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The increasing exposure to environmental chemicals calls for comprehensive non-targeted analysis to detect unrecognized substances in human samples. We examined human serum samples to classify compounds as endogenous or exogenous using public databases and to explore the relationships between exposure markers and metabolic patterns. Serum samples from 84 pregnant women at 32 weeks gestation were analyzed using LC-QToFMS. Using the PubChemLite for Exposomics database, we annotated and classified 106 compounds (51 endogenous, 55 exogenous). The compound patterns were analyzed using three dimensional reduction methods: Principal Component Analysis (PCA), regularized Generalized Canonical Correlation Analysis (rGCCA), and Uniform Manifold Approximation and Projection (UMAP). OPTICS clustering applied to these methods revealed two distinct clusters, with 89 % of significant compounds overlapping between clusters. The detected exogenous compounds included dietary substances, phthalates, nitrogenous compounds, and parabens. Pathway enrichment analysis showed that chemical exposure was linked to changes in amino acid metabolism, protein and mineral transport, and energy metabolism. While we found associations between exposure and metabolite changes, we could not establish causality. Our approach of analyzing both exogenous and endogenous chemicals from the same dataset using PubChemLite database presents a new method for exposome research, despite limitations in sample size and peak annotation accuracy. These findings contribute to understanding multiple chemical exposures and their metabolic effects in human biomonitoring.

Abstract Background Catch-up growth issues among children born small for gestational age (SGA) present a substantial public health challenge. Prenatal exposure to heavy metals can cause adverse effects on birth weight. However, comprehensive studies on the accurate assessment of individual blood concentrations of heavy metals and their effect on the failure to achieve catch-up growth remain unavailable. This study aimed to evaluate the effects of uterine exposure to toxic metals cadmium, lead, and mercury and essential trace metals manganese and selenium at low concentrations on the postnatal growth of children born SGA. Methods Data on newborn birth size and other factors were obtained from the medical record transcripts and self-administered questionnaires of participants in the Japan Environment and Children’s Study. The blood concentrations of lead, cadmium, mercury, selenium, and manganese in pregnant women in their second or third trimester were determined by inductively coupled plasma mass spectrometry. These heavy metal concentrations were also assessed in pregnant women’s cord blood. Furthermore, the relationship between each heavy metal and height measure/catch-up growth in SGA children aged 4 years was analyzed using linear and logistic regression methods. These models were adjusted for confounders. Results We studied 4683 mother–child pairings from 103,060 pregnancies included in the Japan Environment and Children’s Study. Of these, 278 pairs were also analyzed using cord blood. At 3 and 4 years old, 10.7% and 9.0% of children who were born below the 10th percentile of body weight had height standard deviation scores (SDSs) below 2, respectively. Cord blood cadmium concentrations were associated with the inability to catch up in growth by 3 or 4 years old and the height SDS at 3 years old. In maternal blood, only manganese was positively associated with the height SDS of SGA children aged 2 years; however, it was not significantly associated with catch-up growth in these children. Conclusion Cadmium exposure is associated with failed catch-up development in SGA children. These new findings could help identify children highly at risk of failing to catch up in growth, and could motivate the elimination of heavy metal (especially cadmium) pollution to improve SGA children’s growth.

Despite the acknowledged relationship between the usual (preferred) walking speed (UWS) and health, there is currently no practical method available to reliably and accurately detect slight changes in UWS. This study aimed to explore whether either of the following two phenomena occurs during continuous daily walking in various periods: (a) Similarity between the most frequent cadences in the two periods. (b) The occurrence of the most frequent cadence in at least one of the two periods during the other period, with a frequency close to that of the most frequent cadence. In August 2021, invitations to participate in the study were extended via email to participants that took part in the Japan COVID-19 and Society Internet Surveys (JACSIS). A mobile phone application that collected step data during continuous walking was provided to the participants, and data were collected from December 1, 2021, to January 31, 2022. While 1022 participants installed the phone application, only 505 had measurement data for ten days or more in each of the two months of the study duration. The cadence during continuous walking was automatically measured daily from 05:00 to 21:00. Most participants exhibited at least one of the phenomena mentioned above, confirming a common, notably frequent, invariant cadence over time. Overall, this method allows for the identification of minor reductions and lower bounds of decline in UWS. This study illustrates the potential for tracking a decreasing trend in UWS. Early detection of a downward trend permits individuals to take timely remedial action, as recovery is relatively easy, and the confirmation of even a slight recovery bolsters recovery motivation.

Abstract Recently, prediction of gestational diabetes mellitus (GDM) using artificial intelligence (AI) from medical records has been reported. We aimed to evaluate GDM-predictive AI-based models using birth cohort data with a wide range of information and to explore factors contributing to GDM development. This investigation was conducted as a part of the Japan Environment and Children's Study. In total, 82,698 pregnant mothers who provided data on lifestyle, anthropometry, and socioeconomic status before pregnancy and the first trimester were included in the study. We employed machine learning methods as AI algorithms, such as random forest (RF), gradient boosting decision tree (GBDT), and support vector machine (SVM), along with logistic regression (LR) as a reference. GBDT displayed the highest accuracy, followed by LR, RF, and SVM. Exploratory analysis of the JECS data revealed that health-related quality of life in early pregnancy and maternal birthweight, which were rarely reported to be associated with GDM, were found along with variables that were reported to be associated with GDM. The results of decision tree-based algorithms, such as GBDT, have shown high accuracy, interpretability, and superiority for predicting GDM using birth cohort data.

