Selenium protects against the likelihood of fetal neural tube defects partly via the arginine metabolic pathway.

BACKGROUND AND AIMS: Neural tube defects (NTDs) are severe congenital malformations and have a complex etiology. This study aimed to explore the association between selected essential trace elements (ETEs) and metabolic pathway markers in the serum of women and the likelihood of NTDs. METHODS: The study included 99 mothers of offspring with and 114 mothers of offspring without NTDs. Five ETEs (iron, zinc, selenium [Se], cobalt, and molybdenum) and 106 metabolic pathway markers in maternal serum were quantified. The associations between ETEs and metabolic pathway markers and the chance of NTDs were examined. Mediating effects of the metabolic pathway markers on the association between Se and the likelihood of NTDs were evaluated. RESULTS: Compared to a Se concentration below the median, a concentration above the median was associated with a decreased chance of NTDs with an odds ratio of 0.29 (95% confidence interval: 0.11-0.66). The concentrations of 32 metabolic pathway markers differed between mothers of offspring with and without NTDs; five of these (asymmetric dimethylarginine, ornithine, glutamate, proline, and phenylalanine) were associated with increased chances of NTDs, with adjusted odds ratios of 3.01 (1.31-7.31), 2.79 (1.18-6.86), 2.38 (1.03-5.75), 2.41 (1.05-5.75), and 2.27 (1.09-5.40), respectively, for the higher interquartile of concentration compared to the lower one. Three arginine pathway metabolic markers (i.e., dimethylarginine, ornithine, and proline) mediated the association between Se and the occurrence of NTDs. CONCLUSION: This study suggests an association between Se and a reduced chance of NTDs. The arginine pathway may play a role in mediating this association.

Prenatal uranium exposure and risk for fetal neural tube defects: A case-control study in women living in a rural area of northern China.

The adverse effects of uranium exposure on human health are well-known; less is known, however, regarding its association with congenital malformations. We conducted a case-control study to examine the association between prenatal exposure to uranium and risk for fetal neural tube defects (NTDs) using the concentration of uranium in placental tissue as an exposure marker in 408 NTD cases and 593 healthy controls. Uranium concentration was quantified with an inductively coupled plasma mass spectrometer. The odds ratios of NTDs for uranium exposure levels, categorized into quartiles, were estimated using logistic regression. The median concentration of uranium in the NTD group (0.409 ng/g) was significantly higher than that in the control group (0.218 ng/g). The risk for NTDs increased 2.52-fold (95% CI, 1.85-3.45) for concentrations of uranium above the median value for all participants. After adjusting for confounders, the risk for NTDs increased 1.36-fold (95% CI, 1.25-6.17), 1.77-fold (95% CI, 1.09-2.85), and 3.60-fold (95% CI, 2.30-5.64) for the second, third, and fourth quartiles of uranium concentrations compared to the lowest quartile, respectively. Prenatal exposure to uranium is a risk factor for NTDs in this population. Prospective studies are needed to further validate this finding.

Essential trace elements in placental tissue and risk for fetal neural tube defects.

This study examined the associations between concentrations of cobalt (Co), iron (Fe), manganese (Mn), molybdenum (Mo), selenium (Se), and zinc (Zn) in placental tissue and risks for NTDs with a case-control design consisting of 408 fetuses or newborns with neural tube defects (NTDs) and 593 non-malformed fetuses or newborns. The concentrations of Zn and Fe were determined by inductively coupled plasma-emission spectrometer and the other four elements by inductively coupled plasma-mass spectrometer. Element concentrations were presented in ng/g or µg/g dry weight of placental tissue. The associations between the levels of each of the six ETEs and risk for NTDs were evaluated using multivariable logistic regression, and the associations between overall levels of all six ETEs and risk for NTDs were examined using Bayesian kernel machine regression (BKMR). Concentrations above the median concentration of all participants for an individual element were associated with increased risk for NTDs: Mn, 3.17-fold (95% CI 2.35-4.28); Mo, 3.73-fold (95% CI 2.74-5.07); Se, 3.28-fold (95% CI 2.44-4.42); and Zn, 2.85-fold (95% CI 2.13-3.83), and a decreased risk for Co [OR, 0.18 (95% CI 0.14-0.25)]. The risk for NTDs increased with the increase in the concentrations of Mn, Mo, Se, and Zn, but decreased for Co, in the second, third, and fourth quartiles, respectively, compared to their lowest quartile (all Pstrend < 0.01). In BKMR model, the risk for NTDs increased constantly when the overall exposure levels were higher than the median of the six ETEs as a co-exposure mixture, and the associations between Co, Mn, Se, and Zn and NTD risk remained when the remaining five elements were taken into consideration simultaneously. Taken together, when evaluated individually, higher levels of Mn, Se, and Zn in placental tissue are associated with increased risk for NTDs, while higher levels of Co are associated with decreased risk for NTDs; when examined collectively, the risk of NTDs increases continuously when exposure levels are higher than the median of the six ETE mixture.

Selected essential trace elements in maternal serum and risk for fetal orofacial clefts.

