Inadvertent antibiotic exposure during pregnancy may increase the risk for neural tube defects in offspring.

BACKGROUND: As emerging environmental contaminants, antibiotics pose potential threats to human health, in particular to pregnant women and infants. However, the potential harm of inadvertent antibiotic exposure (IAE) is often disregarded in light of the focus on intentional antibiotic use during pregnancy. Currently, little is known about the effects of IAE during pregnancy on fetal neural tube development. METHODS: In this case-control study, we used questionnaire data from 855 subjects to investigate the effects of intentional antibiotic use in early pregnancy on neural tube defects (NTDs). Then we tested for placental antibiotics in mothers who had not intentionally used antibiotics, and the compounds were detected in 379 subjects; these were considered IAE cases. We assessed the association between IAE during pregnancy and fetal NTDs using both multivariable logistic and multi-pollutant exposure models. We also analyzed the correlation between maternal dietary habits and placental antibiotics to explore possible sources of IAE. RESULTS: Only 50 of 855 participants (5.8%) intentionally used antibiotics and such use showed no significant association with NTD risk (odds ratio [OR] = 1.92, confidence interval [95%CI] = [0.66, 5.59]). However, 14 of 15 placental antibiotics were detected in 378 of 379 subjects (99.7%) and multivariable logistic analysis indicated that high levels of placental macrolides were significantly associated with increased NTD risk (4.42 [2.01-10.45]). Multi-pollutant exposure analysis suggested an increase in NTD risk with an increase in exposure to a mixture of placental antibiotics, among which macrolides were the most important contributor. In addition, the level of placental macrolides was positively correlated with the intake frequency of milk. Finally, mothers who drank river, well, or pond water had higher levels of placental macrolides than those who drank only tap water. CONCLUSIONS: Intentional antibiotic use during early pregnancy may not be associated with NTDs, while IAE during pregnancy is associated with higher NTD risk in offspring. Macrolides are crucial risk factors. Milk, and river, well, or pond water may be important sources of IAE.

Association between cooking fuel and folate insufficiency among pregnant women in Northern China.

This study explored whether using a coal or biomass stove for cooking was associated with a greater risk of red blood cell (RBC) folate insufficiency among pregnant women compared to using clean energy. A researcher-designed questionnaire was used to collect information on exposure-related factors and confounding factors. RBC folate concentrations were examined by microbiological assay. Binary logistic regression analysis was used to identify factors related to RBC folate insufficiency. The use of coal or firewood for cooking was associated with an increased risk of RBC folate insufficiency (<906 nmol/L) compared to gas. In subgroup analyses, associations between the use of polluting cooking fuels and folate insufficiency were positive for both urban and rural residents and statistically significant for rural women. Efforts to promote the use of clean energy and proper ventilation, especially in rural areas, are recommended to improve the health of pregnant women and their offspring.

FKBP8 variants are risk factors for spina bifida.

Neural tube defects (NTDs) are a group of severe congenital malformations caused by a failure of neural tube closure during early embryonic development. Although extensively investigated, the genetic etiology of NTDs remains poorly understood. FKBP8 is critical for proper mammalian neural tube closure. Fkbp8-/- mouse embryos showed posterior NTDs consistent with a diagnosis of spina bifida (SB). To date, no publication has reported any association between FKBP8 and human NTDs. Using Sanger sequencing on genomic DNA samples from 472 SB and 565 control samples, we identified five rare (MAF ≤ 0.001) deleterious variants in SB patients, while no rare deleterious variant was identified in the controls (P = 0.0191). p.Glu140* affected FKBP8 localization to the mitochondria and created a truncated form of the FKBP8 protein, thus impairing its interaction with BCL2 and ultimately leading to an increase in cellular apoptosis. p.Ser3Leu, p.Lys315Asn and p.Ala292Ser variants decreased FKBP8 protein level. p.Lys315Asn further increased the cellular apoptosis. RNA sequencing on anterior and posterior tissues isolated from Fkbp8-/- and wildtype mice at E9.5 and E10.5 showed that Fkbp8-/- embryos have an abnormal expression profile within tissues harvested at posterior sites, thus leading to a posterior NTD. Moreover, we found that Fkbp8 knockout mouse embryos have abnormal expression of Wnt3a and Nkx2.9 during the early stage of neural tube development, perhaps also contributing to caudal specific NTDs. These findings provide evidence that functional variants of FKBP8 are risk factors for SB, which may involve a novel mechanism by which Fkbp8 mutations specifically cause SB in mice.