Abstract Background Mother-to-infant bonding (MIB) is critical for the health and well-being of the mother and child. Furthermore, MIB has been shown to boost the social-emotional development of infants, while also giving mothers a sense of happiness in raising their children. Nausea and vomiting during pregnancy (NVP) is a normal complication of pregnancy, occurring in approximately 50–90% of pregnant women in the early stages of pregnancy. Despite widespread knowledge of MIB and postpartum depression, little research attention has been given to the effects of NVP on MIB. This study aimed to investigate the relationship between NVP and MIB and the mediating effects of postpartum depression. Methods We analyzed the data of 88,424 infants and 87,658 mothers from the Japan Environment and Children’s Study (JECS), which is a government-funded nationwide birth prospective cohort study. The Japanese version of the Mother-to-Infant Bonding Scale (MIBS-J) was used to assess MIB, and the Edinburgh Postpartum Depression Scale (EPDS) was utilized to assess postpartum depression. We divided participants into four groups according to a self-reported questionnaire assessing NVP (No NVP, Mild NVP, Moderate NVP, and Severe NVP). MIB disorder was defined as a MIBS-J score ≥ 5. Logistic analysis was performed to evaluate the effect of NVP on MIB disorder at one year after delivery. A mediation analysis was conducted to examine whether postpartum depression mediated the association between NVP and MIBS-J scores. Results The logistic regression analysis results revealed reduced risks of MIB disorder among mothers with Moderate NVP (adjusted OR 0.93; 95% confidence interval, 0.86–0.99) and Severe NVP (adjusted OR 0.81; 95% confidence interval, 0.74–0.89), compared to those with No NVP. The mediation analysis revealed that NVP positively correlated with MIBS-J score in the indirect effect via postpartum depression, while NVP (Mild NVP, Moderate NVP, and Severe NVP) negatively correlated with MIBS-J score in the direct effect. Conclusion The risks of MIB disorder were reduced in the Moderate NVP and Severe NVP mothers, although NVP inhibited the development of MIB via postpartum depression. The development of effective interventions for postpartum depression is important to improve MIB among mothers with NVP.

One-carbon metabolism (OCM) is a complex and interconnected network that undergoes drastic changes during pregnancy. In this study, we investigated the longitudinal distribution of OCM-related metabolites in maternal and cord blood and explored their relationships. Additionally, we conducted cross-sectional analyses to examine the interrelationships among these metabolites. This study included 146 healthy pregnant women who participated in the Chiba Study of Mother and Child Health. Maternal blood samples were collected during early pregnancy, late pregnancy, and delivery, along with cord blood samples. We analyzed 18 OCM-related metabolites in serum using stable isotope dilution liquid chromatography/tandem mass spectrometry. We found that serum S-adenosylmethionine (SAM) concentrations in maternal blood remained stable throughout pregnancy. Conversely, S-adenosylhomocysteine (SAH) concentrations increased, and the total homocysteine/total cysteine ratio significantly increased with advancing gestational age. The betaine/dimethylglycine ratio was negatively correlated with total homocysteine in maternal blood for all sampling periods, and this correlation strengthened with advances in gestational age. Most OCM-related metabolites measured in this study showed significant positive correlations between maternal blood at delivery and cord blood. These findings suggest that maternal OCM status may impact fetal development and indicate the need for comprehensive and longitudinal evaluations of OCM during pregnancy.

Abstract Infants make spontaneous movements from the prenatal period. Several studies indicate that an atypical pattern of body motion during infancy could be utilized as an early biomarker of autism spectrum disorders (ASD). However, to date, little is known about whether the body motion pattern in neonates is associated with ASD risk. The present study sought to clarify this point by examining, in a longitudinal design, the link between features of spontaneous movement at about two days after birth and ASD risk evaluated using the Modified Checklist for Autism in Toddlers by their caregivers at 18 months old. The body movement features were quantified by a recently developed markerless system of infant body motion analysis. Logistic regression analysis revealed that ASD risk at 18 months old is associated with the pattern of spontaneous movement at the neonatal stage. Further, logistic regression based on body movement features during sleep shows better performance in classifying high- and low-risk infants than during the awake state. These findings raise the possibility that early signs of ASD risk may emerge at a developmental stage far earlier than previously thought.

Background: The association of maternal antibiotic exposure during pregnancy with childhood allergic diseases remains unclear. Objective: We aimed to evaluate the association of maternal exposure to antibiotic use during pregnancy with childhood allergic diseases up to the age of 3 years by using data from a large Japanese birth cohort. Methods: We analyzed data on 78,678 pregnant women and their offspring aged 0 to 3 years. Prenatal antibiotic exposure was defined as the use of any antimicrobial agent during pregnancy. Information was collected from maternal interviews and medical record transcripts. The outcome variables in this study included preschool asthma, wheezing, food allergy, atopic dermatitis, eczema, allergic rhinoconjunctivitis, and any allergic disease. We used logistic regression analysis to evaluate the association of antibiotic exposure during pregnancy with childhood allergic diseases. Results: Among the participating mothers, 28.5% used antibiotics during pregnancy. Antibiotic exposure during pregnancy was associated with preschool asthma (adjusted odds ratio [aOR] = 1.12 [95% CI = 1.06-1.19]), wheezing (aOR = 1.11 [95% CI = 1.07-1.15]), allergic rhinoconjunctivitis (aOR = 1.10 [95% CI = 1.03-1.17]) and any allergic disease (aOR = 1.09 [95% CI = 1.05-1.14]) in offspring up to age 3 years. In contrast, maternal antibiotic use was not associated with food allergies, atopic dermatitis, or eczema. Additionally, the significant associations were not influenced by the timing of antibiotic exposure, sex of the infants, or maternal history of allergies. Conclusion: Maternal antibiotic exposure during pregnancy is associated with an increased risk of childhood respiratory allergies.