BACKGROUND: Disturbances in the homeostasis of essential trace elements (ETEs) may interfere with embryonic organogenesis. However, the effect of ETEs on the development of orofacial clefts (OFCs) remains unclear. OBJECTIVES: This study examined associations between concentrations of iron (Fe), zinc (Zn), selenium (Se), cuprum (Cu), cobalt (Co), and molybdenum (Mo) in maternal serum and risk for OFCs in offspring. METHODS: A total of 130 cases of OFCs and 260 nonmalformed controls were included in this study. Concentrations of Fe, Zn, Se, Cu, Co, and Mo in maternal serum were detected by inductively coupled plasma mass spectrometry. We examined associations between levels of the six ETEs in maternal serum and risk for OFCs for each element separately using multilevel mixed-effects logistic regression and for all elements collectively using Bayesian kernel machine regression (BKMR). RESULTS: Higher concentrations of Mo and Co in maternal serum were associated with a decreased risk for OFCs in a dose-dependent manner, with odds ratios and 95% confidence intervals of 0.37 (0.20-0.66) for the second tertile of Mo, 0.28 (0.15-0.54) for the third tertile of Mo, 0.54 (0.29-1.00) for the second tertile of Co, and 0.47 (0.25-0.87) for the third tertile of Co, with the lowest tertile as the referent. When all six ETEs were considered together, increased levels of ETEs were associated with a decreased risk for OFCs. In addition, Mo showed a protective effect against risk for OFCs when the other ETEs were fixed at their 25th, 50th, or 75th percentile, whereas the protective effect of Co turned to a null effect in the BKMR model. No association was observed between levels of Fe, Zn, Se, or Cu and risk for OFCs in either statistical model. CONCLUSION: Elevated concentrations of Mo in maternal serum were associated with a reduced risk for OFCs.

Organochlorine pesticides exposure may disturb homocysteine metabolism in pregnant women.

Maternal exposure to organochlorine pesticides (OCPs) has an adverse impact on maternal and fetal health, and excessive homocysteine is related to a variety of adverse pregnancy outcomes. Biomimetic studies suggest that OCPs interfere with folate-dependent pathways, but little evidence is available from studies with human subjects. This study explored whether exposure to OCPs interferes with the metabolism of homocysteine, which is folate dependent. A total of 313 pregnant women at 12-20 weeks gestation were recruited in Shanxi province, China, from 2014 to 2015. Plasma concentrations of 20 OCPs, including dichlorodiphenyltrichloroethane and metabolites (DDTs), hexachlorobenzene (HCB), and hexachlorocyclohexanes (HCHs), were analyzed by gas chromatography-mass spectrometry. Blood folate concentrations were analyzed by microbiological assay, and plasma homocysteine concentrations were determined by enzyme-linked immunosorbent assay. Information on demographics, lifestyle behaviors, and folic acid supplementation was collected by in-person interview. Of the women, 99% reported having taken folic acid supplements. Results of a logistic regression analysis showed that higher plasma levels of OCPs were associated with increased odds of higher plasma homocysteine after adjustment for potential confounding factors. Positive correlations were observed between plasma OCPs and plasma homocysteine concentrations: HCB (r = 0.176, p = 0.002), ß-HCH (r = 0.172, p = 0.002), ρ,ρ'-DDE (r = 0.132, p = 0.020), ρ,ρ'-DDD (r = 0.161, p = 0.004), and ο,ρ'-DDT (r = 0.144, p = 0.011). Plasma concentrations of OCPs were negatively correlated with red blood cell (RBC) folate in the low-RBC-folate subgroup, but the correlations were not statistically significant. A positive correlation was observed between OCPs and homocysteine in the low-RBC-folate subgroup. These findings suggest that OCPs may disturb the folate-dependent homocysteine metabolism pathway.

Levels of uranium and thorium in maternal scalp hair and risk of orofacial clefts in offspring.

Uranium and thorium are common radioactive elements that exist in the environment. However, few environmental epidemiological studies have focused on their possible effects on congenital malformations. Here, we explored the association between uranium and thorium concentrations in maternal scalp hair grown from 3 months before to 3 months after conception, namely during the periconceptional period and the risk of orofacial clefts (OFCs) in offspring. Our study included 153 women whose pregnancies were affected by OFCs (cases) and 601 women who delivered infants without birth defects (controls) from four provinces in China. Face-to-face interviews were used to collect sociodemographic characteristics with a structured questionnaire. Concentrations of uranium and thorium in maternal scalp hair grown during the periconceptional period were detected using inductively coupled plasma-mass spectrometry. The risk of OFCs in association with higher concentrations of the two radioactive elements was estimated using odds ratios (ORs) and 95% confidence intervals (CIs) while adjusting for potential confounding factors. The levels of uranium and thorium in maternal hair were in agreement with the published literature. After adjusting for several confounders, the ORs of thorium in the highest, upper, and lower quartile versus the lowest quartile were 2.63 (95% CI, 1.41-4.92), 1.98 (95% CI, 1.03-3.79), and 2.73 (95% CI, 1.46-5.12), respectively. No association was found between levels of uranium and the risk of OFCs. Maternal periconceptional exposure to thorium may be a risk factor for OFCs in offspring.