Yu Haiyang, Li Tingting, Cui Yan, Liao Yingjun, Wang Gaoyang, Gao Lanyue, Zhao Fenghong, Jin Yaping
Department of Environmental and Occupational Health, School of Public Health, China Medical University, Shenyang, Liaoning, PR China.
Department of Physiology, China Medical University, Shenyang, Liaoning, PR China.
Toxicology. 2014 Nov 5;325:189-99. doi: 10.1016/j.tox.2014.09.007. Epub 2014 Sep 19.
The aim of this study was to explore the mechanisms of lead neurotoxicity by focusing on the alteration of D-serine metabolism in the hippocampus of mice at the early life. Mother mice and their offspring were exposed to 0, 0.5, 1.0 and 2.0 g/L lead in lead acetate via drinking water from the first day of gestation until the postnatal day (PND) 40. Morris water maze was used to measure the spatial learning and memory ability of PND 40 mice. Expressions of serine racemase (SR), D-amino acid oxidase (DAAO), alanine-serine- cysteine transporter-1 (asc-1) and subunits of N-methyl-D-aspartate receptor (NMDAR) in the hippocampus of PND 10, 20 and 40 mice were examined by western blot and real time RT-PCR. Findings from this study disclosed that the spatial learning ability of mice tested by place trial could be significantly impaired by 0.5 g/L lead exposure, and the spatial memory ability tested by probe trail could be impaired by 1.0 g/L lead exposure. Exposure to 2.0 g/L lead in the water could significantly inhibit the protein and mRNA expression of SR; conversely enhance the expression of DAAO protein and mRNA in the hippocampus during the early developmental stages. However, the protein expressions of DAAO and asc-1 in the hippocampus were significantly enhanced by 0.5 g/L lead exposure at different developmental stages. On the other hand, the protein and mRNA expressions of both NR1 and NR2A were inhibited significantly by 1.0 g/L lead exposure since PND 10, and by 0.5 g/L lead exposure since PND 20. Noteworthy, the protein expression of NR2B was inhibited significantly by 0.5 g/L lead exposure in PND 10 mice, and by 1.0 g/L lead exposure in PND 20 mice, but there was no significant group difference in PND 40 mice. Meanwhile, expressions of asc-1 and NR2B mRNA were not affected obviously by lead exposure. In conclusion, chronic lead exposure during brain development might affect D-serine metabolism by enhancing its degradation, which might be related to the inhibited expression of NMDAR subunits, and furthermore contribute to deficits in learning and memory ability in mice.
本研究旨在通过关注小鼠生命早期海马中D-丝氨酸代谢的变化，探讨铅神经毒性的机制。从妊娠第一天到出生后第40天（PND 40），母鼠及其后代通过饮用含0、0.5、1.0和2.0 g/L醋酸铅的水来接触铅。采用Morris水迷宫测试PND 40小鼠的空间学习和记忆能力。通过蛋白质免疫印迹法和实时逆转录聚合酶链反应检测PND 10、20和40小鼠海马中丝氨酸消旋酶（SR）、D-氨基酸氧化酶（DAAO）、丙氨酸-丝氨酸-半胱氨酸转运体-1（asc-1）和N-甲基-D-天冬氨酸受体（NMDAR）亚基的表达。本研究结果表明，0.5 g/L铅暴露可显著损害通过定位试验测试的小鼠空间学习能力，1.0 g/L铅暴露可损害通过探针试验测试的小鼠空间记忆能力。水中2.0 g/L铅暴露可显著抑制SR的蛋白质和mRNA表达；相反，在早期发育阶段可增强海马中DAAO蛋白质和mRNA的表达。然而，在不同发育阶段，0.5 g/L铅暴露可显著增强海马中DAAO和asc-1的蛋白质表达。另一方面，自PND 10起，1.0 g/L铅暴露可显著抑制NR1和NR2A的蛋白质和mRNA表达，自PND 20起，0.5 g/L铅暴露也可抑制其表达。值得注意的是，PND 10小鼠中0.5 g/L铅暴露可显著抑制NR2B的蛋白质表达，PND 20小鼠中1.0 g/L铅暴露可抑制其表达，但PND 40小鼠中各实验组之间无显著差异。同时，铅暴露对asc-1和NR2B mRNA的表达无明显影响。总之，脑发育过程中的慢性铅暴露可能通过增强D-丝氨酸的降解来影响其代谢，这可能与NMDAR亚基表达受抑制有关，进而导致小鼠学习和记忆能力缺陷。
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