Abstract We investigated umbilical cord serum microRNA (miRNA) profiles to identify biomarkers of a risk for obesity later in life. Participating children were divided into high‐ and low‐risk groups of obesity based on the timing of adiposity rebound and the body mass index (BMI) at 5 years and randomly selected from each group for this study. 3D‐Gene® Human miRNA Oligo Chip was performed using cord serum in five children of both groups. The most relevant miRNAs were confirmed in 33 children of the groups using the TaqMan® microRNA assay. We detected five cord serum miRNAs differentially expressed in children at high risk of obesity compared with the levels in children at low risk, namely, miR‐516‐3p and miR‐130a‐3p with increased levels and miR‐1260b, miR‐4709‐3p, and miR194‐3p with decreased levels. This study provides the first identification of altered umbilical cord serum miRNAs in childhood obesity.

A fetal growth restriction is related to adverse child outcomes. We investigated risk ratios and population-attributable fractions (PAF) of small-for-gestational-age (SGA) infants in the Japanese population. Among 28,838 infants from five ongoing prospective birth cohort studies under the Japan Birth Cohort Consortium, two-stage individual-participant data meta-analyses were conducted to calculate risk ratios and PAFs for SGA in advanced maternal age, pre-pregnancy underweight, and smoking and alcohol consumption during pregnancy. Risk ratio was calculated using modified Poisson analyses with robust variance and PAF was calculated in each cohort, following common analyses protocols. Then, results from each cohort study were combined by meta-analyses using random-effects models to obtain the overall estimate for the Japanese population. In this meta-analysis, an increased risk (risk ratio, [95% confidence interval of SGA]) was significantly associated with pre-pregnancy underweight (1.72 [1.42–2.09]), gestational weight gain (1.95 [1.61–2.38]), and continued smoking during pregnancy (1.59 [1.01–2.50]). PAF of underweight, inadequate gestational weight gain, and continued smoking during pregnancy was 10.0% [4.6–15.1%], 31.4% [22.1–39.6%], and 3.2% [−4.8–10.5%], respectively. In conclusion, maternal weight status was a major contributor to SGA births in Japan. Improving maternal weight status should be prioritized to prevent fetal growth restriction.

Abstract Maternal tobacco smoke exposure during pregnancy impairs fetal body size, including head circumference (HC) at birth; however, the mechanism still remains unclear. This analysis using a large prospective cohort study evaluated the impact of maternal tobacco exposure on their offspring’s HC and the relationship with placental weight ratio (PWR) and placental abnormalities. Parents-children pairs (n = 84,856) were included from the 104,065 records of the Japan Environmental and Children’s Study. Maternal perinatal clinical and social information by self-administered questionnaires, offspring’s body size, and placental information were collected. Data were analyzed with binominal logistic regression analysis and path analysis. Logistic regression showed significantly elevated adjusted odds ratio (aOR) (1.653, 95% CI 1.387–1.969) for the impact of maternal smoking during pregnancy on their offspring’s smaller HC at birth. Maternal exposure to environmental tobacco smoke in the non-smoking group did not increase aOR for the smaller HC. Path analysis showed that maternal smoking during pregnancy decreased the offspring’s HC directly, but not indirectly via PWR or placental abnormalities. The quitting smoking during pregnancy group did not increase aOR for the smaller HC than the non-smoking group, suggesting that quitting smoking may reduce their offspring’s neurological impairment even after pregnancy.

Constipation is common in children and can significantly affect quality of life. Prebiotics are reportedly helpful for constipation in adults, but few studies have examined their use in young children. In this study, the effect of 1-kestose (kestose), which has excellent bifidobacterial growth properties, on constipation in kindergarten children (n = 11) was compared with that of maltose (n = 12) in a randomized, double-blind study. Three grams of kestose per day for 8 weeks did not affect stool properties, but significantly increased the number of defecations per week (Median; 3 → 4 times/week, p = 0.017, effect size = 0.53). A significant decrease in Intestinibacter, a trend toward increased bifidobacteria, and a trend toward decreased Clostridium sensu stricto were observed after kestose ingestion, while concentrations of short-chain fatty acids in stools were unchanged.

Background: Growth restriction in the prenatal period is a significant public health concern. Metals can negatively affect birth size, and pregnant women may be exposed to metal mixtures. Comprehensive studies analyzing the effects of combined metal exposure with accurate individual blood metal concentrations are limited. The current study investigated the associations between maternal metal exposure and birth size in a large, nationwide Japanese cohort using individual and mixed model approaches. Methods: Lead, cadmium, mercury, selenium, and manganese blood concentrations were measured in pregnant women in the Japan Environment and Children’s Study (JECS). Measurements of infant birth size—including body weight, body length, and head and chest circumference—were collected. Linear and logistic regressions were used for birth size measurements and the odds of an infant being small in size for gestational age, respectively. Associations between combined metal mixtures and measurements at birth were evaluated using quantile g-computation and Bayesian kernel machine regression (BKMR). Results: Of the 103,060 JECS pregnancies, 93,739 mother–infant pairs were analyzed. The linear regression models showed that lead, selenium, cadmium, and manganese—but not mercury—were associated with body weight. Cadmium was associated with length and chest circumference and mercury was associated with head circumference. Quantile g-computation revealed that manganese increased infant birth weight, length, head circumference, and chest circumference. Lead was the strongest negative factor for infant birth weight, length, head circumference, and chest circumference. The BKMR analysis revealed that the metals had an additive, rather than a synergistic effect. Conclusion: Metal exposure is associated with infant birth size, with lead and manganese playing a more significant role in Japan. The effects of prenatal combined metal exposure at low levels warrant public health attention.