Maternal Periconceptional Folic Acid Supplementation and Risk for Fetal Congenital Heart Defects.

OBJECTIVE: To determine the effects of maternal periconceptional supplementation with folic acid or multiple micronutrients containing folic acid on the prevention of fetal congenital heart defects (CHDs). STUDY DESIGN: Data were drawn from a Prenatal Health Care System and a Birth Defects Surveillance System in a district of Beijing, China. A total of 63 969 singleton births, live or stillborn, 308 CHDs among them, during 2013 to 2018 were included. Associations between different patterns of supplementation and risk for total CHDs or main types of CHDs were evaluated with risk ratios (RRs). RESULTS: For folic acid or multiple micronutrients containing folic acid users compared with nonusers, the adjusted RRs (ARRs) for total CHDs, critical CHD, and ventricular septal defect (VSD) were 0.60 (95% CI, 0.44-0.83), 0.41 (95% CI, 0.26-0.67), and 0.47 (95% CI, 0.30-0.74), respectively. When we compared multiple micronutrients containing folic acid users with folic acid users, the ARRs were 0.84 (95% CI, 0.66-1.09), 0.64 (95% CI, 0.41-1.00), and 0.94 (95% CI, 0.63-1.41) for total CHDs, critical CHD, and VSD, respectively. We also found that, compared with supplementation initiated after conception, supplementation initiated before conception was associated with a lower risk for CHDs: the ARRs were 0.68 (95% CI, 0.48-0.95) for total CHDs and 0.26 (95% CI, 0.10-0.71) for critical CHD, but 1.08 (95% CI, 0.63-1.83) for VSD. CONCLUSIONS: Maternal periconceptional supplementation with folic acid or multiple micronutrients containing folic acid seems to decrease the risk for CHDs, especially critical CHD, in offspring. Supplementation confers a greater protective effect when it is initiated before conception. We did not find any difference between folic acid and multiple micronutrients containing folic acid in terms of preventing CHDs.

Elevated concentrations of chromium in maternal serum, umbilical cord serum, and cord tissue are associated with an increased risk for orofacial clefts.

Chromium (Cr) exposure during gestation causes malformations in animal experiments. In this multicenter case-control study, we initially involved 130 orofacial clefts (OFCs) and 260 controls to assess the association between Cr concentration and risk for OFCs. Then, umbilical cord serum (49 vs. 119) and cord tissue (84 vs. 142) were used to validate the association between Cr and OFCs. We found that maternal serum Cr concentrations in OFC cases were significantly higher than those in controls. Compared with the lowest tertile of maternal serum Cr concentration, the highest tertile of Cr increased the risk for OFCs [OR = 2.14 (1.14-4.05)]. In the validation cohort of umbilical cord serum and tissue, higher concentrations of Cr were associated with increased risks for OFCs in a dose-dependent manner (all Ps for trends <0.05). Cr concentrations in maternal serum and cord serum showed a positive correlation. The Cr concentration in cord serum was inversely correlated with egg and milk consumption frequencies, and the Cr concentration in cord tissue was positively associated with indoor coal burning. In conclusion, prenatal Cr exposure is a risk factor for OFCs, and indoor coal burning during pregnancy may be one of the sources of Cr exposure.

Maternal exposure to heavy metals and risk for severe congenital heart defects in offspring.

