Essential trace elements in umbilical cord tissue and risk for neural tube defects.

Deficient or excessive quantities of essential trace elements (ETEs)1 in the fetal environment can compromise developmental processes. We investigated whether concentrations of zinc (Zn), manganese (Mn), selenium (Se), cobalt (Co), molybdenum (Mo), and nickel (Ni) in umbilical cord tissue are associated with risk for neural tube defects (NTDs). Umbilical cord tissues from 166 cases of NTD cases and 166 matched controls were collected and element concentrations were measured using inductively coupled plasma-mass spectrometry. Associations between ETE concentrations and the risk for NTDs were estimated using multivariate logistic regression while adjusting for potential confounders. Bayesian kernel machine regression (BKMR) was used to examine the joint effects of these ETEs. We found that median concentrations of Ni were higher but those of Mo and Co were lower in the NTD group than in the control group. Co was the only element that was associated with NTD risk after adjusting for confounders (OR 0.31, 95 % CI 0.12-0.79 for the second and OR 0.37, 95 % CI 0.15-0.91 for the top tertile relative to the lowest tertile). The association between Co and NTD risk was confirmed with the BKMR model. In addition, a joint effect of the six ETE mixture on NTD risk was observed: the risk decreased with the levels of the mixture from 25th percentile through 75th percentile. In conclusion, higher levels of Co were associated with lower risk for NTDs, and NTD risk decreased with the levels of the six ETEs as a co-exposure mixture, suggesting a protective effect.

[Study on maternal-fetal status of Pb, Cd, As, Hg, Mn and Se elements and transplacental transfer efficiency].

Objective: To understand the levels of Pb, Cd, As, Hg, Mn, and Se in maternal and umbilical cord blood, and to explore the transplacental transfer efficiency (TTE). Methods: From September 2010 to December 2013, a total of 773 pregnant women and their newborns (Laizhou Bay Birth Cohort) were recruited from a second grade hospital in the south bank of Laizhou Bay, Bohai, Shandong Province. According to different detection methods, the six measured elements are classified into three groups including the Hg measurement group (595 mother-newborn pairs), the Pb measurement group (534 mother-newborn pairs), and the Cd, As, Mn and Se measurement group (244 mother-newborn pairs). The demographic characteristics of pregnant women and their newborns were obtained by the questionnaire. The concentrations of elements in maternal and umbilical cord blood were detected and the TTE of each element (elemental concentration in cord blood/elemental concentration in maternal blood) was calculated. The correlation of elements between maternal and cord blood was analyzed using Spearman's rank correlation coefficient. Results: The mean±SD of maternal age, gestational week and newborn birth weight of 773 mother-infant pairs were (28.34±4.50) years, (39.47±1.39) weeks and (3 419.47±497.39) g respectively. The median concentrations of Pb, Cd, As, Hg, Mn and As in maternal and cord blood were 31.12 and 30.02, 1.19 and 0.47, 8.05 and 6.03, 0.69 and 1.26, 100.70 and 105.55, 127.25 and 115.00 µg/L, respectively. The TTE of Pb, Cd, As, Hg, Mn, and Se was 0.98, 0.41, 0.73, 1.73, 0.96 and 0.91, respectively. Pb, Cd, Hg, Mn, and Se showed a significant positive correlation between maternal blood and cord blood, with Spearman correlation coefficients of 0.397, 0.298, 0.698, 0.555, and 0.285 (all P values<0.001). Conclusion: Each element was commonly detected in maternal blood and cord blood. The TTE of Hg was the highest.

Umbilical cord as an analytical matrix - A technical note.

The umbilical cord (UC) connects the fetal blood supply to the placenta, so is exposed to all systemic endo- and xenobiotics. We have extensive experience using UC as an analytical matrix for detecting and/or quantitating drugs, chemicals and endogenous compounds. This technical note describes advantages (large amount available, ease of collection, small sample needed for use, rapid availability) and challenges (clinical relationships, processing difficulties, matrix effects on analytes and detection technologies) of UC as an analytical matrix in ELISA and LC/MS platforms, and provides guidance for successfully working with this tissue.

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.

Application of molecularly imprinted polymers for the analysis of polycyclic aromatic hydrocarbons in lipid matrix-based biological samples.

