Orofacial clefts and spina bifida: N-acetyltransferase phenotype,maternal smoking,and medication use

BACKGROUND: Orofacial clefts and spina bifida are midline defects with a multifactorial etiology. Maternal smoking and medication use periconceptionally have been studied as risk factors for these malformations. The biotransformation enzyme N-acetyltransferase 2 (NAT2), plays a part in the inactivation of toxic compounds in cigarette smoke and medication. We investigated maternal NAT2 phenotype and the interaction with smoking and medication use periconceptionally on orofacial cleft and spina bifida risk in offspring. METHODS: In this case-control study of 45 mothers of orofacial cleft children, 39 mothers of spina bifida children and 73 control mothers, NAT2 acetylator status was determined by measuring urinary caffeine metabolites. RESULTS: Slow NAT2 acetylators showed no increased risk for orofacial cleft (OR = 1.0, 95% CI: 0.4-2.3) or spina bifida offspring (OR = 0.7, 95% CI: 0.3-1.7) compared to fast NAT2 acetylators. More mothers with orofacial cleft and spina bifida offspring smoked cigarettes (36% and 23% respectively) and used medication periconceptionally (38% and 44% respectively) compared to control mothers (smoking:18%, medication use:19%). No interaction between maternal NAT2 acetylator status and smoking or medication use was observed for orofacial cleft and spina bifida risk. CONCLUSIONS: Maternal smoking and medication use is associated with orofacial cleft risk as well as medication use is with spina bifida. The maternal NAT2 acetylator status, however, was not associated with an increased risk for orofacial cleft or spina bifida offspring, nor in combination with periconceptional smoking or medication use.     

Anencephaly and spina bifida among Hispanics: Maternal,sociodemographic, and acculturation factors in the National Birth Defects Prevention Study

BACKGROUND : We used data from the multisite National Birth Defects Prevention Study for expected delivery dates from October 1997 through 2003, to determine whether the increased risk in anencephaly and spina bifida (neural tube defects (NTDs)) in Hispanics was explained by selected sociodemographic, acculturation, and other maternal characteristics. METHODS : For each type of defect, we examined the association with selected maternal characteristics stratified by race/ethnicity and the association with Hispanic parents' acculturation level, relative to non‐Hispanic whites. We used logistic regression and calculated crude odds ratios (ORs) and their 95% confidence intervals (CIs). RESULTS : Hispanic mothers who reported the highest level of income were 80% less likely to deliver babies with spina bifida. In addition, highly educated Hispanic and white mothers had 76 and 35% lower risk, respectively. Other factors showing differing effects for spina bifida in Hispanics included maternal age, parity, and gestational diabetes. For spina bifida there was no significant elevated risk for U.S.–born Hispanics, relative to whites, but for anencephaly, corresponding ORs ranged from 1.9 to 2.3. The highest risk for spina bifida was observed for recent Hispanic immigrant parents from Mexico or Central America residing in the United States <5 years (OR = 3.28, 95% CI = 1.46–7.37). CONCLUSIONS : Less acculturated Hispanic parents seemed to be at highest risk of NTDs. For anencephaly, U.S.–born and English‐speaking Hispanic parents were also at increased risk. Finally, from an etiologic standpoint, spina bifida and anencephaly appeared to be etiologically heterogeneous from these analyses. Birth Defects Research (Part A), 2009. © 2009 Wiley‐Liss, Inc.     

Association between maternal COMT gene polymorphisms and fetal neural tube defects risk in a Chinese population

Maternal tea consumption was reported to increase the risk of fetal neural tube defects (NTDs). Catechol‐O‐methyltransferase (COMT) may be involved in the metabolism of polyphenolic methylation of tea, thus influence the risk of fetal NTDs. Methods: A total of 576 fetuses or newborns with NTDs and 594 healthy newborns were included in the case–control study. Information on maternal tea consumption, sociodemographic characteristics, reproductive history, and related behavior was collected through face‐to‐face interviews. Maternal blood samples were collected to examine polymorphisms in COMT, and the possible interaction of COMT and tea consumption was analyzed. RESULTS: After controlling for potential confounders, homozygotes of rs737865 showed an elevated risk for total NTDs (odds ratio [OR] = 2.04, 95% confidence interval [CI], 1.24–3.35) and for the anencephaly subtype (OR = 1.99, 95% CI, 1.17–3.39). The CC genotype of rs4633 was positively associated with the overall risk of NTDs (OR = 3.66, 95% CI, 1.05–12.83). Heterozygotes for rs4680 were associated with a decreased risk of spina bifida (OR = 0.71, 95% CI, 0.51–0.98). The COMT rs4680 A allele was negatively related with the risk of spina bifida, with adjusted OR = 0.64 (95% CI, 0.45–0.89). An interaction between tea consumption (1 to 2 cups/day) and the rs4680AA/AG genotype was found in the spina bifida subtype (P_interaction = .08). Conclusion: Several COMT variants were associated with elevated risk of NTDs in a Chinese population. Maternal tea consumption may be associated with an increased risk for fetal NTDs in genetically susceptible subgroups. Birth Defects Research (Part A) 100:22–29, 2014. © 2013 Wiley Periodicals, Inc.     