BACKGROUND: Congenital heart defects (CHDs) are the most common congenital malformations with a complex etiology, and environmental factors play an important role. Large epidemiology studies on prenatal exposure to selected heavy metals and their association with risk for CHDs are scarce and joint effects are not well understood. OBJECTIVES: To examine the association between prenatal exposure to selected heavy metals and risk for CHDs. METHODS: Inductively coupled plasma mass spectrometry (ICP-MS) was used to determine the maternal plasma concentrations of arsenic, cadmium, mercury, lead, and manganese were in 303 CHD cases and 303 healthy controls that were recruited in eight hospitals in China. Generalized linear mixed model (GLMM) and Bayesian kernel machine regression (BKMR) were fitted to evaluate the individual and joint effects of metal concentrations on CHDs. RESULTS: In GLMM, two metals were each significantly associated with an increased risk for CHDs [adjusted odds ratio (95% confidence interval): mercury, 2.88 (1.22-6.77); lead, 2.74 (1.00-7.57)]. In BKMR, CHD risk increased with mixture levels of the five metals when their concentrations were at the 40th percentile or higher, compared to when all metals were below their 35th percentile, and mercury was the major metal that contributed to the mixture effect. The interaction between mercury and lead was observed in BKMR. CONCLUSIONS: Using metal concentrations in maternal plasma obtained during the second or third trimester as exposure markers, we found that the risk of CHDs increased with the levels of the mixtures of As, Cd, Hg, Pb, and Mn, with Hg being the most important contributor to the mixture effect.

Folic acid supplementation and risk for fetal abdominal wall defects in China: results from a large population-based intervention cohort study.

Folic acid (FA) can reduce the risk for selected birth defects other than neural tube defects. We examined whether FA has preventive effects against fetal abdominal wall defects (AWD) in a unique intervention cohort in China. Birth outcomes of 247 831 singleton births from a population-based cohort study with detailed pre-conceptional FA intake information were collected in China in 1993-1996. Information on births at 20 complete gestational weeks, including live births, stillbirths and pregnancy terminations, and all structural birth defects regardless of gestational week were recorded. The birth prevalence of omphalocele, gastroschisis and total fetal AWD was classified by maternal FA supplementation. The prevalence of total AWD was 4·30 per 10 000 births among women who took FA compared with 13·46 per 10 000 births among those who did not take FA in northern China and 6·28 and 5·18 per 10 000 births, respectively, in southern China. The prevalence of omphalocele was 0·54 per 10 000 births among women who took FA compared with 3·74 per 10 000 births among those who did not take FA in northern China and 1·79 and 1·44 per 10 000 births, respectively, in southern China. FA supplementation significantly prevented total AWD in multivariate analysis (relative risk 0·26, 95 % CI 0·11, 0·61) in northern China, although no preventive effect of FA on AWD was observed in southern China. FA supplementation successfully reduced the prevalence of AWD in northern China.

Maternal periconceptional folic acid supplements use and fetus risk for limb defects.

BACKGROUND: Associations between the periconceptional folic acid only (FAO) or multiple micronutrients containing folic acid (MMFA) supplementation and risk for limb defects are inconsistent. OBJECTIVE: To explore the association between periconceptional folic acid supplements use and risk for limb defects, including clubfoot, polydactyly, syndactyly, and limb deficiencies. METHODS: Data were derived from a cohort based on a pregnancy registry in a district of Beijing, China, from 2013 to 2018. Information on maternal periconceptional FAO and MMFA supplementation was collected via face-to-face interviews at first trimester. Pregnancy outcomes including limb defects were ascertained in livebirths, stillbirths, and elective pregnancy terminations and were recorded into the system. Propensity score methods were used to adjust for potential confounders. RESULTS: A total of 63 969 women with a singleton delivery were included. The overall prevalence of limb defects was 47.5 per 10 000 (n = 63 969) singleton deliveries. Decreased prevalence of limb defects was found among FAO/MMFA users compared with women who did not take supplements (nonusers) (46.1 vs. 61.9 per 10 000 births, adjusted risk ratio [RR] 0.80, 95% confidence interval [CI] 0.56, 1.12). Compared with nonusers (n = 6462, 10.2%), women who took either FAO (n = 26 567, 42.0%) or MMFA (n = 30 259, 47.8%) had a lower risk for total clubfoot (RR 0.40, 95% CI 0.20, 0.84), and for isolated clubfoot (RR 0.41, 95% CI 0.17, 0.97). For other limb defects except clubfoot, FAO supplementation did not appear to be associated with reduced risk, while MMFA supplementation group had 30%-50% reduced risks for other limb defects. A lower risk for limb defects or isolated limb defects was found with MMFA supplementation when FAO supplementation was used as a control. CONCLUSIONS: Maternal periconceptional supplements with either FAO or MMFA had inverse association with clubfoot in offspring, and MMFA was associated with lower risk for isolated limb defects compared with FAO.

