Cleft Palate In Offspring Research Articles

Hypermethylation of WNT3A gene and non-syndromic cleft lip and/or palate in association with in utero exposure to lead: A mediation analysis

ObjectivesWe aim to investigate association between WNT3A methylation and risk of non-syndromic cleft lip and/or palate (NSCL/P), and examine mediating effect of WNT3A methylation on the association of NSCL/P and lead (Pb) exposure in fetuses. MethodsDNA methylation of WNT3A in umbilical cord blood was determined among 59 NSCL/P cases and 118 non-malformed controls. Mediation analysis was performed to evaluate the potential mediating effect of WNT3A methylation on association between concentrations of Pb in umbilical cord and risk for NSCL/P. Additionally, an animal experiment in which cleft palates were induced by lead acetate was conducted. ResultsThe overall average methylation level of WNT3A was significant higher in NSCL/P cases as compared to controls. The risk for NSCL/P was increased by 1.90-fold with hypermethylation of WNT3A. Significant correlation was observed between concentrations of Pb in umbilical cord and methylation level of WNT3A. The hypermethylation of WNT3A had a mediating effect by 9.32% of total effect of Pb on NSCL/P risk. Gender-specific association between WNT3A methylation and NSCL/P was observed in male fetuses, and the percentage of the mediating effect increased to 14.28%. Animal experiment of mice showed that maternal oral exposure to lead acetate may result in cleft palate in offspring. ConclusionHypermethylation of WNT3A was associated with the risk for NSCL/P and may be partly explain the association between exposure to Pb and risk for NSCL/P. The teratogenic and fetotoxic effects of Pb were found in mice.

Association between Maternal MTHFR Polymorphisms and Nonsyndromic Cleft Lip with or without Cleft Palate in Offspring, A Meta-Analysis Based on 15 Case-Control Studies.

The methylenetetrahydrofolate reductase (MTHFR) is thought to be involved in the development of nonsyndromic cleft lip with or without cleft palate (NSCL/P). However, conflicting results have been obtained when evaluating the association between maternal MTHFR C677T and A1298C polymorphisms and the risk of NSCL/P. In light of this gap, a meta-analysis of all eligible case-control studies was conducted in the present study. A total of 15 case-control studies were ultimately identified after a comprehensive literature search and Hardy-Weinberg equilibrium (HWE) examination. Cochrane's Q test and index of heterogeneity (I(2)) indicated no obvious heterogeneity among studies. Fixed or random-effects models were used to calculate the pooled odds ratios (ORs). The results showed that the TT genotype in mothers increased the likelihood of having NSCL/P offspring 1.25 times (95% CI: 1.047-1.494) more than the CC homozygotes. Meanwhile, maternal TT genotype increased the risk of producing NSCL/P offspring in recessive model (OR=1.325, 95% CI: 1.124-1.562). However, the CT heterozygote and the CT+TT dominant models had no association with NSCL/P offspring compared with the CC wild-type homozygote model. Subgroup analyses based on ethnicity indicated that maternal TT genotype increased the likelihood of having NSCL/P offspring in Whites (OR=1.308, 95% CI: 1.059-1.617) and Asians (OR=1.726, 95% CI: 1.090-2.733) in recessive model. Also, subgroup analyses based on source of control showed that mothers with the 677TT genotype had a significantly increased susceptibility of having NSCL/P children in hospital based population (HB) when compared with CC homozygotes (OR=1.248, 95% CI: 1.024-1.520) and un- der the recessive model (OR=1.324, 95% CI: 1.104-1.588). Furthermore, maternal A1298C polymorphism had no significant association with producing NSCL/P offspring (dominant model OR=0.952, 95% CI: 0.816-1.111, recessive model OR=0.766, 95% CI: 0.567-1.036). MTHFR C677T polymorphism is associated with the risk of generating NSCL/P offspring, and being a 677TT homozygote is a risk factor. MTHFR A1298C polymorphism was not associated with generating NSCL/P offspring. However, further work should be performed to confirm these findings.