Porting the synthetic D‐glucaric acid pathway from Escherichia coli to Saccharomyces cerevisiae

D‐Glucaric acid can be produced as a value‐added chemical from biomass through a de novo pathway in Escherichia coli. However, previous studies have identified pH‐mediated toxicity at product concentrations of 5 g/L and have also found the eukaryotic myo‐inositol oxygenase (MIOX) enzyme to be rate‐limiting. We ported this pathway to Saccaromyces cerevisiae, which is naturally acid‐tolerant and evaluate a codon‐optimized MIOX homologue. We constructed two engineered yeast strains that were distinguished solely by their MIOX gene – either the previous version from Mus musculus or a homologue from Arabidopsis thaliana codon‐optimized for expression in S. cerevisiae – in order to identify the rate‐limiting steps for D‐glucaric acid production both from a fermentative and non‐fermentative carbon source. myo‐Inositol availability was found to be rate‐limiting from glucose in both strains and demonstrated to be dependent on growth rate, whereas the previously used M. musculus MIOX activity was found to be rate‐limiting from glycerol. Maximum titers were 0.56 g/L from glucose in batch mode, 0.98 g/L from glucose in fed‐batch mode, and 1.6 g/L from glucose supplemented with myo‐inositol. Future work focusing on the MIOX enzyme, the interplay between growth and production modes, and promoting aerobic respiration should further improve this pathway.     

Maternal genetic effects,exerted by genes involved in homocysteine remethylation,influence the risk of spina bifida

There is currently considerable interest in the relationship between variation in genes that are involved in the folate-homocysteine metabolic axis and the risk of spina bifida. The evaluation of this relationship is, however, complicated by the potential involvement of both the maternal and the embryonic genotype in determination of disease risk. The present study was designed to address questions regarding both maternal and embryonic genetic risk factors for spina bifida by use of the two-step transmission/disequilibrium test. Analysis of data on variants of two genes involved in homocysteine remethylation/methionine biosynthesis--methionine synthase (MTR) A2756G and methionine synthase reductase (MTRR) A66G--provided evidence that both variants influence the risk of spina bifida via the maternal rather than the embryonic genotype. For both variants, the risk of having a child with spina bifida appears to increase with the number of high-risk alleles in the maternal genotype: MTR (R1=2.16, 95% CI 0.92-5.06; R2=6.58, 95% CI 0.87-49.67) and MTRR (R1=2.05, 95% CI 1.05-3.99; R2=3.15, 95% CI 0.92-10.85). These findings highlight the importance of considering both the maternal and embryonic genotype when evaluating putative spina bifida susceptibility loci.     

Polymorphisms of the 5,10-methylenetetrahydrofolate and the methionine synthase reductase genes as independent risk factors for spina bifida

We analyzed the role of the C677T polymorphism of the 5,10-methylenetetrahydrofolate and the A66G polymorphism of the methionine synthase reductase genes as risk factors for occurrence of spina bifida. The studied population included 106 mothers and 104 children from affected families, and a control group of 100 adults. We found statistically significant differences between the occurrence of the homozygosity in these polymorphisms in the groups of mothers and children with thoracolumbal defects (C677T polymorphism) and lumbosacral defects (A66G polymorphism). We postulate that these polymorphisms should be regarded as independent risk factors for spina bifida.     

