Homocysteine Oxidation and Apoptosis: A Potential Cause of Cleft Palate

Knott, Lynda; Hartridge, Tom; Brown, Nathan; Mansell, Jason P.; Sandy, JR

doi:10.1290/1543-706x(2003)039<0098:hoaaap>2.0.co;2

Cited by 24 publications

(12 citation statements)

References 51 publications

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“…In these cases, high homocysteine levels in the embryo may disrupt the normal palate development, which might be through apoptosis induced by oxidative stress. 43,44 Therefore, based on the data reported here, it is reasonable to speculate that slightly higher maternal homocysteine levels might be teratogenic possibly depending on the fetus genotype and fetal BCL3 gene expression might be regulated by the homocysteine metabolic pathway.…”

Section: Gene -Gene Interactionsmentioning

confidence: 70%

Maternal MTHFR interacts with the offspring's BCL3 genotypes, but not with TGFA, in increasing risk to nonsyndromic cleft lip with or without cleft palate

et al. 2004

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The 677 C-T polymorphism in the 5-10 methylenetetrahydrofolate reductase (MTHFR) gene has been associated with nonsyndromic cleft lip with or without cleft palate (CL/P) in some populations, but not others. Previous studies (ie, case-control and transmission disequilibrium tests (TDT)) in Brazilian families with CL/P have been unable to replicate this putative association. However, our group observed a lower proportion of CT heterozygotes among the mothers of CL/P probands, suggesting that the maternal genotype for this polymorphism might influence predisposition to CL/P. In order to further examine this issue, we performed a case-control study of the 677 C-T/MTHFR polymorphism in families with CL/P ascertained in two regions of Brazil: 172 from São Paulo (SP) and 252 from Ceará (CE). The control samples included 243 individuals from SP and 401 from CE. TDT was carried out in 102 patients with CL/P and their parents. No evidence of an association was observed between the 677 C-T/MTHFR polymorphism and CL/P using the case-control design, while borderline significance was obtained with the TDT (P ¼ 0.055). We have also looked for an interaction between maternal MTHFR genotypes and the propositi offspring's genotypes at two candidate susceptibility loci for CL/P, TGFA and BCL3. Interestingly, we observed an interaction between the maternal MTHFR and offspring's BCL3 genotypes (OR: 2.3; 95% CI: 1.1 -4.8; P ¼ 0.03) but not with the offspring's TGFA genotypes. Therefore, our results reinforce the idea that the maternal MTHFR genotype plays a significant role in susceptibility to CL/P, but its teratogenic effect depends on the genotype of the offspring.

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Section: Gene -Gene Interactionsmentioning

confidence: 70%

Maternal MTHFR interacts with the offspring's BCL3 genotypes, but not with TGFA, in increasing risk to nonsyndromic cleft lip with or without cleft palate

et al. 2004

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“…Deficient folate levels in the mother result in elevated homocysteine levels. Homocysteine induced oxidative stress has been proposed as a potential factor for causing apoptosis and disrupting palate development and causing cleft palate [166]. Oxidative stress mediated damage of the macromolecules has been proposed as a mechanism of thalidomide induced embryopathy and other embryopathies [167,168].…”

Section: Reviewmentioning

confidence: 99%

Role of oxidative stress in female reproduction

Agarwal

Gupta

Sharma

2005

Reprod Biol Endocrinol

1,216

500

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In a healthy body, ROS (reactive oxygen species) and antioxidants remain in balance. When the balance is disrupted towards an overabundance of ROS, oxidative stress (OS) occurs. OS influences the entire reproductive lifespan of a woman and even thereafter (i.e. menopause). OS results from an imbalance between prooxidants (free radical species) and the body's scavenging ability (antioxidants). ROS are a double-edged sword -they serve as key signal molecules in physiological processes but also have a role in pathological processes involving the female reproductive tract. ROS affect multiple physiological processes from oocyte maturation to fertilization, embryo development and pregnancy. It has been suggested that OS modulates the age-related decline in fertility. It plays a role during pregnancy and normal parturition and in initiation of preterm labor. Most ovarian cancers appear in the surface epithelium, and repetitive ovulation has been thought to be a causative factor. Ovulationinduced oxidative base damage and damage to DNA of the ovarian epithelium can be prevented by antioxidants. There is growing literature on the effects of OS in female reproduction with involvement in the pathophsiology of preeclampsia, hydatidiform mole, free radical-induced birth defects and other situations such as abortions. Numerous studies have shown that OS plays a role in the pathoysiology of infertility and assisted fertility. There is some evidence of its role in endometriosis, tubal and peritoneal factor infertility and unexplained infertility. This article reviews the role OS plays in normal cycling ovaries, follicular development and cyclical endometrial changes. It also discusses OS-related female infertility and how it influences the outcomes of assisted reproductive techniques. The review comprehensively explores the literature for evidence of the role of oxidative stress in conditions such as abortions, preeclampsia, hydatidiform mole, fetal embryopathies, preterm labour and preeclampsia and gestational diabetes. The review also addresses the growing literature on the role of nitric oxide species in female reproduction. The involvement of nitric oxide species in regulation of endometrial and ovarian function, etiopathogenesis of endometriosis, and maintenance of uterine quiescence, initiation of labour and ripening of cervix at parturition is discussed. Complex interplay between cytokines and oxidative stress in the etiology of female reproductive disorders is discussed. Oxidant status of the cell modulates angiogenesis, which is critical for follicular growth, corpus luteum formation endometrial differentiation and embryonic growth is also highlighted in the review. Strategies to overcome oxidative stress and enhance fertility, both natural and assisted are delineated. Early interventions being investigated for prevention of preeclampsia are enumerated. Trials investigating combination intervention strategy of vitamin E and vitamin C supplementation in preventing preeclampsia are highlighted. Antioxidants are ...