Maternal Occupational Exposure to Polycyclic Aromatic Hydrocarbons and Risk of Oral Cleft-Affected Pregnancies

To evaluate whether there is an association between maternal occupational exposure to polycyclic aromatic hydrocarbons and oral clefts in offspring. This is the first human study of polycyclic aromatic hydrocarbons and clefts of which the authors are aware. Case-control study. Data for 1997 to 2002 from the National Birth Defects Prevention Study, a large population-based case-control study in the United States, were analyzed. Maternal telephone interviews yielded information on jobs held in the month before through 3 months after conception. Two industrial hygienists independently assessed occupational exposure to polycyclic aromatic hydrocarbons; all jobs rated as exposed or with rating difficulty were reviewed with a third industrial hygienist to reach consensus on all exposure parameters. Logistic regression estimated crude and adjusted odds ratios with 95% confidence intervals for cleft lip with or without cleft palate and cleft palate alone. There were 2989 controls (3.5% exposed), 805 cases of cleft lip with or without cleft palate (5.8% exposed), and 439 cases of cleft palate alone (4.6% exposed). The odds of maternal occupational exposure to polycyclic aromatic hydrocarbons (any versus none) during pregnancy was increased for cleft lip with or without cleft palate cases as compared with controls (odds ratio, 1.69; 95% confidence interval, 1.18 to 2.40); the odds ratio was 1.47 (95% confidence interval 1.02 to 2.12) when adjusted for maternal education. There was a statistically significant adjusted exposure-response relationship for cleft lip with or without cleft palate (Ptrend = .02). Odd ratios for cleft palate alone were not statistically significant. Maternal occupational exposure to polycyclic aromatic hydrocarbons was associated with increased risk of cleft lip with or without cleft palate in offspring.

Topiramate in pregnancy and risk of oral clefts: Margulis et al

See related article, page 405 Topiramate was approved in the United States in 1996 for the treatment of generalized tonic-clonic and partial seizures. An indication for migraine prophylaxis was added in 2004. The drug has been used on an off-label basis for eating, sleep, and psychiatric disorders. Recently, a combination of phentermine and topiramate was approved for chronic weight management in overweight or obese adults with a weight-related disorder. Margulis and colleagues, noting that some of these conditions are particularly prevalent among women of child-bearing age, looked for a link between topiramate use in pregnancy and cleft lip with or without cleft palate in offspring.

Involvement of apoptotic cell death and cell cycle perturbation in retinoic acid-induced cleft palate in mice

Retinoic acid (RA), a metabolite of vitamin A, plays a key role in a variety of biological processes and is essential for normal embryonic development. On the other hand, exogenous RA could cause cleft palate in offspring when it is given to pregnant animals at either the early or late phases of palatogenesis, but the pathogenetic mechanism of cleft palate caused by excess RA remains not fully elucidated. The aim of the present study was to investigate the effects of excess of RA on early palatogenesis in mouse fetuses and analyze the teratogenic mechanism, especially at the stage prior to palatal shelf elevation. We gave all- trans RA (100 mg/kg) orally to E11.5 ICR pregnant mice and observed the changes occurring in the palatal shelves of their fetuses. It was found that apoptotic cell death increased not only in the epithelium of the palatal shelves but also in the tongue primordium, which might affect tongue withdrawal movement during palatogenesis and impair the horizontal elevation of palatal shelves. In addition, RA was found to prevent the G 1/S progression of palatal mesenchymal cells through upregulation of p21 Cip1 , leading to Rb hypophospholylation. Thus, RA appears to cause G 1 arrest in palatal mesenchymal cells in a similar manner as in various cancer and embryonic cells. It is likely that apoptotic cell death and cell cycle disruption are involved in cleft palate formation induced by RA.

Myo-inositol, glucose and zinc status as risk factors for non-syndromic cleft lip with or without cleft palate in offspring: a case-control study.