Maternal BMI and country of birth as indicators of childhood obesity in children of Mexican origin

Objective: The goal of this study was to evaluate the relationship between maternal and childhood BMI at baseline in a group of 5‐ to 18‐year‐old children and their mothers, all of whom were of Mexican origin, low socioeconomic status, and enrolled in a cohort study in Houston, TX. Research Methods and Procedures: Using data from 438 mother‐child dyads residing in the same household, we completed logistic regression analyses to determine maternal factors associated with the child being overweight or at‐risk‐for‐overweight, after adjusting for the child's gender, age, and level of physical activity and other maternal confounders. Results: Almost one‐half of the boys and girls (47% and 44%, respectively) were either overweight or at‐risk‐for‐overweight. Obese mothers were twice as likely to have an overweight and/or at‐risk‐for‐overweight child compared with normal‐weight mothers. Women born in the U.S. were twice as likely to have an overweight and/or at‐risk‐for‐overweight child compared with women born in Mexico. In addition, women with less than a high school education were twice as likely to have an overweight child compared with their more educated peers. Discussion: The high prevalence of overweight or at‐risk‐for‐overweight among Mexican‐origin children of low socioeconomic status suggests a continued need to develop and implement culturally sensitive preventive interventions for this minority population. Our data also suggest a need to tailor such interventions particularly for children of obese mothers and those born in the U.S.     

Spina bifida phenotypes in infants or fetuses of obese mothers

BACKGROUND: A twofold or greater risk of neural tube defect (NTD)-affected pregnancy has been associated with prepregnant obesity, where obesity was defined as body mass index (BMI) of >29 kg/m(2). Risks have been more elevated for spina bifida than for anencephaly. METHODS: We investigated whether finer phenotypic classifications of spina bifida, in combination with other factors, were associated with a BMI of >29 kg/m(2). Data were derived from a case-control study of fetuses and infants with NTDs among 1989-1991 California births. Interviews were conducted with mothers of 277 spina bifida cases and 517 nonmalformed controls. RESULTS: Women with a BMI of >29 kg/m(2) compared with those 29 kg/m(2) compared with males whose mothers were 相似文献   

Plasma zinc concentrations of mothers and the risk of oral clefts in their children in Utah

BACKGROUND: The role of maternal zinc nutrition in human oral clefts (OCs) is unclear. We measured plasma zinc concentrations (PZn) of case and control mothers to evaluate the associations between PZn and risk of OCs with and without other malformations. METHODS: Case mothers were ascertained by the Utah Birth Defects Network and control mothers were selected from Utah birth certificates by matching for child gender and delivery month and year. Maternal blood was collected >1 year after the last pregnancy. PZn was available for 410 case mothers who were divided into four subgroups: isolated cleft lip with or without cleft palate (CL/P‐I, n = 231), isolated cleft palate (CP‐I, n = 74), CL/P with other malformations (CLP‐M, n = 42), and CP with other malformations (CP‐M, n = 63). PZn was available for 447 control mothers. The mean age of children at blood sampling was 3.7 years for all cases combined and 4.3 years for controls. RESULTS: Mean PZns of all groups were similar, and low PZn (<11.0 μmol/L) was found in 59% of cases and 62% of controls. Risk of OCs did not vary significantly across PZn quartiles for the four subgroups individually and all OC groups combined. CONCLUSIONS: We previously reported that poor maternal zinc status was a risk factor for OCs in the Philippines, where OC prevalence is high and maternal PZn is low. In Utah, however, no such association was found, suggesting that poor maternal zinc status may become a risk factor only when zinc status is highly compromised. Birth Defects Research (Part A), 2009. © 2008 Wiley‐Liss, Inc.     

Altered neurochemical profile in the McGill‐R‐Thy1‐APP rat model of Alzheimer's disease: a longitudinal in vivo 1H MRS study

We investigated metabolite levels during the progression of pathology in McGill‐R‐Thy1‐APP rats, a transgenic animal model of Alzheimer's disease, and in healthy age‐matched controls. Rats were subjected to in vivo ¹H magnetic resonance spectroscopy (MRS) of the dorsal hippocampus at age 3, 9 and 12 months and of frontal cortex at 9 and 12 months. At 3 months, a stage in which only Aβ oligomers are present, lower glutamate, myo‐inositol and total choline content were apparent in McGill‐R‐Thy1‐APP rats. At age 9 months, lower levels of glutamate, GABA, N‐acetylaspartate and total choline and elevated myo‐inositol and taurine were found in dorsal hippocampus, whereas lower levels of glutamate, GABA, glutamine and N‐acetylaspartate were found in frontal cortex. At age 12 months, only the taurine level was significantly different in dorsal hippocampus, whereas taurine, myo‐inositol, N‐acetylaspartate and total creatine levels were significantly higher in frontal cortex. McGill‐R‐Thy1‐APP rats did not show the same changes in metabolite levels with age as displayed in the controls, and overall, prominent and complex metabolite differences were evident in this transgenic rat model of Alzheimer's disease. The findings also demonstrate that in vivo ¹H MRS is a powerful tool to investigate disease‐related metabolite changes in the brain.     