High-accuracy analyses of polycyclic aromatic hydrocarbons (PAHs) in lipid matrix-based biological samples are highly necessary. We investigated the cleanup performance of the commercially available molecularly imprinted polymers (MIPs) to analyze PAHs in various biological samples (i.e., butter, peanut oil, pork belly, and human umbilical cord), and compared this method with the commonly used gel permeation chromatography (GPC). After primary cleanup with a MIP or GPC column, the extracts were further cleaned with a neutral aluminum oxide column. Then, we measured 16 PAH congeners using gas chromatography-mass spectrometry. The MIP method allowed PAH recovery levels as high as those measured with the GPC method to be obtained. More than 95% of the crude fats of butter, peanut oil, and pork belly were removed, although only ~ 50% were removed for human umbilical cord. The scan-mode ion chromatograms of the final extracts cleaned with the MIP method had responses similar to solvent blank for the four types of samples, which were slightly better than those cleaned with GPC. Moreover, the PAH concentrations in the MIP operation blank were generally lower than those of GPC operation blanks. These results indicated that MIP could be applied to the analysis of PAHs in various lipid matrix-based biological samples. Graphical abstract The schematic diagram of a molecularly imprinted polymer column and the elution curves of polycyclic aromatic hydrocarbons and crude fats of various biological samples.

Vitamin D metabolite concentrations in umbilical cord blood serum and associations with clinical characteristics in a large prospective mother-infant cohort in Ireland.

Vitamin D deficiency is widespread among mothers and neonates and quality clinical and analytical data are lacking. We used a CDC-accredited LC-MS/MS method to analyze vitamin D metabolites in cord sera from 1050 maternal-infant dyads in the prospective SCOPE Ireland Pregnancy and BASELINE Birth cohort studies, based in Cork, Ireland. The mean±SD total 25(OH)D was 34.9±18.1nmol/L; 35% of cords (50% during winter) had 25(OH)D <25nmol/L, 46% were <30nmol/L and 80% were <50nmol/L. In this predominantly white cohort, the main predictor of cord 25(OH)D [adj. mean difference in nmol/L (95% CI)] was summer delivery [19.2 (17.4, 20.9), P<0.0001]. Maternal smoking during pregnancy (9% prevalence) was negatively associated (P<0.002) with cord 25(OH)D [-4.83 (-7.9, -1.5) nmol/L]. There were no associations between cord 25(OH)D and birth weight or any anthropometric measures at birth. Despite the high prevalence of vitamin D deficiency at birth, there were no documented musculoskeletal complications during infancy, which was likely due to widespread supplementation with vitamin D. The mean±SD concentration of 3-epi-25(OH)D3, detectable in 99.4% of cord samples, was 3.3±1.9nmol/L. The proportion of 25(OH)D as 3-epi-25(OH)D3 was 11.2%. Cord 3-epi-25(OH)D3 concentrations were positively predicted by cord 25(OH)D3 [0.101 (0.099, 0.103) nmol/L, P<0.0001] and negatively by gestational age [-0.104 (-0.131, -0.076) nmol/L, P<0.0001] and maternal age [-0.010 (-0.019, -0.001) nmol/L, P<0.05]. 25(OH)D2 was detected in 98% of cord sera (mean±SD; 2.2±1.9nmol/L) despite low antenatal consumption of vitamin D2 supplements. In conclusion, these first CDC-accredited data of vitamin D metabolites in umbilical cord blood emphasise the high risk of very low vitamin D status in infants born to un-supplemented mothers. Experimental data to define maternal vitamin D requirements for prevention of neonatal deficiency at high latitude are required.

Association between maternal vitamin E status and alpha-tocopherol levels in the newborn and colostrum.

Vitamin E is important because of its antioxidant activity in situations of oxidative stress, especially postnatally. Hence, the objective was to verify whether maternal alpha-tocopherol level is associated with the alpha-tocopherol levels of the newborn and colostrum. This is a cross-sectional study of 58 women and their term newborns from a public hospital. Blood and colostrum were collected to measure alpha-tocopherol levels by high-performance liquid chromatography. Mothers with serum alpha-tocopherol levels <16.2 mmol L(-1) and newborns <11.6 mmol L(-1) were indicative of deficiency or low levels. Mothers were divided into two groups: <16.2 mmol L(-1) and those with levels ≥16.2 mmol L(-1) . The mean (95% confidence interval) serum alpha-tocopherol levels of mothers, umbilical cords and colostrum were 28 (24-32), 6 (5-8) and 39 mmol L(-1) (32-45), respectively (P < 0.001); 19% of the women and 90% of the newborns had low alpha-tocopherol levels. Maternal alpha-tocopherol level was associated with that of the umbilical cord. Newborns from mothers at risk of deficiency had low alpha-tocopherol levels (P < 0.001). Colostrum levels of vitamin E were not influenced by maternal serum. Maternal deficiency influenced the vitamin E level of the umbilical cord but does not in the colostrum, evidencing distinct transfer mechanisms via the mammary gland.

