Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, Insurgentes Sur 3877, 14269, Mexico City, Mexico.
Facultad de Ciencias, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico.
Neurotox Res. 2020 Aug;38(2):287-298. doi: 10.1007/s12640-020-00220-1. Epub 2020 May 28.
Monovalent thallium (Tl) is a cation that can exert complex neurotoxic patterns in the brain by mechanisms that have yet to be completely characterized. To learn more about Tl toxicity, it is necessary to investigate its major effects in vivo and its ability to trigger specific signaling pathways (such as the antioxidant SKN-1 pathway) in different biological models. Caenorhabditis elegans (C. elegans) is a nematode constituting a simple in vivo biological model with a well-characterized nervous system, and high genetic homology to mammalian systems. In this study, both wild-type (N2) and skn-1 knockout (KO) mutant C. elegans strains subjected to acute and chronic exposures to Tl [2.5-35 μM] were evaluated for physiological stress (survival, longevity, and worm size), motor alterations (body bends), and biochemical changes (glutathione S-transferase regulation in a gst-4 fluorescence strain). While survival was affected by Tl in N2 and skn-1 KO (worms lacking the orthologue of mammalian Nrf2) strains in a similar manner, the longevity was more prominently decreased in the skn-1 KO strain compared with the wild-type strain. Moreover, chronic exposure led to a greater compromise in the longevity in both strains compared with acute exposure. Tl also induced motor alterations in both skn-1 KO and wild-type strains, as well as changes in worm size in wild-type worms. In addition, preconditioning nematodes with the well-known antioxidant S-allylcysteine (SAC) reversed the Tl-induced decrease in survival in the N2 strain. GST fluorescent expression was also decreased by the metal in the nematode, and recovered by SAC. Our results describe and validate, for the first time, features of the toxic pattern induced by Tl in an in vivo biological model established with C. elegans, supporting an altered redox component in Tl toxicity, as previously described in mammal models. We demonstrate that the presence of the orthologous SKN-1 pathway is required for worms in evoking an efficient antioxidant defense. Therefore, the nematode represents an optimal model to reproduce mammalian Tl toxicity, where toxic mechanisms and novel therapeutic approaches of clinical value may be successfully pursued.
单价态铊 (Tl) 是一种阳离子，它可以通过尚未完全阐明的机制在大脑中产生复杂的神经毒性模式。为了更多地了解 Tl 的毒性，有必要研究其在体内的主要作用及其在不同生物模型中触发特定信号通路（如抗氧化剂 SKN-1 通路）的能力。秀丽隐杆线虫 (C. elegans) 是一种线虫，构成了一种具有特征性神经系统的简单体内生物模型，与哺乳动物系统具有高度的遗传同源性。在这项研究中，对暴露于 Tl [2.5-35 μM] 的野生型 (N2) 和 skn-1 敲除 (KO) 突变体 C. elegans 菌株的生理应激（存活、寿命和蠕虫大小）、运动改变（身体弯曲）和生化变化（在 gst-4 荧光株中调节谷胱甘肽 S-转移酶）进行了评估。虽然 Tl 以相似的方式影响 N2 和 skn-1 KO（缺乏哺乳动物 Nrf2 同源物的蠕虫）菌株的存活，但与野生型菌株相比，skn-1 KO 菌株的寿命更明显降低。此外，与急性暴露相比，慢性暴露也导致两种菌株的寿命更大程度受损。Tl 还诱导了 skn-1 KO 和野生型菌株的运动改变，以及野生型蠕虫的体型变化。此外，用已知的抗氧化剂 S-烯丙半胱氨酸 (SAC) 预处理线虫可逆转 N2 菌株中 Tl 诱导的存活率降低。该金属还降低了线虫中的 GST 荧光表达，并通过 SAC 恢复。我们的结果首次描述并验证了 Tl 在 C. elegans 建立的体内生物模型中诱导的毒性模式的特征，支持先前在哺乳动物模型中描述的 Tl 毒性中的氧化还原成分改变。我们证明，存在同源 SKN-1 途径对于引发有效抗氧化防御的蠕虫是必需的。因此，线虫是再现哺乳动物 Tl 毒性的理想模型，在该模型中可以成功探索具有临床价值的毒性机制和新的治疗方法。