Additive Interactions of Maternal Prepregnancy BMI and Breast‐feeding on Childhood Overweight

Objective: To examine the interactions of maternal prepregnancy BMI and breast‐feeding on the risk of overweight among children 2 to 14 years of age. Research Methods and Procedures: The 1996 National Longitudinal Survey of Youth, Child and Young Adult data in the United States were analyzed (n = 2636). The weighted sample represented 51.3% boys, 78.0% whites, 15.0% blacks, and 7.0% Hispanics. Childhood overweight was defined as BMI ≥95th percentile for age and sex. Maternal prepregnancy obesity was determined as BMI ≥30 kg/m². The duration of breast‐feeding was measured as the weeks of age from birth when breast‐feeding ended. Results: After adjusting for potential confounders, children whose mothers were obese before pregnancy were at a greater risk of becoming overweight [adjusted odds ratio (OR), 4.1; 95% confidence interval (CI), 2.6, 6.4] than children whose mothers had normal BMI (<25 kg/m²; p < 0.001 for linear trend). Breast‐feeding for ≥4 months was associated with a lower risk of childhood overweight (OR, 0.6; 95% CI, 0.4, 1.0; p = 0.06 for linear trend). The additive interaction between maternal prepregnancy obesity and lack of breast‐feeding was detected (p < 0.05), such that children whose mothers were obese and who were never breast‐fed had the greatest risk of becoming overweight (OR, 6.1; 95% CI, 2.9, 13.1). Discussion: The combination of maternal prepregnancy obesity and lack of breast‐feeding may be associated with a greater risk of childhood overweight. Special attention may be needed for children with obese mothers and lack of breast‐feeding in developing childhood obesity intervention programs.     

A common ABCC2 promoter polymorphism is not a determinant of the risk of spina bifida

BACKGROUND: There is compelling evidence that the risk of spina bifida, a malformation of the caudal neural tube, is associated with maternal and/or embryonic disturbances in folate/homocysteine metabolism. Hence, functional variants of genes that influence folate/homocysteine metabolism constitute a biologically plausible group of candidate risk factors for spina bifida and other neural tube defects. One such candidate is ABCC2, the gene encoding ABCC2, (a.k.a. canalicular multispecific organic anion transporter [cMOAT], multidrug resistance related protein 2 [MRP2]), a member of the ABC transporter family that effluxes natural folates and anti-folate drugs such as methotrexate. METHODS: The association between the risk of spina bifida and both the maternal and embryonic ABCC2 C(-24)T genotype was evaluated by using the transmission disequilibrium test and log-linear modeling. RESULTS: These analyses provided no evidence that the risk of spina bifida was significantly related to either the maternal or embryonic ABCC2 C(-24)T genotype. CONCLUSIONS: The results of the present analyses suggest that the C(-24)T variant of the ABCC2 gene is not a major determinant of spina bifida risk.     

Developmental control of inositol phosphate biosynthesis is altered in the brain of both curly and phenotypically normal straight tail mutant mice

