Abstract
Background
Lithium carbonate (Li2CO3) is widely used in the treatment of clinical-affective psychosis. Exposure to Li2CO3 during pregnancy increases the risk of neural tube defects (NTDs) in offspring, which are severe birth defects of the central nervous system. The mechanism of Li2CO3-induced NTDs remains unclear.
Methods
C57BL/6 mice were injected with different doses of Li2CO3 intraperitoneally on gestational day 7.5 (GD7.5), and embryos collected at GD11.5 and GD13.5. The mechanisms of Li2CO3 exposure-induced NTDs were determined utilizing immunohistochemistry, western blotting, EdU imaging, enzymatic method, gas chromatography-mass spectrometry (GC-MS), ELISA and HE staining.
Results
The NTDs incidence was 33.7% following Li2CO3 exposure. Neuroepithelial cell proliferation and phosphohistone H3 level were significantly increased in NTDs embryos, compared with control group (P < 0.01), while the expressing levels of p53 and caspase-3 were significantly decreased. IMPase and GSK-3β activity was inhibited in Li2CO3-treated maternal and embryonic neural tissues (P < 0.01 and P < 0.05, respectively), along with decreased levels of inositol and metabolites, compared with control groups (P < 0.01).
Conclusions
Lithium-induced NTDs model in C57BL/6 mice was established. Enhanced cell proliferation and decreased apoptosis following lithium exposure were closely associated with the impairment of inositol biosynthesis, which may contribute to lithium-induced NTDs.
Impact
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Impairment of inositol biosynthesis has an important role in lithium exposure-induced NTDs in mice model.
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Lithium-induced NTDs model on C57BL/6 mice was established. Based on this NTDs model, lithium-induced impairment of inositol biosynthesis resulted in the imbalance between cell proliferation and apoptosis, which may contribute to lithium-induced NTDs.
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Providing evidence to further understand the molecular mechanisms of lithium-induced NTDs and enhancing its primary prevention.
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Acknowledgements
We appreciate the help offered by Dr. Xiaodai Cui, Prof. Jing Pan and Mr. Yunsong Lyu during the process. This study was supported by the National Key Research and Development Program of China (2018YFC10025002), The Joint Foundation Program of Beijing Municipal Natural Science Foundation and Beijing Municipal Education Commission (KZ201810028045), Beijing Natural Science Foundation (7172038, 7174285), National Natural Science Foundation of China (No. 81571443, 81801451, 81600984, 81701441), Research Foundation of Capital Institute of Pediatrics (FX-2018-05, PY-2018-03).
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S.L. and D.L. developed the concepts, study design, obtained grant funding from J.G. and J.W. T.Z., B.N., F.Z. and R.Z. were also associated in concepts. S.L. and D.L. performed animal studies for data and image acquisition. S.L., H.Y., T.G. performed data analysis and GSK3β activity detection. S.L., X.W. and J.Q. developed Edu imaging analysis, IMPase activity and inositol level. S.L., Z.G., Y.Y. and J.L. performed immunohistochemistry, WB experiments and PIP2 detection. H.Y., Y.L., F.W. performed statistical analysis and interpretation. S.L. and D.L. performed data verification and interpretation. S.L. created figures and tables. S.L., D.L., J.G. and J.W. were involved with manuscript writing, editing, and approval of the final version.
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Li, S., Luo, D., Yue, H. et al. Neural tube defects: role of lithium carbonate exposure in embryonic neural development in a murine model. Pediatr Res 90, 82–92 (2021). https://doi.org/10.1038/s41390-020-01244-1
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DOI: https://doi.org/10.1038/s41390-020-01244-1
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