Han Gao-Chao, Jing Hai-Ming, Zhang Wen-Jing, Zhang Nan, Li Zi-Nan, Zhang Guo-Yan, Gao Shan, Ning Jun-Yu, Li Guo-Jun
Institute of Toxicology, Beijing Center for Disease Prevention and Control/Beijing Research Center for Preventive Medicine/Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing, 100013, PR China; School of Public Health, Capital Medical University, Beijing, 100069, PR China.
Institute of Toxicology, Beijing Center for Disease Prevention and Control/Beijing Research Center for Preventive Medicine/Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing, 100013, PR China.
Toxicology. 2022 Jan 15;465:153012. doi: 10.1016/j.tox.2021.153012. Epub 2021 Oct 27.
Rare earth elements (REEs) are widely used in the industry, agriculture, biomedicine, aerospace, etc, and have been shown to pose toxic effects on animals, as such, studies focusing on their biomedical properties are gaining wide attention. However, environmental and population health risks of REEs are still not very clear. Also, the REEs damage to the nervous system and related molecular mechanisms needs further research. In this study, the L1 and L4 stages of the model organism Caenorhabditis elegans were used to evaluate the effects and possible neurotoxic mechanism of lanthanum(III) nitrate hexahydrate (La(NO)·6HO). For the L1 and L4 stage worms, the 48-h median lethal concentrations (LCs) of La(NO)·6HO were 93.163 and 648.0 mg/L respectively. Our results show that La(NO)·6HO induces growth inhibition and defects in behavior such as body length, body width, body bending frequency, head thrashing frequency and pharyngeal pumping frequency at the L1 and L4 stages in C. elegans. The L1 stage is more sensitive to the toxicity of lanthanum than the L4 stage worms. Using transgenic strains (BZ555, EG1285 and NL5901), we found that La(NO)·6HO caused the loss or break of soma and dendrite neurons in L1 and L4 stages; and α-synuclein aggregation in L1 stage, indicating that Lanthanum can cause toxic damage to dopaminergic and GABAergic neurons. Mechanistically, La(NO)·6HO exposure inhibited or activated the neurotransmitter transporters and receptors (glutamate, serotonin and dopamine) in C. elegans, which regulate behavior and movement functions. Furthermore, significant increase in the production of reactive oxygen species (ROS) was found in the L4 stage C. elegans exposed to La(NO)·6HO. Altogether, our data show that exposure to lanthanum can cause neuronal toxic damage and behavioral defects in C. elegans, and provide basic information for understanding the neurotoxic effect mechanism and environmental health risks of rare earth elements.
稀土元素（REEs）广泛应用于工业、农业、生物医药、航空航天等领域，并且已被证明对动物具有毒性作用，因此，关注其生物医学特性的研究正受到广泛关注。然而，稀土元素对环境和人群健康的风险仍不太明确。此外，稀土元素对神经系统的损害及相关分子机制有待进一步研究。在本研究中，使用模式生物秀丽隐杆线虫的L1和L4阶段来评估六水合硝酸镧（La(NO₃)₃·6H₂O）的影响及可能的神经毒性机制。对于L1和L4阶段的线虫，La(NO₃)₃·6H₂O的48小时半数致死浓度（LC₅₀）分别为93.163和648.0毫克/升。我们的结果表明，La(NO₃)₃·6H₂O在秀丽隐杆线虫的L1和L4阶段诱导生长抑制和行为缺陷，如体长、体宽、身体弯曲频率、头部摆动频率和咽部抽吸频率。L1阶段比L4阶段的线虫对镧的毒性更敏感。使用转基因菌株（BZ555、EG1285和NL5901），我们发现La(NO₃)₃·6H₂O导致L1和L4阶段的体细胞和树突神经元丢失或断裂；并且在L1阶段出现α-突触核蛋白聚集，表明镧可对多巴胺能和γ-氨基丁酸能神经元造成毒性损伤。从机制上讲，暴露于La(NO₃)₃·6H₂O会抑制或激活秀丽隐杆线虫中调节行为和运动功能的神经递质转运体和受体（谷氨酸、5-羟色胺和多巴胺）。此外，在暴露于La(NO₃)₃·6H₂O的L4阶段秀丽隐杆线虫中发现活性氧（ROS）的产生显著增加。总之，我们的数据表明，暴露于镧会导致秀丽隐杆线虫的神经元毒性损伤和行为缺陷，并为理解稀土元素的神经毒性作用机制和环境健康风险提供基础信息。