Associations between prenatal exposure to cadmium and lead with neural tube defect risks are modified by single-nucleotide polymorphisms of fetal MTHFR and SOD2: a case-control study.

BACKGROUND: Prenatal exposure to heavy metals is implicated in the etiology of birth defects. We investigated whether concentrations of cadmium (Cd) and lead (Pb) in umbilical cord tissue are associated with risk for neural tube defects (NTDs) and whether selected genetic variants of the fetus modify their associations. METHODS: This study included 166 cases of NTD fetuses/newborns and 166 newborns without congenital malformations. Umbilical cord tissue was collected at birth or elective pregnancy termination. Cd and Pb concentrations were assessed by inductively coupled plasma-mass spectrometry, and 20 single-nucleotide polymorphisms (SNPs) in 9 genes were genotyped. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the risk for NTDs in association with metal concentrations or genotype using logistic regression. Multiplicative-scale interactions between the metals and genotypes on NTD risk were assessed with logistic regression, and additive-scale interactions were estimated with a non-linear mixed effects model. RESULTS: Higher concentrations of Cd were observed in the NTD group than in the control group, but no difference was found for Pb. Concentrations of Cd above the median level showed a risk effect, while the association between Pb and NTD risk was not significant in univariate analyses. The association of Cd was attenuated after adjusting for periconceptional folic acid supplementation. Fetuses with the AG and GG genotypes of rs4880 in SOD2 (superoxide dismutase 2) tended to have a lower risk, but fetuses with the CT and TT genotypes of rs1801133 in MTHFR (5,10-methylenetetrahydrofolatereductase) have a higher risk for NTDs when compared to their respective wild-type. rs4880 and Cd exhibited a multiplicative-scale interaction on NTD risk: the association between higher Cd and the risk for NTDs was increased by over fourfold in fetuses carrying the G allele [OR 4.43 (1.30-15.07)] compared to fetuses with the wild-type genotype. rs1801133 and Cd exposure showed an additive interaction, with a significant relative excess risk of interaction [RERI 0.64 (0.02-1.25)]. CONCLUSIONS: Prenatal exposure to Cd may be a risk factor for NTDs, and the risk effect may be enhanced in fetuses who carry the G allele of rs4880 in SOD2 and T allele of rs1801133 in MTHFR.

Folic acid supplementation and risk for congenital hydrocephalus in China.

OBJECTIVE: We examined whether folic acid (FA) supplementation prevented congenital hydrocephalus (CH) in more than 200 000 births in China. DESIGN: A large population-based cohort study. SETTING: All births at 20 complete gestational weeks, including live births, stillbirths and pregnancy terminations, and all structural birth defects regardless of gestational week were recorded. The prevalence of births with CH was classified by maternal characteristics and FA supplementation. CH was diagnosed in accordance with code 742.3 of the International Classification of Diseases, Ninth Revision, Clinical Modification, while non-neural tube defect (NTD) CH refers to CH without anencephaly (740), spina bifida (741) or encephalocele (742·0). PARTICIPANTS: A total of 247 831 pregnant women who delivered with known outcomes were included. RESULTS: A total of 206 cases of CH (0·83 per 1000 births) and 170 cases of non-NTD CH (0·69 per 1000 births) were recorded in the study. The prevalence of CH and non-NTD CH was higher in women in the no supplementation group than those in the FA supplementation group (0·92 and 0·72 v. 0·75 and 0·65 per 1000 births, respectively). FA supplementation during the periconceptional period significantly prevented CH (OR = 0·29, 95 % CI 0·12, 0·69) and non-NTD CH (OR = 0·34, 95 % CI 0·12, 0·97) in northern China, especially in a high-compliance group (≥ 80 %). CONCLUSIONS: Periconceptional FA supplementation did not significantly prevent CH overall in the current study. However, in the north of China with common maternal folate insufficiency, there was some evidence.

Formate rescues neural tube defects caused by mutations in Slc25a32.