To investigate myo-inositol, glucose and zinc status in mothers and their infants on cleft lip with or without cleft palate risk (CLP). Case-control study. University Medical Centre Nijmegen, the Netherlands. Eighty-four mothers and their CLP child and 102 mothers and their healthy child. Venous blood samples were obtained to determine serum myo-inositol and glucose and red blood cell zinc concentrations in mothers and children. Geometric means were calculated and compared between the groups. The blood parameters were dichotomised with cutoff points based on control values, <P10 for myo-inositol and zinc concentrations and >P90 for glucose concentrations. Geometric means (P5-P95) and odds ratios (95% confidence intervals). The CLP children (P= 0.003) and their mothers (P= 0.02) had significantly lower red blood cell zinc concentrations than controls. A low maternal serum myo-inositol concentration (<13.5 micromol/L) and a low red blood cell zinc concentration (<189 micromol/L) increased CLP risk [odds ratio 3.0 (95% CI 1.2-7.4) and 2.0 (95% CI 0.8-4.8), respectively]. Children with low myo-inositol (<21.5 micromol/L ) or low red blood cell zinc concentrations (<118 micromol/L) were more likely to have CLP [odds ratio 3.4 (95% CI 1.3-8.6) and 3.3 (95% CI 1.3-8.0), respectively]. Glucose was not a risk factor for CLP in mothers and children. Maternal and child myo-inositol as well as zinc concentrations were slightly, albeit significantly correlated, r(Pearson)= 0.33 (P= 0.0006) and r(Pearson)= 0.23 (P= 0.01), respectively. This study demonstrates for the first time that zinc and myo-inositol are important in the aetiology of CLP.

Inhibition of 3,3′,4,4′,5-Pentachlorobiphenyl-induced fetal cleft palate and immunotoxicity in C57BL/6 mice by 2,2′,4,4′,5,5′-hexachlorobiphenyl

3,3′,4,4′,5-Pentachlorobiphenyl (pentaCB) caused a dose-dependent induction of fetal cleft palate in offspring from pregnant C57BL/6 mice exposed to a single dose (783 or 1044 μg/kg) of this compound on gestation and 10. In contrast 2,2′,4,4′,5,5′-hexaCB did not cause cleft palate at a dose 271 mg/kg and, in pregnant mice cotreated with 2,2′,4,4′,5,5′-hexaCB (271 mg/kg) plus 783 or 1044 μg/kg 3,3′,4,4′,5-pentaCB, fetal cleft plane formation was significantly inhibited. 3,3′,4,4′-PentaCB (6 μg/kg) also inhibited the splenic plaque-forming cell (PFC) response and serum IgM levels in C57BL/6 mice treated with the T cell-independent antigen trinitrophenyl-lipopolysaacharide. At doses as high as 72 mg/kg, 2,2′,4,4′,5,5′-hexaCB was not immunotoxic; however, in mice cotreated with a immunotoxic dose of 3,3′,4,4′,5-pentaCB plus different doses of 2,2′,4,4′,5,5′-hexaCB (18, 36 and 72 mg/kg), there was a dose-dependent inhibition of 3,3′,4,4′,5-pentaCB-induced immunotoxicity. These non-additive (antagonistic) interactions of prototypical polychlorinated biphenyl (PCB) congeners may be an important consideration in development of a toxic equivalency factor approach for hazard and risk assessment of PCB mixtures.

Biochemical mechanism of corticoid-induced cleft palate in rats linked to anti-inflammatory action

Glucocorticoids produce cleft palate in offspring of rodents in direct relation to their anti-inflammatory potency. Recently,the anti-inflammatory action of glucocorticoids has been shown to be inhibition of arachidonic acid release from membrane phospholipids in several different models of inflammation in direct relation to anti-inflammatory potency. Thus,we have determined whether the production of cleft palate in rat fetuses by dexamethasone 3.5 mg/kg on days 12 to 15 of gestation is affected by concurrent injections of arachidonic acid 300 mg/kg. This produced a marked correction of the degree of cleft palate produced by dexamethasone (59/146, 40.4% vs. 129/180, 71.7%; P=0. 034 Mann-Whitney test). Pregnant rats were also treated with either dexamethasone or saline on days 12 to 14 and 3H-arachidonic acid on day 15. After four hours fetuses of dexamethasone-treated animals had significantly increased uptake of 3H vs. controls. Moreover, the increased 3H was incorporated chiefly into phospholipid demonstrating a reverse of release of fetal palatal arachidonic acid.Thus, the teratogenic action of corticoids appears to be due to their anti-inflammatory action.

Serum proteins and glycoproteins in 2 strains of mice differing in teratogenic potential.

SummaryIn 2 strains of mice, Strong A and C3H, which are respectively susceptible and resistant to induction of cleft palate in offspring when cortisone is given to pregnant mothers, it was found that cortisone, pregnancy per se and pregnancy plus cortisone lead to definite and different effects on serum proteins, protein fractions, and protein-bound carbohydrate fractions. A direct connection between protein metabolism and cleft palate is not inferred from the results.