Relationships between trace element concentrations in chorionic tissue of placenta and umbilical cord tissue: potential use as indicators for prenatal exposure.

The role of the placenta was assessed by comparing the profiles of methylmercury (MeHg), inorganic mercury (I-Hg), lead (Pb), cadmium (Cd), selenium (Se), zinc (Zn), and copper (Cu) in freeze-dried chorionic tissue of the placenta and umbilical cord tissue. The significance of the placenta and cord tissue as predictors of prenatal exposure to these trace elements in pregnant women and newborns was also examined by comparing the element profiles among placenta and cord tissue, and maternal and cord blood red blood cells (RBCs). The samples were collected from 48 mother-child pairs at birth in the general population of Japanese. The concentrations of all elements, except for MeHg, were significantly higher in placenta than in cord tissue. In particular, the Cd showed the highest placenta vs. cord tissue ratio (59:1), followed by I-Hg (2.4:1), indicating that the placental barrier works most strongly against Cd among the examined toxic elements. Contrary to the other elements, the MeHg concentration in cord tissue was significantly higher (1.6 times) than that in placenta, indicating its exceptionally high placental transfer. The MeHg in placenta showed significant correlations with total mercury (T-Hg) in maternal and cord RBCs (rs=0.80 and 0.91, respectively). The MeHg in cord tissue also showed significant correlations with T-Hg in maternal and cord RBCs (rs=0.75 and 0.85, respectively). Therefore, both placenta and cord tissue are useful for predicting maternal and fetal exposure to MeHg. The Se concentration in placenta showed significant but moderate correlations with that in maternal and cord RBCs (rs=0.38 and 0.57, respectively). The Pb, Zn, and Cu concentrations in placenta and cord tissue showed no significant correlations with those in maternal and cord RBCs. As an exception, the Cd concentration in placenta showed a moderate but significant correlation (rs=0.41) with that in maternal RBCs, suggesting that the placenta is useful for predicting maternal exposure to Cd during gestation.

Effects of dietary L-arginine or N-carbamylglutamate supplementation during late gestation of sows on the miR-15b/16, miR-221/222, VEGFA and eNOS expression in umbilical vein.

Placental vascular formation and blood flow are crucial for fetal survival, growth and development, and arginine regulates vascular development and function. This study determined the effects of dietary arginine or N-carbamylglutamate (NCG) supplementation during late gestation of sows on the microRNAs, vascular endothelial growth factor A (VEGFA) and endothelial nitric oxide synthase (eNOS) expression in umbilical vein. Twenty-seven landrace×large white sows at day (d) 90 of gestation were assigned randomly to three groups and fed the following diets: a control diet and the control diet supplemented with 1.0% L-arginine or 0.10% NCG. Umbilical vein of fetuses with body weight around 2.0 kg (oversized), 1.5 kg (normal) and 0.6 kg (intrauterine growth restriction, IUGR) were obtained immediately after farrowing for miR-15b, miR-16, miR-221, miR-222, VEGFA and eNOS real-time PCR analysis. Compared with the control diets, dietary Arg or NCG supplementation enhanced the reproductive performance of sows, significantly increased (P<0.05) plasma arginine and decreased plasma VEGF and eNOS (P<0.05). The miR-15b expression in the umbilical vein was higher (P<0.05) in the NCG-supplemented group than in the control group. There was a trend in that the miR-222 expression in the umbilical vein of the oversized fetuses was higher (0.05

Influence of maternal cigarette smoking during pregnancy on neonatal serum folate levels.

PURPOSE: Folate is an essential micronutrient for fetal development because of its role in de novo synthesis of DNA. The aim of this study was to compare neonatal serum folate levels of babies born to smoking and non-smoking mothers. METHODS: Infants of consenting pregnant mothers presenting at ≥37 weeks of gestation were enrolled. Subjects were divided into two groups based on their mother's smoking habits. Blood samples were obtained at birth (from the umbilical cord) and 1 month after delivery for the determination of serum folate levels using a chemiluminescence method. RESULTS: Among 140 consenting subjects, 108 (77%) brought their newborns to their scheduled visit 1 month after delivery, 68 of whom were non-smokers and 40 were smokers. Babies born to smoking mothers had significantly lower serum folate levels compared to those born to non-smoking mothers, both at birth (17.2 ± 5 vs. 24.3 ± 4.9; p < 0.01) and 1 month after delivery (11 ± 4.1 vs. 17.5 ± 4.3; p < 0.01). CONCLUSION: Our study is the first of its kind to demonstrate that smoking results in significant reductions in serum folate levels of newborns. These results suggest that folic acid supplementation may be required for expectant smoking mothers throughout pregnancy, not just during the first trimester. Similar supplementation may also be warranted for infants born to such mothers.