Periconceptional folic acid (FA) supplementation significantly reduces the prevalence of neural tube defects (NTDs). Unfortunately, some NTDs are FA resistant, and as such, NTDs remain a global public health concern. Previous studies have identified SLC25A32 as a mitochondrial folate transporter (MFT), which is capable of transferring tetrahydrofolate (THF) from cellular cytoplasm to the mitochondria in vitro. Herein, we show that gene trap inactivation of Slc25a32 (Mft) in mice induces NTDs that are folate (5-methyltetrahydrofolate, 5-mTHF) resistant yet are preventable by formate supplementation. Slc25a32gt/gt embryos die in utero with 100% penetrant cranial NTDs. 5-mTHF supplementation failed to promote normal neural tube closure (NTC) in mutant embryos, while formate supplementation enabled the majority (78%) of knockout embryos to complete NTC. A parallel genetic study in human subjects with NTDs identified biallelic loss of function SLC25A32 variants in a cranial NTD case. These data demonstrate that the loss of functional Slc25a32 results in cranial NTDs in mice and has also been observed in a human NTD patient.

Rare earth elements in umbilical cord and risk for orofacial clefts.

Questions remain about the effects of rare earth elements (REEs) on reproductive health, and no study has explored in utero exposure to REEs and risk of orofacial clefts (OFCs). We recruited subjects from a case-control study conducted in Shanxi Province, China. Concentrations of fifteen REEs were quantified in umbilical cord samples by means of Inductively Coupled Plasma Mass Spectrometry measurements. We employed logistic regression and weighted quantile sum (WQS) regression models to estimate the association between REEs exposures and OFCs. Of 226 subjects included in our study, 34 were cleft lip only, 44 were cleft lip with cleft palate and 6 were cleft palate only. In the logistic regression model, concentrations above the median of all subjects were associated with an increased OFCs risk of 2.35-fold (95% CI: 1.22, 4.53) for Lanthanum and 2.12-fold for Neodymium (95% CI: 1.10, 4.10) adjusting for maternal age, BMI, gestational weeks, sex of infants and passive smoking. In WQS model, a quartile increase in the index resulting in an increase of 3.10 (95% CI: 1.38, 6.96) in the odds of OFC. Lanthanum and Neodymium were suggested to be important factors. The results were largely consistent for OFC subtypes. In conclusion, in utero exposure to mixtures of REEs increased the risk of OFCs. Lanthanum and Neodymium were likely to be important factors in the development of OFCs.

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

OBJECTIVES: We 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. METHODS: DNA 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. RESULTS: The 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. CONCLUSION: Hypermethylation 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.

Environmental titanium exposure and reproductive health: Risk of low birth weight associated with maternal titanium exposure from a nested case-control study in northern China.

Titanium (Ti) is commonly used in additives in the form of titanium dioxide (TiO2). However, our understanding of the effect of Ti on reproductive health remains limited. This nested case-control study, performed in a Ti mining exposure field, investigated the association between maternal blood Ti concentration and the risk of low birth weight (LBW), as well as the potential biological mechanism. A total of 45 women who delivered LBW infants (cases) and 352 women with normal birth weight infants (controls) were included. We collected maternal peripheral blood samples in the first or early second trimester to measure Ti concentration in serum (Tisr) and blood cells (Tibc), as well as inflammatory, lipid, and oxidative stress biomarkers thereof. The demographic characteristics of the women included in the study were also obtained. The results showed that the median total blood Ti concentration (Titb) in the case group was significantly higher than that in the control group (134 vs. 129 ng/mL, P = 0.039). A higher Titb level was associated with a greater risk of LBW [odds ratio = 2.62; 95% confidence interval (CI): 1.16-5.90], but no such association was observed for Tisr or Tibc after adjusting for potential confounders. The serum lipid biomarkers TC, TG, and total lipids (TL) were all negatively associated with Tisr and Titb. Serum 8-OHdG was positively associated with Tibc. We concluded that a high Titb during early pregnancy may increase the risk of LBW. Lipid metabolism and oxidative stress may play an important role in the adverse health effects associated with Ti exposure. Thus, our results merit more attention to the probable adverse effects of titanium exposure during pregnancy.

Distribution of mercury in serum and blood cells and risk of spontaneous preterm birth: A nested case-control study in China.

