Research progress of hyperhomocysteinemia in inducing neural tube defects

SHEN Fu-hui; YIN Li-qin; WANG Fan

doi:10.11852/zgetbjzz2022-1140

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Chinese Journal of Child Health Care ›› 2023, Vol. 31 ›› Issue (2) : 176-179. DOI: 10.11852/zgetbjzz2022-1140

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Research progress of hyperhomocysteinemia in inducing neural tube defects

SHEN Fu-hui, YIN Li-qin, WANG Fan

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Abstract

Neural tube defects (NTDs) are one of the most common central nervous system defects in newborns. Neural plate development, neural plate shape, neural plate curling, and nerve fold fusion are the four stages of neural tube closure, where genetic and environmental risk factors are involved. Through oxidative stress, Ca²⁺ overload, and a decreased S-adenosyl methionine(SAM)/S-adenosylhomocysteine(SAH) ratio, hyperhomocysteinemia(HHcy) causes overall DNA hypomethylation in the embryo, which results in high expression of genes involved in neural tube closure through histone modifications, gene polymorphisms, and methionine synthetase(MTR), as well as the activation of related signaling pathways(such as the Wnt/β-catenin signaling pathway and the PI3K/AKT signaling pathway), impairing the proper development of the neural tube, upsetting the equilibrium between cell proliferation and apoptosis, ultimately resulting in NTDs. Using data from earlier studies, this review strengthens the correlation between HHcy and NTDs, offers a theoretical framework for clinical NTD diagnosis and prevention, and goes into greater detail about the aforementioned pathways and their connection to HHcy.

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neural tube defects / hyperhomocysteinemia / DNA methylation / oxidative stress

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SHEN Fu-hui, YIN Li-qin, WANG Fan. Research progress of hyperhomocysteinemia in inducing neural tube defects[J]. Chinese Journal of Child Health Care. 2023, 31(2): 176-179 https://doi.org/10.11852/zgetbjzz2022-1140