Background: Manganese (Mn) is an essential trace metal and a neurotoxicant. Adverse effects of Mn exposure on the neurodevelopment of children have been reported. However, there is limited information on the effects of maternal exposure during pregnancy. Objectives: We aimed to investigate the association between maternal and cord blood Mn levels and neurodevelopment in children aged between 6 months and 3 years using data from a Japanese nationwide birth cohort study. Methods: We used the data of 63,767 mother–child pairs with maternal blood Mn measurements recorded during the second and third trimester and of 3,787 mother–child pairs with cord blood Mn measurements. Neurodevelopment was assessed using the Japanese version of the Ages and Stages Questionnaires, third edition (J-ASQ-3), which was completed by parents or guardians at 6 months, 1 year, 1.5 years, 2 years, 2.5 years, and 3 years of age. Results: The median maternal and cord blood Mn levels were 15.2 and 44.5 ng/g, respectively. After adjusting for covariates, both maternal and cord blood Mn levels were negatively associated with J-ASQ-3 scores. Maternal blood Mn levels were negatively associated with gross motor function scores at all ages except for that at 1.5 years (adjusted β: −0.55 to −1.23 for a two-fold increase in maternal Mn levels). The risk of developmental delay (score below the cut-off) in gross motor function increased at the same time points (adjusted odds ratio: 1.08 to 1.13). In the subgroup, cord blood Mn levels were negatively associated with gross motor function scores at 1, 2, and 2.5 years (adjusted β: −1.84 to −3.27). Discussion: Maternal blood Mn levels during pregnancy and cord blood Mn levels were negatively associated with neurodevelopment in children up to 3 years of age. Excessive maternal and fetal exposure to Mn may have adverse effects on neuromotor function in children.

Abstract Aims/Introduction Gut microbiota have various effects on human health. Some previous reports have shown that gut microbiota change during pregnancy and affect metabolism, but others have shown that microbiota do not change. Here, we examined the gut microbiota and glycoalbumin levels of 45 healthy Japanese women during pregnancy. Materials and Methods We carried out 16S rRNA gene sequencing analyses of maternal stool samples and compared the gut microbiota composition of samples from women in early and late pregnancy. We also examined the association between gut microbiota and maternal characteristics, including glycoalbumin. Results Microbiota composition in early and late pregnancy did not differ, according to principal coordinate analysis of weighted and unweighted UniFrac distances. Shannon indices were not different between early and late pregnancy. The proportion of one phylum, TM7, significantly decreased in late pregnancy compared with early pregnancy, but the proportions of other major phyla did not change. The Shannon index of late pregnancy was negatively associated with pregestational body mass index and positively correlated with glycoalbumin level, with adjustment of covariates. Conclusions We concluded that Japanese women did not show obvious differences in gut microbiota during pregnancy, except for TM7, and that the diversity of gut microbiota might affect maternal metabolism. As this study had limited statistical power, further large‐scale studies are required.

Abstract Purpose This study aimed to investigate neurodevelopment in children conceived via in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) with several types of embryo transfers. Methods We analyzed data for 77 928 children and their mothers included in a Japanese birth cohort study. Among the included children, 4071 were conceived via IVF, while 1542 were conceived via ICSI. Neurodevelopmental delay at the age of 3 years was assessed using the Japanese version of the Ages and Stages Questionnaires, 3rd edition. Results In the crude model, the odds ratios for developmental delay in 1–4 domains were higher among children conceived via IVF, ICSI, and non‐ART (ovulatory induction or intrauterine insemination) than in spontaneously conceived children. After adjusting for parental background factors and the child's sex, there were no differences in the risk of developmental delay when comparing singletons conceived by IVF, ICSI, or non‐ART and those conceived spontaneously. Higher odds ratios for developmental delay in one domain were observed in singleton girls conceived via IVF when compared with those who were spontaneously conceived. Conclusion Most cases of developmental delay may be associated with multiple pregnancies and factors related to infertility, such as parental age, irrespective of the use of ART.

Bile acids are major components of bile; they emulsify dietary lipids for efficient digestion and absorption and act as signaling molecules that activate nuclear and membrane receptors. The vitamin D receptor (VDR) is a receptor for the active form of vitamin D and lithocholic acid (LCA), a secondary bile acid produced by the intestinal microflora. Unlike other bile acids that enter the enterohepatic circulation, LCA is poorly absorbed in the intestine. Although vitamin D signaling regulates various physiological functions, including calcium metabolism and inflammation/immunity, LCA signaling remains largely unknown. In this study, we investigated the effect of the oral administration of LCA on colitis in a mouse model using dextran sulfate sodium (DSS). Oral LCA decreased the disease activity of colitis in the early phase, which is a phenotype associated with the suppression of histological injury, such as inflammatory cell infiltration and goblet cell loss. These protective effects of LCA were abolished in VDR-deleted mice. LCA decreased the expression of inflammatory cytokine genes, but this effect was at least partly observed in VDR-deleted mice. The pharmacological effect of LCA on colitis was not associated with hypercalcemia, an adverse effect induced by vitamin D compounds. Therefore, LCA suppresses DSS-induced intestinal injury in its action as a VDR ligand.

