRH. NO scavenging agent (haemoglobin) and free radical scavenging agent (N-acetylcysteine) partially reversed mitochondrial damage, and Z-VAD-FMK increased the levels of GH and decreased the levels of caspase 3, 8 and 9, while haemoglobin decreased the levels of caspase 3, 8 and 9, indicating that NO is the primary target of DON-mediated inhibition. Present research study firstly demonstrated that NO is a key mediator of DON-induced growth inhibition and plays critical roles in the interference of GH transcription and synthesis. The current research is conducive to future research on the molecular mechanisms of DON-induced growth inhibition in humans, especially children.
DON 通常存在于食品和饲料中；它存在健康风险，特别是会增加人类，尤其是婴儿和幼儿的生长抑制。然而，目前针对 DON 介导的生长迟缓机制的研究相对较少。有趣的是，我们的研究结果表明，DON 不会导致任何显著的 ROS 产生，而是导致持续且显著的 NO 释放，同时伴有 iNOS 活性增加、线粒体超微结构改变和 ΔΨm 降低。此外，DON 诱导的 GH 产生和分泌的显著减少呈剂量依赖性，同时伴随着 caspase 3、8 和 9、IL-11、IL-lβ 和 GHRH 的增加。NO 清除剂（血红蛋白）和自由基清除剂（N-乙酰半胱氨酸）部分逆转了线粒体损伤，Z-VAD-FMK 增加了 GH 的水平，降低了 caspase 3、8 和 9 的水平，而血红蛋白降低了 caspase 3、8 和 9 的水平，表明 NO 是 DON 介导的抑制的主要靶标。本研究首次表明，NO 是 DON 诱导的生长抑制的关键介质，在 GH 转录和合成的干扰中发挥关键作用。目前的研究有助于未来研究 DON 诱导的人类生长抑制的分子机制，尤其是儿童。