References

[1] Yang X, Zeng J, Gu Y, et al. Birth defects data from hospital-based birth defect surveillance in Guilin, China, 2018-2020[J]. Front Public Health, 2022, 10:961613.
[2] Xiang Y, Zhao Q, Wang N, et al. Association of obesity with the risk of hyperhomocysteinemia among the Chinese community residents:A prospective cohort study in Shanghai, China[J]. Nutrients, 2021, 13(10):3648.
[3] Blachier F, Andriamihaja M, Blais A. Sulfur-containing amino acids and lipid metabolism[J]. J Nutr, 2020, 150(Suppl 1):2524-2531.
[4] Naninck EFG, Stijger PC, Brouwer-Brolsma EM. The importance of maternal folate status for brain development and function of offspring[J]. Adv Nutr, 2019, 10(3):502-519.
[5] Froese DS, Fowler B, Baumgartner MR. Vitamin B12, folate, and the methionine remethylation cycle-biochemistry, pathways, and regulation[J]. J Inherit Metab Dis, 2019, 42(4):673-685.
[6] Isaković J, Šimunić I, Jagečić D, et al. Overview of neural tube defects:Gene-environment interactions, preventative approaches and future perspectives[J]. Biomedicines, 2022, 10(5):965.
[7] Henderson AM, Aleliunas RE, Loh SP, et al. 1-5-Methyltetrahydrofolate supplementation increases blood folate concentrations to a greater extent than folic acid supplementation in malaysian women[J]. J Nutr, 2018, 148(6):885-890.
[8] Kohlrausch FB, Berteli TS, Wang F, et al. Control of LINE-1 expression maintains genome integrity in germline and early embryo development[J]. Reprod Sci, 2022, 29(2):328-340.
[9] Baloula V, Fructuoso M, Kassis N, et al. Homocysteine-lowering gene therapy rescues signaling pathways in brain of mice with intermediate hyperhomocysteinemia[J]. Redox Biol, 2018, 19:200-209.
[10] Lin S, Ren A, Wang L, et al. Aberrant methylation of Pax3 gene and neural tube defects in association with exposure to polycyclic aromatic hydrocarbons[J]. Clin Epigenetics, 2019, 11(1):13.
[11] Wang R, Han ZJ, Song G, et al. Homocysteine-induced neural tube defects in chick embryos via oxidative stress and DNA methylation associated transcriptional down-regulation of miR-124[J]. Toxicol Res (Camb), 2021, 10(3):425-435.
[12] Perla-Kajan J, Jakubowski H. Dysregulation of epigenetic mechanisms of gene expression in the pathologies of hyperhomocysteinemia[J]. Int J Mol Sci, 2019, 20(13):3140.
[13] Pizzorusso T, Tognini P. Interplay between metabolism, nutrition and epigenetics in shaping brain DNA methylation, neural function and behavior[J]. Genes (Basel), 2020, 11(7):742.
[14] Mei X, Qi D, Zhang T, et al. Inhibiting MARSs reduces hyperhomocysteinemia-associated neural tube and congenital heart defects[J]. EMBO Mol Med, 2020, 12(3):e9469.
[15] Yan Y, Wang G, Luo X, et al. Endoplasmic reticulum stress-related calcium imbalance plays an important role on Zinc oxide nanoparticles-induced failure of neural tube closure during embryogenesis[J]. Environ Int, 2021, 152:106495.
[16] Fofou-Caillierez MB, Gueant-Rodriguez RM, Alberto JM, et al. Vitamin B-12 and liver activity and expression of methionine synthase are decreased in fetuses with neural tube defects[J]. Am J Clin Nutr, 2019, 109(3):674-683.
[17] Rossokha Z, Fishchuk L, Vorobei L, et al. Hyperhomocysteinemia in men and women of married couples with reproductive disorders. What is the difference?[J]. Syst Biol Reprod Med, 2022:1-11.
[18] Senousy SM, Farag MK, Gouda AS, et al. Association between biomarkers of vitamin B12 status and the risk of neural tube defects[J]. J Obstet Gynaecol Res, 2018, 44(10):1902-1908.
[19] Kucha W, Seifu D, Tirsit A, et al. Folate, vitamin B12, and homocysteine levels in women with neural tube defect-affected pregnancy in Addis Ababa, Ethiopia[J]. Front Nutr, 2022, 9:873900.
[20] Zhang Q, Bai B, Mei X, et al. Elevated H3K79 homocysteinylation causes abnormal gene expression during neural development and subsequent neural tube defects[J]. Nat Commun, 2018, 9(1):3436.
[21] Wan C, Liu X, Bai B, et al. Regulation of the expression of tumor necrosis factorrelated genes by abnormal histone H3K27 acetylation:Implications for neural tube defects[J]. Mol Med Rep, 2018, 17(6):8031-8038.
[22] Gray de Cristoforis A, Ferrari F, Clotman F, et al. Differentiation and localization of interneurons in the developing spinal cord depends on DOT1L expression[J]. Mol Brain, 2020, 13(1):85.
[23] Bai B, Zhang Q, Wan C, et al. CBP/p300 inhibitor C646 prevents high glucose exposure induced neuroepithelial cell proliferation[J]. Birth Defects Res, 2018, 110(14):1118-1128.
[24] Yu J, Wang L, Pei P, et al. Reduced H3K27me3 leads to abnormal Hox gene expression in neural tube defects[J]. Epigenetics Chromatin, 2019, 12(1):76.
[25] Cai CQ, Fang YL, Shu JB, et al. Association of neural tube defects with maternal alterations and genetic polymorphisms in one-carbon metabolic pathway[J]. Ital J Pediatr, 2019, 45(1):37.
[26] Jones P, Lucock M, Martin C, et al. Independent and interactive influences of environmental UVR, Vitamin D levels, and folate variant MTHFD1-rs2236225 on homocysteine levels[J]. Nutrients, 2020, 12(5):1455.
[27] Leng S, Zhao A, Zhang J, et al. Methylenetetrahydrofolate reductase gene C677T polymorphism-dietary pattern interaction on hyperhomocysteinemia in a Chinese population:A cross-sectional study[J]. Front Cardiovasc Med, 2021, 8:638322.
[28] Chen L, Chen H, Wang X, et al. Association of homocysteine with IVF/ICSI outcomes stratified by MTHFR C677T polymorphisms:A prospective cohort study[J]. Reprod Biomed Online, 2021, 43(1):52-61.