The increase in fetal requirements of long-chain polyunsaturated fatty acids (LCPUFAs) during pregnancy alters maternal fatty acid metabolism, and therefore, fatty acid desaturase (FADS) gene polymorphisms may change blood fatty acid composition or concentration differently during pregnancy. We investigated the relationship between a FADS1 single-nucleotide polymorphism (SNP) and maternal serum LCPUFA levels in Japanese pregnant women during the first and third trimesters and at delivery. Two hundred and fifty-three pregnant women were included, and fatty acid compositions of glycerophospholipids in serum (weight %) and the FADS1 SNP rs174547 (T/C) were analyzed. LCPUFAs, including arachidonic acid (ARA) and docosahexaenoic acid (DHA), significantly decreased from the first to the third trimester of pregnancy. Furthermore, DHA significantly decreased from the third trimester of pregnancy to delivery. At all gestational stages, linoleic acid (LA) and α-linolenic acid were significantly higher with the number of minor FADS1 SNP alleles, whereas γ-linolenic acid and ARA and the ARA/LA ratio were significantly lower. DHA was significantly lower with the number of minor FADS1 SNP alleles only in the third trimester and at delivery, suggesting that genotype effects become more obvious as pregnancy progresses.

Background: Discontinuing chemotherapy worsens cancer prognosis. This study aimed to investigate the relationship between nutritional status at the start of chemotherapy and chemotherapy discontinuation in patients with ovarian, fallopian tube, and primary peritoneal cancer. Methods: This was a retrospective cohort study. One hundred and forty-six patients to whom weekly paclitaxel and carboplatin were administered as postoperative chemotherapy were included. Six courses in 21-day cycles were defined as complete treatment. As nutritional indicators, body mass index, weight change rate, serum albumin, total lymphocyte count, prognostic nutritional index, and C-reactive protein-to-albumin ratio (CAR) were compared between complete and incomplete treatment groups. Patients were divided into two groups according to CAR. The number of chemotherapy cycles was compared between these two groups. A Cox proportional hazard model was used for covariate adjustment. Results: Several indicators differed between complete and incomplete treatment groups, and among the indicators, CAR had the highest discriminatory ability. The number of chemotherapy cycles was shorter in the high CAR group than in the low CAR group. A high CAR was associated with chemotherapy interruption even after adjusting for covariates. Conclusion: Based on CAR, nutritional status before chemotherapy is suggested to be associated with the risk of chemotherapy discontinuation.

Neonicotinoid pesticides (NPs) are neurotoxic substances. They are highly effective as insecticides owing to their water solubility, permeability, and long-lasting activity. These molecules are structurally similar to nicotine and act as nicotinic acetylcholine receptor agonists. The administration of NPs to experimental animals reportedly causes neuromuscular and reproductive disorders. Moreover, recently reported problems caused by NPs include damage to land-dwelling creatures (such as mammals and birds), hydrobiology, and ecosystems. This review summarizes the recent reports on NP concentrations detected in river systems in several Japanese regions. These values were lower than the environmental standard values; however, seasonal variations were observed. Furthermore, reports on NP-induced testicular and ovarian toxicity were examined, revealing that the mechanism of injury is mainly driven by oxidative stress. The use of NPs is declining worldwide, except in Japan; therefore, continuous monitoring remains necessary.

Abstract Aims/Introduction We aimed to explore novel predictive markers for gestational diabetes mellitus using metabolomic analysis in pregnant Japanese women. Materials and Methods We carried out a case–control study with a cohort of participants enrolled during the first or early second trimester in the Center of Chiba Unit of the Japan Environment and Children's Study. Participants were classified as either gestational diabetes mellitus cases or matched controls based on age, body mass index and parity. Metabolite levels of their serum and urine obtained randomly before the diagnosis of gestational diabetes mellitus were analyzed using hydrophilic interaction chromatography tandem mass spectrometry. Orthogonal projections to latent structures discriminant analysis was carried out to investigate metabolome profiles for the different groups. Metabolites with a variable importance in projection value of >1.5 were identified as potential markers. Results In total, 242 participants were enrolled in the study, of which 121 were cases. The R2X, R2Y and Q2 parameters for the discrimination ability of the resulting models were 0.388, 0.492 and 0.45 for serum, and 0.454, 0.674 and 0.483 for urine, respectively. We finally identified three metabolites in serum and 20 in urine as potential biomarkers. Glutamine in serum and ethanolamine and 1,3‐diphosphoglycerate in urine showed >0.8 area under the receiver operating characteristic curves. Conclusions The present study identified serum and urine metabolites that are possible predictive markers of subsequent gestational diabetes mellitus in Japanese women. Further studies are required to elucidate their efficacy.