[Time serial changes in the concentrations of the etiological agents of fetal Yusho--PCDDs and PCDFs].

We determined polychlorinated dibenzofurans (PCDFs) and polychlorinated dibenzo-p-dioxins (PCDDs) in 6 preserved umbilical cords of fetal Yusho patients and in 11 preserved umbilical cords of Yusho suspected persons who were born to mothers with Yusho from 1970 to 2002, which were Yusho group. As a control, we also analyzed PCDFs and PCDDs in 15 preserved umbilical cords of babies who were born to healthy mothers, which was healthy group, in the same period of time. As a result, 2,3,4,7,8-pentachlorodibenzofuran and 1,2,3,4,7,8-hexachlorodibenzofuran, true causal agents of fetal Yusho, were only determined in the umbilical cords of fetal Yusho patients, except for one umbilical cords of Yusho suspected persons. Decreasing rate in concentrations of PCDFs and PCDDs seemed to greater in Yusho group than in healthy group during this period of time. Therefore, we considered due to high exposure to PCDFs some drug metabolizing enzymes such as aryl hydrocarbon hydroxylase were induced and the excretion of PCDFs and PCDDs were enhanced from the bodies of Yusho group. In order to clarify this hypothesis, further more detail researches are required.

[Time serial changes in the concentrations of the related agents to fetal Yusho--dioxin-like PCBs and PCBs].

We determined dioxin-like polychlorinated biphenyls (PCBs) and PCBs in 6 preserved umbilical cords of fetal Yusho patients and in 11 preserved umbilical cords of Yusho suspected persons who were born to mothers with Yusho from 1970 to 2002, which were Yusho group. As a control, we also analyzed dioxin-like PCBs and PCBs in 15 preserved umbilical cords of babies who were born to healthy mothers, which was healthy group, in the same period of time. As a result, concentrations of three dioxin-like PCBs, that is, #156, #157 and #189 which were 6 to 20 times higher in fetal Yusho patients than in healthy babies were still 4 to 6 times greater in Yusho group than in healthy group about 20 years after the outbreak of Yusho, but could not recognize this characteristic anymore about 30 years after the outbreak. Decreasing rate in concentrations of dioxin-like PCBs and PCBs seemed to higher in Yusho group than in healthy group during this period of time. Therefore, we considered due to heavy exposure to PCDFs some drug metabolizing enzymes such as aryl hydrocarbon hydroxylase were induced and excretion of the related agents to fetal Yusho were enhanced from the bodies of Yusho group. In order to clarify this hypothesis, further more detail studies are needed.

Higher de novo synthesized fatty acids and lower omega3- and omega6-long-chain polyunsaturated fatty acids in umbilical vessels of women with preeclampsia and high fish intakes.

Umbilical veins (UV) and arteries (UA) of preeclamptic women in Curaçao harbor lower long-chain polyunsaturated fatty acids (LCP). The present aim was to test these findings in Mwanza (Tanzania), whose inhabitants have high LCPomega3 and LCPomega6 intakes from Lake Victoria fish. Women with preeclampsia (n=28) in Mwanza had lower PUFA and higher 20:0 in UV and UA, compared with normotensive/non-proteinuric controls (n=31). Their UV 22:6omega3, 22:4omega6, LCPomega6, omega6, and LCPomega3+omega6 were lower, while saturated FA, potentially de novo synthesized FA (Sigmade novo) and (Sigmade novo)/(LCPomega3+omega6) ratio were higher. Their UA had higher 16:1omega7, omega7, 18:0, and 16:1omega7/16:0. Umbilical vessels in Mwanza had higher 22:6omega3, LCPomega3, omega3, and 16:0, and lower 22:5omega6, 20:2omega6, 18:1omega9, and omega9, compared to those in Curaçao. Preeclampsia in both Mwanza and Curaçao is characterized by lower LCP and higher Sigmade novo. An explanation of this might be placental dysfunction, while the similarity of umbilical vessel FA-abnormalities in preeclamptic and diabetic pregnancies suggests insulin resistance as a common denominator.