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“…9 for review). In the progeny, hHCY has been associated with fetal death (10), premature birth (11), intrauterine growth retardation (12), neural tube defects (13), craniofacial anomalies (14), cardiac malformation (15), and hepatic steatosis (16).…”

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confidence: 99%

Mild Neonatal Hypoxia Exacerbates the Effects of Vitamin-Deficient Diet on Homocysteine Metabolism in Rats

et al. 2005

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Elevated plasma homocysteine has been linked to pregnancy complications and developmental diseases. Whereas hyperhomocysteinemia is frequently observed in populations at risk of malnutrition, hypoxia may alter the remethylation of homocysteine in hepatocytes. We aimed to investigate the combined influences of early deficiency in nutritional determinants of hyperhomocysteinemia and of neonatal hypoxia on homocysteine metabolic pathways in developing rats. Dams were fed a standard diet or a diet deficient in vitamins B12, B2, folate, month, and choline from 1 mo before pregnancy until weaning of the offspring. The pups were divided into four treatment groups corresponding to "no hypoxia/standard diet," "hypoxia (100% N2 for 5 min at postnatal d 1)/standard diet," "no hypoxia/ deficiency," and "hypoxia/deficiency," and homocysteine metabolism was analyzed in their liver at postnatal d 21. Hypoxia increased plasma homocysteine in deficient pups (21.2 Ϯ 1.6 versus 13.3 Ϯ 1.2 M, p Ͻ 0.05). Whereas mRNA levels of cystathionine ␤-synthase remained unaltered, deficiency reduced the enzyme activity (48.7 Ϯ 2.9 versus 83.6 Ϯ 6.3 nmol/h/mg, p Ͻ 0.01), an effect potentiated by hypoxia (29.4 Ϯ 4.7 nmol/h/mg, p Ͻ 0.05). The decrease in methylene-tetrahydrofolate reductase activity measured in deficient pups was attenuated by hypoxia (p Ͻ 0.05), and methionine-adenosyltransferase activity was slightly reduced only in the "hypoxia/deficiency" group (p Ͻ 0.05). Finally, hypoxia enhanced the deficiency-induced drop of the S-adenosylmethionine/S-adenosylhomocysteine ratio, which is known to influence DNA methylation and gene expression. In conclusion, neonatal hypoxia may increase homocysteinemia mainly by decreasing homocysteine transsulfuration in developing rats under methyl-deficient regimen. Plasma accumulation of HCY is known to be linked to cardiovascular diseases and ageing-associated disabilities (1-3). Moderate hHCY can arise from genetic determinants (4,5) but is also frequently related to dietary deficiency in vitamins B12, B2, and folate. In newborns, the risk of hHCY is closely related to elevated maternal HCY concentrations during pregnancy, which is determined by the status of B vitamins (6 -8).A strong relationship has been documented between HCY accumulation and pregnancy complications, including recurrent miscarriages, preeclampsia, and placenta abruption (see Ref. 9 for review). In the progeny, hHCY has been associated with fetal death (10), premature birth (11), intrauterine growth retardation (12), neural tube defects (13), craniofacial anomalies (14), cardiac malformation (15), and hepatic steatosis (16).HCY production involves the demethylation of methionine, and, under normal conditions, is essentially regulated in the liver. As summarized in Figure 1, it originates from the hydrolysis of SAH, a product of transmethylation reactions through SAM, and is metabolized via two pathways of remethylation and one pathway of transsulfuration. HCY metabolism strongly depends on the nutritional intake of B vitamins,

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Homocysteine Oxidation and Apoptosis: A Potential Cause of Cleft Palate

Cited by 24 publications

References 51 publications

Maternal MTHFR interacts with the offspring's BCL3 genotypes, but not with TGFA, in increasing risk to nonsyndromic cleft lip with or without cleft palate

Maternal MTHFR interacts with the offspring's BCL3 genotypes, but not with TGFA, in increasing risk to nonsyndromic cleft lip with or without cleft palate

Role of oxidative stress in female reproduction

Mild Neonatal Hypoxia Exacerbates the Effects of Vitamin-Deficient Diet on Homocysteine Metabolism in Rats

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