Background The relationship between radiation dose to the ipsilateral lung and subsequent radiation‐induced lung disease (RILD) in breast cancer patients with pectus excavatum (PE) undergoing radiation therapy (RT) to residual breast tissue after breast‐conserving surgery has not yet been established. The incidence of RILD in such patients with PE, meaning that a large volume of the lung is within the radiation field, has not been determined. Therefore, the aim of this study was to determine the relationship between these factors. Methods The study cohort comprised 133 women who underwent three‐dimensional conformal RT to residual breast tissue after breast‐conserving surgery for breast cancer. Diagnoses of PE were based on Haller's, frontosagittal, and Monden's depression indices. Radiation doses to the ipsilateral lung were established from dose‐volume histograms. Results Fifty of the 133 participants (37.6%) were diagnosed with RILD; all were asymptomatic. Multivariate analysis revealed a significant correlation between the incidence of RILD and the administration of > 30 Gy (V30). Surprisingly, although patients with PE received higher ipsilateral lung doses, they were less likely to develop RILD than those without PE. Conclusions Our data indicate that the incidence of RILD is correlated with the administration of > 30 Gy (V30) and that PE is not a risk factor for RILD after RT to residual breast tissue after breast‐conserving surgery for breast cancer. Surprisingly, individuals with PE may have a lower incidence of RILD than those without this condition.

Background The Ki‐67 labeling index (LI) is a well‐known prognostic factor for primary breast cancer, but its clinical significance for metachronous axillary lymph node (ALN) recurrence has not been well documented. Methods Ki‐67 expression in primary tumors (PTs) and ALN metastases (ALNMs) was evaluated in 21 patients and quantified to investigate the relationship between Ki‐67 LIs in PTs and metachronous ALNMs. Results The median Ki‐67 LIs in the PTs and ALNMs were 25.2% (range: 2.3–80.2%) and 70% (range: 10.4–97.4%), respectively. A majority of patients had higher Ki‐67 LIs in ALNMs than in PTs (76.2%, 16/21). Disease‐specific survival was significantly better in patients with a lower‐than‐median ALNM Ki‐67 LI (P = 0.019, log‐rank test). Receiver operating characteristic curves showed a PT Ki‐67 LI of 62.8% as the optimal cutoff value and an ALNM Ki‐67 LI of 65.1%. Accordingly, we divided the patients into four groups: PT Ki‐67 LI lower than 62.8%/ALNM Ki‐67 LI lower than 65.1%, PT Ki‐67 LI lower/ALNM Ki‐67 LI higher, PT Ki‐67 LI higher/ALNM Ki‐67 LI higher, and PT Ki‐67 LI higher/ALNM Ki‐67 LI lower. Disease‐specific survival was significantly better in patients with Ki‐67 LI lower/ALNM Ki‐67 LI lower than in the other groups. Conclusion This is the first study to show that the Ki‐67 LI in metachronous ALNM is a prognostic factor for patients with metachronous ALN recurrence of breast cancer.

Existing evidence on the correlation between maternal vitamin D concentrations and birth outcomes is conflicting. Investigation of these associations requires accurate assessment of vitamin D status, especially in individuals with low 25-hydroxyvitamin D (25(OH)D) concentrations. This study examined the correlations between birth outcomes and the maternal vitamin D metabolite ratio (VMR) 1 (defined as the ratio of 24,25(OH)2D3 to 25(OH)D) and VMR2 (defined as the ratio of 3-epi-25(OH)D3 to 25(OH)D) using data from the Japan Environment and Children’s Study at Chiba Regional Center. A total of 297 mother–neonate pairs were analyzed. Using liquid chromatography–tandem mass spectrometry, we measured 25(OH)D2, 25(OH)D3, 24,25(OH)2D3, and 3-epi-25(OH)D3 concentrations in maternal serum samples. These data were analyzed in relation to birth anthropometric data using multivariable linear regression. Of the study participants, 85.2% showed insufficient vitamin D concentrations. VMR1 was strongly correlated with 25(OH)D concentrations, whereas VMR2 showed a weak correlation. Only VMR2 was associated with all anthropometric data. VMR2 in pregnant women with low vitamin D blood concentrations is a useful marker for neonatal anthropometric data and is independent of 25(OH)D. Accurate measurement of vitamin D metabolites could help better understand the effects of vitamin D on birth outcomes.

Inadequate maternal iodine intake affects thyroid function and may impair fetal brain development. This study investigated the association between maternal iodine intake during pregnancy and neurodevelopmental delay in offspring at 1 and 3 years of age using a nationwide birth cohort: the Japan Environment and Children’s Study. We assessed dietary iodine intake during pregnancy using a food frequency questionnaire and child neurodevelopment using the Japanese translation of the Ages and Stages Questionnaire, Third Edition. The risk of delay (score below the cut-off value) for fine motor domain at 1 year of age was increased in the lowest quintile iodine intake group compared with the fourth quintile iodine intake group. The risk of delay for problem-solving at 1 year of age was increased in the lowest and second quintile iodine intake group and decreased in the highest quintile iodine intake group. The risk of delay for communication, fine motor, problem-solving, and personal–social domains at 3 years of age was increased in the lowest and second quintile iodine intake group compared with the fourth quintile iodine intake group, while the risk of delay for fine motor and problem-solving domains was decreased in the highest quintile iodine intake group. Low iodine intake levels in pregnancy may affect child neurodevelopment.

