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Inositol is closely related to the occurrence of neural tube defects (NTDs). Inositol 1, 3, 4-trisphosphate 5/6-kinase (ITPK1) gene encoded an essential regulatory enzyme ITPK1, which is involved in inositol metabolism and has a critical role in the development of neural tube and axial mesoderm. It had been reported that some polymorphisms of critical genes in inositol pathways, including ITPK1, were associated with NTDs in Chinese pregnant women; however, the association between fetus ITPK1 polymorphisms and NTDs had not been reported. In a high incidence of NTDs region of China, a case–control study was performed to evaluate the association between fetal ITPK1 polymorphisms and NTDs. The ITPK1 polymorphisms were genotyped by iPLEX® Gold assay. Inositol levels in fetus brain tissues were analyzed. Three genetic polymorphisms of fetus ITPK1's, including rs3818175, rs2295394, and rs4586354, were statistically associated with spina bifida (NTD subtypes). A higher risk of spina bifida was associated with genotype GG of rs3818175, genotype CC of rs4586354, and genotype TT of rs2295394 (OR = 2.66, 95% CI [1.17–6.05], P = 0.017; OR = 2.22, 95% CI [1.02–4.80], P = 0.041; and OR = 2.33, 95% CI [1.00–5.48], P = 0.047), when compared with the other wild-type genotypes CC, TT, and CC, respectively. Decreased brain inositol level was found in NTDs fetuses, compared to normal controls. Inositol levels were found to significantly decrease with rs2295394 (CC genotype), rs4586354 (TT genotype), and rs3818175 (GC genotype) (P < 0.05). The polymorphisms of fetus ITPK1 were associated with the incidence of NTDs and might be a genetic risk factor for spina bifida. [ABSTRACT FROM AUTHOR]

Chemotherapeutic agents such as methotrexate (MTX), raltitrexed (RTX), 5-fluorouracil (5-FU), hydroxyurea (HU), and retinoic acid (RA), and valproic acid (VPA), an antiepileptic drug, all can cause malformations in the developing central nervous system (CNS), such as neural tube defects (NTDs). However, the common pathogenic mechanisms remain unclear. This study aimed to explore the mechanisms of NTDs caused by MTX, RTX, 5-FU, HU, RA, and VPA (MRFHRV), based on network pharmacology and molecular biology experiments. The MRFHRV targets were integrated with disease targets, to find the potential molecules related to MRFHRV-induced NTDs. Protein–protein interaction analysis and molecular docking were performed to analyze these common targets. Utilizing the kyoto encyclopedia of genes and genomes (KEGG) signaling pathways, we analyzed and searched the possible causative pathogenic mechanisms by crucial targets and the signaling pathway. Results showed that MRFHRV induced NTDs through several key targets (including TP53, MAPK1, HSP90AA1, ESR1, GRB2, HDAC1, EGFR, PIK3CA, RXRA, and FYN) and multiple signaling pathways such as PI3K/Akt pathway, suggesting that abnormal proliferation and differentiation could be critical pathogenic contributors in NTDs induced by MRFHRV. These results were further validated by CCK8 assay in mouse embryonic stem cells and GFAP staining in embryonic brain tissue. This study indicated that chemotherapeutic and antiepileptic agents induced NTDs might through predicted targets TP53, MAPK1, GRB2, HDAC1, EGFR, PIK3CA, RXRA, and FYN and multiple signaling pathways. More caution was required for the clinical administration for women with childbearing potential and pregnant. [ABSTRACT FROM AUTHOR]

Apurinic/apyrimidinic endonuclease 1/redox-factor 1 (APE1/Ref-1) gene encodes a multifunctional protein involved in the DNA base excision repair (BER) pathway, which initiates repair of apurinic/apyrimidinic (AP) sites in DNA by catalyzing hydrolytic incision of the phosphodiester backbone. APE1/Ref-1 polymorphisms are related to the occurrence of neural tube defects (NTDs), but the association between APE1/Ref-1 polymorphisms and NTDs is not reported in Chinese Han population. The aim of the present study was to evaluate the association of APE1/Ref-1 polymorphism and the risk of NTD occurrence for Han population in a high-risk area of China. APE1/Ref-1 genotypes were determined by iPLEX Gold SNP genotyping. AP sites and folate level of brain tissues were measured. The results showed that three polymorphisms (rs3136817, rs77794916, and rs1760944) of APE1/Ref-1 were statistically associated with NTD subtypes. Allele C of rs3136817, allele T of rs77794916, and allele G of rs1760944 were associated with an increased risk for encephalocele (OR = 2.52, 95% CI [1.25–5.07], P < 0.01; OR = 1.80, 95% CI [1.04–3.12], P = 0.04; and OR = 1.96, 95% CI [1.12–3.45], P = 0.02), compared with those harboring the alleles T, C, and T, respectively. The folate level in NTDs was lower than that in controls. DNA AP sites in the encephalocele were significantly higher than the control (P < 0.01). The three polymorphisms of APE1/Ref-1 were significantly related to NTD occurrence, which indicated that APE1/Ref-1 might be a potential genetic risk factor for encephalocele in a high-risk area of NTDs in China. [ABSTRACT FROM AUTHOR]