BACKGROUND : Altered levels of inositol phosphate in the central nervous system (CNS) are hypothesized to produce distorted brain signaling and lead to numerous neurologic maladies. Little is known of mechanisms controlling the complex metabolic flux of inositol phosphate. Less is known of controls that regulate inositol‐phosphate biosynthesis in the mammalian brain. The expression of 1L‐myo‐inositol?1 phosphate synthase (MIP), the only enzyme known to synthesize inositol phosphate, was studied in the brain of normal (CBA) and curly tail (CT) mutant mice. The CT strain exhibits a neural tube defect, spina bifida, responsive to inositol supplementation, but not to folic acid treatment. METHODS : Utilizing enzyme assays to determine the specific activity of MIP, Western blotting to detect expression, gas chromatography/mass spectrometry to measure inositol concentration, and statistical analyses to evaluate quantitative data, MIP expression was analyzed in newborn, young, and adult brains of CBA and CT (curly tail [ct‐CT] and straight tail [st‐CT]) mutant mice. RESULTS : Data analyses suggest there is a significant difference in MIP activity in the brain of CBA mice as compared to that of CT mutant mice and that temporal and spatial control of MIP expression and inositol concentrations are altered in the brain of both the ct‐CT and phenotypically normal st‐CT mutant. Moreover, two differentially expressed forms of MIP were identified in the adult mouse brain. CONCLUSIONS : These findings implicate a role for MIP in the maturation of the CNS and evoke a hypothesis regarding the regulation of inositol phosphate biosynthesis in brain development. Birth Defects Research (Part A), 2009. © 2009 Wiley‐Liss, Inc.     

Spina Bifida and Potatoes

The results of a retrospective survey of the dietetic and other habits of the mothers of 83 children with spina bifida (mostly schoolchildren with meningomyelocele) were compared with 85 carefully matched controls. The survey was particularly concerned with the consumption of or contact with potatoes by the mothers. No significant differences were found in the amount of potatoes eaten as reported by the mothers (mean for spina bifida group 3·60 1b (1630 g), and for controls 3·98 1b (1800 g) per week). Of the seven other comparisons associated with potatoes only one (obtaining them from the chip shop or restaurant) was significant, the mothers of the children with spina bifida being more likely to obtain some of them from this source.When examining other aspects of diet it was found that the mothers of spina bifida children reported a lower consumption of a number of important foods, though the deficiency was not significant in any instance. These mothers were also significantly more likely to have been prescribed drugs other than iron and vitamins early in pregnancy and to have reported a wider variety of illnesses.The results in general do not support the hypothesis that the quantity of potatoes taken is important. They do lend support to the view that poor dietary habits are associated with a higher incidence of spina bifida irrespective of social class. Furthermore, general ill health in the mother may be implicated.     

Neural-tube defects: importance of a history of abortion in aetiology.

The overall incidence of anencephaly and spina bifida (ASB) in 69,056 pregnancies was 4.7/1000 births. ASB was more common (8.4/1000 births) among children of mothers who had had two or more abortions, but the increased risk was confined to spina bifida. A history of abortion was more common in older women and women of higher parity, but this was not matched by a similar increase in the incidence of ASB. The incidence of ASB was related to social class, but the prevalence of previous abortions was similar in all classes. The results suggest that expectant mothers with a history of two or more abortions have an increased risk of producing a child with spina bifida. The abortions are considered to be a manifestation of previous abnormal conceptions rather than the primary cause.     

Microsatellites proximal to leptin and leptin receptor as risk factors for spina bifida

Several recent studies have observed an association between neural tube defect risk and prepregnant obesity. This association was generally stronger for spina bifida and was observed irrespective of additional maternal factors, including periconceptional intake of vitamin supplements. Other studies have identified mutations within the genes that code for leptin (LEP) and its receptor (LEPR), which have been linked to obesity in mice and humans. We investigated the potential association between nucleotide variation at the LEP and LEPR loci, and increased risk of spina bifida. We searched specifically for allelic association at a pair of highly polymorphic microsatellites closely linked to either the LEP or LEPR gene. Data were derived from a population-based case-control study that had previously identified an association between a woman's prepregnant obesity and her risk of delivering an infant with spina bifida. A total of 56 spina bifida case infants and 126 nonmalformed control infants were genotyped for 10 microsatellite alleles closely linked to the LEP gene, and 49 cases and 125 controls were genotyped for 10 microsatellite alleles closely linked to the LEPR gene. In general, alleles were not observed to be exclusively associated with substantially greater spina bifida risk in the body mass index (BMI) category (obese) of >29 kg/m(2) compared with the BMI category (nonobese) of 29 kg/m; (2) having either allele and BMI 29 kg/m(2). The odds ratios (95% confidence interval) for these comparisons were: for allele 257, 4.5 (1.1-19.4), 1.9 (0.5-6.3), and 2.9 (1.3-6.4), respectively, and for allele 271, 6.7 (1.6-30.4), 2.7 (0.7-10.9), and 2.7 (1.2-5.9), respectively. Owing to the exploratory nature of this investigation, the significance of these latter results is unclear.