Background: Several studies have reported the adverse effects of caffeine intake during pregnancy on fetal health. However, the effects of caffeine intake from green and oolong teas has not been investigated, despite the considerable consumption of these teas in Japan and the potential inhibitory effects of catechins—chemicals present at relatively high levels in green and oolong teas—on folic acid absorption. The potential associations of serum folate levels with caffeinated beverage consumption and catechin levels remain largely unstudied. The present study aimed to determine these associations in pregnant Japanese women. Methods: Pregnant women (n = 2,701) not receiving folate supplementation were enrolled at the Chiba Unit Center, a regional site of the Japan Environment and Children’s Study (JECS). Serum folate levels were measured using an Access folate assay kit, and nutrient and caffeine intakes were assessed using a self-administered food frequency questionnaire that was previously evaluated in Japanese populations. Results: The low and normal serum folate groups reported caffeine intakes of 42.3 mg/1,000 kcal and 34.4 mg/1,000 kcal, respectively, and tannin intakes of 40.8 mg/1,000 kcal and 36.3 mg/1,000 kcal, respectively. Multiple regression analyses revealed negative associations of serum folate levels with caffeine and tannin intakes and a positive association between serum folate levels and dietary folate intake. Conclusions: Considering the negative associations of caffeine and tannin levels with serum folate levels, pregnant women should consume caffeinated beverages, such as coffee and green/oolong teas, with caution.

Background: α-cyclodextrin (α-CD) is one of the dietary fibers that may have a beneficial effect on cholesterol and/or glucose metabolism, but its efficacy and mode of action remain unclear. Methods: In the present study, we examined the anti-hyperglycemic effect of α-CD after oral loading of glucose and liquid meal in mice. Results: Administration of 2 g/kg α-CD suppressed hyperglycemia after glucose loading, which was associated with increased glucagon-like peptide 1 (GLP-1) secretion and enhanced hepatic glucose sequestration. By contrast, 1 g/kg α-CD similarly suppressed hyperglycemia, but without increasing secretions of GLP-1 and insulin. Furthermore, oral α-CD administration disrupts lipid micelle formation through its inclusion of lecithin in the gut luminal fluid. Importantly, prior inclusion of α-CD with lecithin in vitro nullified the anti-hyperglycemic effect of α-CD in vivo, which was associated with increased intestinal mRNA expressions of SREBP2-target genes (Ldlr, Hmgcr, Pcsk9, and Srebp2). Conclusions: α-CD elicits its anti-hyperglycemic effect after glucose loading by inducing lecithin inclusion in the gut lumen and activating SREBP2, which is known to induce cholecystokinin secretion to suppress hepatic glucose production via a gut/brain/liver axis.

Chemokine (C-C motif) ligand 17 (CCL17) is a pro-allergic factor: high CCL17 levels in cord blood (CB) precede later allergic predisposition. Short-chain fatty acid (SCFA) treatment during pregnancy has been shown to protect mouse pups against allergic diseases. The maternal microbial metabolome during pregnancy may affect fetal allergic immune responses. We therefore examined the associations between CB CCL17 and gut SCFA levels in healthy pregnant Japanese women. CB CCL17 serum levels at birth, and maternal non-specific IgE levels in maternal sera at 32 weeks of gestation were measured. Maternal stool samples were collected at 12 (n = 59) and 32 (n = 58) weeks of gestation for gut microbiota analysis, based on barcoded 16S rRNA sequencing and metabolite levels. The CB CCL17 levels correlated negatively with butyrate concentrations and positively with isobutyrate at 12 weeks; CB CCL17 correlated positively with valerate and lactate at 32 weeks. Similarly, butyrate levels correlated negatively with maternal non-specific IgE levels, whereas the lactate concentration correlated positively with IgE levels. At 32 weeks, the Shannon diversity index (SDI) of Firmicutes and Proteobacteria correlated negatively with CB CCL17 levels, while those of the total microbiota correlated positively with the CB CCL17 levels. These metabolites may alter fetal immune responses. This study provides the first link between maternal metabolites during pregnancy and the risk of allergic diseases in human offspring.

Polychlorinated biphenyls (PCBs) have been associated with adverse human reproductive and fetal developmental measures or outcomes because of their endocrine-disrupting effects; however, the biological mechanisms of adverse effects of PCB exposure in humans are not currently well established. In this study, we aimed to identify the biological pathways and potential biomarkers of PCB exposure in maternal and umbilical cord serum using a hydrophilic interaction chromatography-tandem mass spectrometry (HILIC-MS/MS) metabolomics platform. The median concentration of total PCBs in maternal (n = 93) and cord serum (n = 93) were 350 and 70 pg g−1 wet wt, respectively. PCB levels in maternal and fetal serum from the Chiba Study of Mother and Children's Health (C-MACH) cohort are comparable to those of earlier cohort studies conducted in Japan, the USA, and European countries.We used the random forest model with the metabolome profile to predict exposure levels of PCB (first quartile [Q1] and fourth quartile [Q4]) for pregnant women and fetuses. In the prediction model for classification of Q1 versus Q4 (area-under-curve [AUC]: pregnant women = 0.812 and fetuses = 0.919), citraconic acid level in maternal serum and ethanolamine, p-hydroxybenzoate, and purine levels in cord serum had >0.70 AUC values. These candidate biomarkers and metabolite included in composited models were related to glutathione and amino acid metabolism in maternal serum and the amino acid metabolism and ubiquinone and other terpenoid-quinone biosynthesis in cord serum (FDR

Background: The prenatal maternal microbiome, including the gut microbiota, has been suggested to influence the incidence of allergies in offspring. Moreover, epidermal barrier dysfunction in early infancy has been attributed to the development of subsequent allergies. We hypothesized that the prenatal microbiome may affect the gut microbiota, acting as an initial trigger to alter immune development in the foetus. The maternal microbial composition may be linked to the prevalence of dermatitis in early infancy (DEI) of the offspring, leading to subsequent allergic symptoms. Methods: This study was conducted as part of the Chiba Study of Mother and Child Health (C-MACH) birth cohort that was initiated in 2013; 434 healthy pregnant women at