Supplementation of n-3 fatty acids during pregnancy and lactation reduces maternal plasma lipid levels and provides DHA to the infants.

OBJECTIVE: Docosahexaenoic acid (DHA, 22:6 n-3) is considered an essential fatty acid for the fetus and newborn infant, but the optimal level of supply is not known. We studied the effect of supplementing pregnant and lactating women with marine n-3 polyunsaturated fatty acids (PUFAs) as compared to n-6 PUFAs related to maternal and infant lipid levels. STUDY DESIGN: Five hundred and ninety pregnant women in weeks 17-19 of pregnancy were recruited. They were given either 10 mL cod liver oil (n-3 PUFAs) or corn oil (n-6 PUFAs) daily until three months after delivery, and 341 women took part in the study until giving birth. RESULTS: Maternal supplementation with cod liver oil increased the concentration of DHA in maternal as well as infant plasma and umbilical tissue phospholipids, as compared to corn oil. The maternal plasma triacylglycerol increase during pregnancy was less pronounced in women supplemented with cod liver oil as compared to corn oil. The concentration of high-density lipoprotein (HDL)-cholesterol was unchanged during pregnancy in the cod liver oil group, whereas it decreased in the corn oil group, promoting a greater increase in the ratio of total cholesterol/HDL-cholesterol in the corn oil group. CONCLUSION: Maternal supplementation with n-3 fatty acids during pregnancy and lactation provides more DHA to the infant and reduces maternal plasma lipid levels compared to supplementation with n-6 fatty acids.

Neurologic condition of healthy term infants at 18 months: positive association with venous umbilical DHA status and negative association with umbilical trans-fatty acids.

Prenatal long-chain polyunsaturated fatty acids (LCPUFAs) and trans-fatty acids may affect neurodevelopment. In healthy term children, we determined relationships between relative fatty acid contents of umbilical arteries and veins and neurodevelopment at 18 mo. The study comprised a mixed group of 317 breast-fed, formula-fed, and LCPUFA formula-fed children. Study endpoints were the Hempel neurologic examination resulting in a neurologic classification and neurologic optimality score (NOS), and the Bayley Psychomotor Developmental Index (PDI) and Mental Developmental Index (MDI). Fifteen children showed minor neurologic dysfunction (MND). The umbilical vein trans, trans-18:2n-6 content was higher in children with MND than in the normal group. The NOS was significantly reduced in infants with an umbilical vein docosahexaenoic acid (DHA) content within the lowest quartile. Umbilical vein arachidonic acid (AA) was related to NOS in univariate statistics but not in multivariate analyses. The sum of trans-fatty acids and that of C18 trans-fatty acids showed a negative association with NOS in both univariate and multivariate analyses. No associations were found between AA, DHA and total trans-fatty acids with PDI or MDI. In conclusion, neonates with a relatively low DHA status and those with high trans-fatty acid levels have a less favorable neurologic condition at 18 mo.

Morphometric analysis of brain lesions in rat fetuses prenatally exposed to low-level lead acetate: correlation with lipid peroxidation.

The effect of prenatal lead acetate exposure was studied microscopically together with the concentration of lead and lipid fluorescent products (LFP) in the brain of rat fetuses. Wistar rats were intoxicated with a lead solution containing either 160 or 320 ppm of lead acetate solution during 21 days through drinking water. The control group (ten rats) received deionized water for the same period. The rats were killed on gestation day 21 and fetuses were obtained; the placenta, umbilical cord and parietal cortex (Cx), striatum (St), thalamus (Th) and cerebellum (Ce) were collected for measuring tissue lead concentration, LFP as an index of lipid peroxidation and histopathologic examination. Lead contents were increased in placenta, umbilical cord, St, Th and Cx in both lead-exposed groups. Lead exposure increased (LFP) in placenta and umbilical cord, St, Th and Ce as compared to the control group. Histopathological examination showed severe vascular congestion in placenta, the Cx, St, Th and Ce with hyperchromatic and shrunken cells. Interstitial oedema was found in all regions studied of both lead exposed groups. The morphometric evaluation of the studied brain regions showed an absolute decrease in total cell number and increased number of damaged cells and interstitial oedema. Our results show that morphological changes in rat brain are correlated with increased lipid peroxidation, and the lead levels of the umbilical cord, however it is not clear whether oxidative stress is the cause or the consequence of these neurotoxic effects of lead.