The relationship between maternal mercury (Hg) intake and the risk of spontaneous preterm birth (SPB) remains unclear. We conducted a nested case-control study from a prospective cohort in Shanxi Province, China, to explore their associations. In total, 126 pregnant women with SPB (cases) and 348 controls with term delivery were included. We measured the Hg concentrations in their serum (Hgs) and blood cell (Hgc) fractions and calculated the concentration ratio of Hg in serum to Hg in blood cells (Hgs/c). We found that only the Hgs/c in the case group was slightly higher than that in control group. The OR of Hgs/c associated with SPB risk was 1.57 [95%CI: 0.99-2.46] with adjusting confounders. After stratification by sampling time, the association above was only statistically significant in the first trimester. High Hgs/c may increase the risk of SPB in the first trimester among women with relatively low Hg exposure.

Rare copy number variations of planar cell polarity genes are associated with human neural tube defects.

Select single-nucleotide variants in planar cell polarity (PCP) genes are associated with increased risk for neural tube defects (NTDs). However, whether copy number variants (CNVs) in PCP genes contribute to NTDs is unknown. Considering that CNVs are implicated in several human developmental disorders, we hypothesized that CNVs in PCP genes may be causative factors to human NTDs. DNA from umbilical cord tissues of NTD-affected fetuses and parental venous blood samples were collected. We performed a quantitative analysis of copy numbers of all exon regions in the VANGL1, VANGL2, CELSR1, SCRIB, DVL2, DVL3, and PTK7 genes using a CNVplex assay. Quantitative real-time PCR (qPCR) was carried out to confirm the results of CNV analysis. As a result, 16 CNVs were identified among the NTDs. Of these CNVs, 5 loci were identified in 11 NTD probands with CNVs involving DVL2 (exons 1-15), VANGL1 (exons 1-7, exon 8), and VANGL2 (exons 5-8, exons 7 and 8). One CNV (DVL2 exons 1-15) was a duplication and the remaining 15 CNVs were deletions. Eleven CNVs were confirmed by qPCR. One de novo CNV in VANGL1 and one DVL2 were detected from two cases. Compared with unaffected control populations in 1000 Genome, ExAC, MARRVEL, DGV, and dbVar databases, the frequencies of de novo deletion in VANGL1 (1.14%) and de novo duplication in DVL2 (0.57%) were significantly higher in our NTD subjects (p < 0.05). This study demonstrates that de novo CNVs in PCP genes, notably deletions in VANGL1 and gains in DVL2, could contribute to the risk of NTDs.

Somatic mutations in planar cell polarity genes in neural tissue from human fetuses with neural tube defects.

Extensive studies that have sought causative mutation(s) for neural tube defects (NTDs) have yielded limited positive findings to date. One possible reason for this is that many studies have been confined to analyses of germline mutations and so may have missed other, non-germline mutations in NTD cases. We hypothesize that somatic mutations of planar polarity pathway (PCP) genes may play a role in the development of NTDs. Torrent™ Personal Genome Machine™ (PGM) sequencing was designed for selected PCP genes in paired DNA samples extracted from the tissues of lesion sites and umbilical cord from 48 cases. Sanger sequencing was used to validate the detected mutations. The source and distribution of the validated mutations in tissues from different germ layers were investigated. Subcellular location, western blotting, and luciferase assays were performed to better understand the effects of the mutations on protein localization, protein level, and pathway signaling. ix somatic mutations were identified and validated, which showed diverse distributions in different tissues. Three somatic mutations were novel/rare: CELSR1 p.Gln2125His, FZD6 p.Gln88Glu, and VANGL1 p.Arg374His. FZD6 p.Gln88Glu caused mislocalization of its protein from the cytoplasm to the nucleus, and disrupted the colocalization of CELSR1 and FZD6. This mutation affected non-canonical WNT signaling in luciferase assays. VANGL1 p.Arg374His impaired the co-localization of CELSR1 and VANGL1, increased the protein levels of VANGL1, and influenced cell migration. In all, 7/48 (14.5%) of the studied NTD cases contained somatic PCP mutations. Somatic mutations in PCP genes (e.g., FZD6 and VANGL1) are associated with human NTDs, and they may occur in different stages and regions during embryonic development, resulting in a varied distribution in fetal tissues/organs.

Does Low Maternal Exposure to Per- and Polyfluoroalkyl Substances Elevate the Risk of Spontaneous Preterm Birth? A Nested Case-Control Study in China.