The DOHaD (developmental origins of health and disease) hypothesis claims that fetal malnutrition or exposure to environmental pollutants may affect their lifelong health. Epigenetic changes may play significant roles in DOHaD; however, access to human fetuses for research has ethical and technical hurdles. Umbilical cord blood (CB) has been commonly used as an epigenetic surrogate of fetuses, but it does not provide direct evidence of fetal exposure to pollutants. Here, we propose umbilical cord tissue (UC), which accumulates substances delivered to fetuses during gestation, as an alternative surrogate for epigenetic studies on fetuses. To explore the feasibility to examine UC epigenome by deep sequencing, we determined CpG methylation profiles of human postnatal UC by reduced representation bisulfite sequencing. Principal component analysis clearly separated the DNA methylomes of UC and CB pairs isolated from the same newborn (n = 10). Although all UC chromosomes were modestly hypomethylated compared to CB chromosomes, GO analysis revealed strong enrichment of differentially methylated regions (DMRs) at promoter-associated CpG islands in the HOX gene clusters and other genes encoding transcription factors involved in determination of the body pattern. DNA methylomes of UC autosomes were largely comparable between males and females. Deficiency of folate during pregnancy has been suggested to affect fetal DNA methylation to cause congenital anomalies. Whereas DNA methylome of UC was not significantly affected by early-gestational (12 weeks) low levels of maternal plasma folate (< 8 ng/ml, n = 10) compared to controls (>19 ng/mL, n = 10), two specific loci of LTR12C endogenous retroviruses in chromosome 12 were significantly hypermethylated in the low-folate group. Our study suggests that UC is useful as an alternative surrogate for studying environmental effects on DNA methylation in human fetuses, compensating CB by providing additional information about epigenetic regulation of genes involved in developmental body patterning and endogenous retroviruses.

Downwind turbines have favorable characteristics such as effective energy capture in up-flow wind conditions over complex terrains. They also have reduced risk of severe accidents in the event of disruptions to electrical networks during strong storms due to the free-yaw effect of downwind turbines. These favorable characteristics have been confirmed by wind-towing tank experiments and computational fluid dynamics (CFD) simulations. However, these advantages have not been fully demonstrated in field experiments on actual wind farms. In this study—although the final objective was to demonstrate the potential advantages of downwind turbines through field experiments—field measurements were performed using a vertical-profiling light detection and ranging (LiDAR) system on a wind farm with downwind turbines installed in complex terrains. To deduce the horizontal wind speed, vertical-profiling LiDARs assume that the flow of air is uniform in space and time. However, in complex terrains and/or in wind farms where terrain and/or wind turbines cause flow distortion or disturbances in time and space, this assumption is not valid, resulting in erroneous wind speed estimates. The magnitude of this error was evaluated by comparing LiDAR measurements with those obtained using a cup anemometer mounted on a meteorological mast and detailed analysis of line-of-sight wind speeds. A factor that expresses the nonuniformity of wind speed in the horizontal measurement plane of vertical-profiling LiDAR is proposed to estimate the errors in wind speed. The possibility of measuring and evaluating various wind characteristics such as flow inclination angles, turbulence intensities, wind shear and wind veer, which are important for wind turbine design and for wind farm operation is demonstrated. However, additional evidence of actual field measurements on wind farms in areas with complex terrains is required in order to obtain more universal and objective evaluations.

“Total” folate in blood has usually been measured to evaluate the folate status of pregnant women. However, folate is composed of many metabolites. The main substrate is 5-methyltetrahydrofolate (5-MTHF), with folic acid (FA) representing a very small component as an unmetabolized species in blood. We longitudinally evaluated 5-MTHF, FA and total homocysteine in maternal and cord blood from Japanese pregnant women. Subjects were 146 pregnant women who participated in the Chiba study of Mother and Child Health (C-MACH) prospective cohort study. Sera were obtained in early and late pregnancy, at delivery, and from cord blood. Species levels were measured by isotope-dilution mass spectrometry. Both 5-MTHF and FA levels were lower than reported levels from pregnant women in populations from countries with mandatory FA fortification. As gestational age progressed, serum 5-MTHF levels decreased, whereas serum FA levels were slightly reduced only at delivery compared to early pregnancy. A significant negative association between serum 5-MTHF and total homocysteine was shown at all examined times, but no associations with FA were evident. At delivery, cord 5-MTHF was significantly higher than maternal levels, while FA again showed no significant correlation. These results suggest that 5-MTHF is actively transported to the fetus through placental transporters and may reflect folate status during pregnancy as a physiologically important species.

Thyroid hemiagenesis is a very rare anomaly. We herein report a case with right thyroid lobe agenesis, which was incidentally found during the assessment of primary hyperparathyroidism. A 42-year-old male presenting with urinary lithiasis was suspected of having primary hyperparathyroidism, and had elevated levels of both serum calcium and intact parathyroid hormone. Both computed tomography and ultrasonography demonstrated the absence of right thyroid lobe and a mass of 1 cm in diameter at the left lower pole of the thyroid. The patient underwent lower left parathyroidectomy, which confirmed the right thyroid hemiagenesis, as well as the absence of both upper and lower right parathyroid glands. The resected left lower parathyroid gland was pathologically diagnosed as adenoma. The postoperative course was favourable and he was discharged on the 2nd day after surgery, without complications.