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Effects of lead exposure on d-serine metabolism in the hippocampus of mice at the early developmental stages

Yu, Haiyang, Li, Tingting, Cui, Yan, Liao, Yingjun, Wang, Gaoyang, Gao, Lanyue, Zhao, Fenghong, Jin, Yaping
Toxicology 2014 v.325 pp. 189-199
Western blotting, cysteine, developmental stages, drinking water, gene expression, hippocampus, lead, lead acetate, memory, messenger RNA, mice, neurotoxicity, pregnancy, progeny, protein synthesis, quantitative polymerase chain reaction, reverse transcriptase polymerase chain reaction, serine
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 2.0g/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 0.5g/L lead exposure, and the spatial memory ability tested by probe trail could be impaired by 1.0g/L lead exposure. Exposure to 2.0g/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 0.5g/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 1.0g/L lead exposure since PND 10, and by 0.5g/L lead exposure since PND 20. Noteworthy, the protein expression of NR2B was inhibited significantly by 0.5g/L lead exposure in PND 10 mice, and by 1.0g/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.