Previous animal and human studies suggest potential links between maternal exposure to per- and polyfluoroalkyl substances (PFASs) and adverse birth outcomes. As spontaneous preterm birth (SPB) represents a major cause of infant mortality and precursor to future morbidity, we conducted a prospective nested case-control study in Shanxi Province, China to investigate the association between prenatal PFAS exposure and SPB risk, as well as the associations with biomarkers of oxidative stress and systemic inflammation. Among 4229 women enrolled during 2009-2013, 144 SPB cases and 375 controls were included in this study. Seventeen PFASs, as well as monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), and heme oxygenase-1 (HO-1), were measured in maternal plasma or serum collected during 4th-22nd gestational weeks. Perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), and its alternative chlorinated polyfluoroether sulfonic acid (6:2 Cl-PFESA) were detected in more than 90% samples with a median concentration of 0.79, 1.79, and 0.34 ng/mL, respectively. The analyses revealed no significant associations between plasma PFASs and the SPB risk after adjusting for potential confounders. However, concentrations of PFOS and 6:2 Cl-PFESA were both significantly and positively associated with MCP-1 levels, while PFOA was inversely associated with IL-8. Our findings suggested that maternal exposure to the determined low levels of PFAS did not induce an elevated risk of SPB, but the exposure may disturb potential biochemical pathways of inflammation. The latter has important implications for possible birth outcome effects and developmental effects in fetuses and newborns, which warrants close attention.

Uranium concentration in umbilical cord may increase the risk for orofacial clefts.

BACKGROUND: Orofacial clefts (OFCs) are common kind of congenital malformations. The teratogenicity of uranium (U) has been documented in animal study that maternal exposure to U can increase incidence of external malformations including cleft palate. However, there is limited evidence of the association of in utero exposure to U with OFCs risk in humans. OBJECTIVE: This study aimed to investigate the association between in utero exposure to U and the risk of OFCs and its subtypes. METHOD: All subjects were from a case-control study in Shanxi Province, northern China. Eighty-four OFCs cases and 142 healthy controls were included in this study. We used U concentration in umbilical cord as biomarkers to represent intrauterine exposure, which was detected by inductively coupled plasma mass spectrometry. Unconditional logistic regression was used to investigated the association between U level and the risk of OFCs and its subtypes. RESULTS: The median of U concentration in umbilical cord is 0.745 ng/g in case group and 0.455 ng/g in control group. When the U concentration was divided into two categories, high level of U exposure increased the risk of OFCs (OR: 2.08, 95% CI: 1.13-3.86) and its subtype cleft lip with cleft palate (CLP) (OR: 2.72, 95% CI: 1.21-6.14). When divided into three categories, high level of U elevated the risk for OFCs (OR: 2.40, 95% CI: 1.14-5.06) and CLP (OR: 3.04, 95% CI: 1.20-7.74). Meanwhile, a dose-response relationship between the U concentration and the risk of total OFCs (P for trend = 0.009) and CLP (P for trend = 0.007) was found. CONCLUSION: Our study found that in utero exposure to high level of U was associated with increased risk of OFCs and its subtype CLP.

Association between gestational weight gain and exclusive breast-feeding for the first 6 months postpartum in Chinese women.

OBJECTIVE: The association between gestational weight gain (GWG) and exclusive breast-feeding (EBF) practices remains unclear. The present study evaluated the association between GWG and EBF in the first 6 months postpartum among primiparas in rural China. DESIGN: The study population was drawn from a previous randomized controlled trial, and the relevant data were obtained from an electronic, population-based perinatal system and a monitoring system for child health care. GWG was categorized according to the guidelines of the Institute of Medicine. SETTING: Five rural counties in Hebei Province, China.ParticipantsA total of 8449 primiparas. RESULTS: Of the women, 58·7 % breast-fed exclusively for the first 6 months postpartum. Overweight women who gained either more or less weight than the recommended GWG tended to experience failure of EBF (OR=0·49; 95 % CI 0·34, 0·70; P<0·001 and OR=0·79; 95 % CI 0·63, 0·99; P=0·048, respectively). The same results were also observed among obese women; the OR for lower and greater weight gain were 0·28 (95 % CI 0·08, 0·94; P=0·04) and 0·55 (95 % CI 0·32, 0·95; P=0·03), respectively. CONCLUSIONS: GWG that is below or above the Institute of Medicine recommendations is associated with EBF behaviour for the first 6 months postpartum in overweight and obese primiparas in rural China.