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Summary:. Acrodysostosis, a rare congenital syndrome, is characterized by peripheral dysostosis, nasal hypoplasia, mental retardation, and other skeletal deformities. Although severe saddle nose associated with midfacial hypoplasia causes great distress to patients, no studies have reported conducting rhinoplasty. In our experience, we suspected a boy with a significant saddle nose as having acrodysostosis and conducted genetic testing on the boy and his parents. Genetic analyses revealed that the patient had a deleterious mutation in the PDE4D gene that was not seen in either of his parents. Thus, the patient was diagnosed with de novo acrodysostosis. Rhinoplasty of the saddle nose using autogenous costal cartilage was planned; however, a major concern in using costal cartilage is the distortion caused by warping. To prevent this problem, a counterbalancing technique was used. After the surgery, no warping was observed during follow-up, and the patient and his family were satisfied with the outcomes. To our knowledge, we present the first case of surgical treatment of a patient with a saddle nose caused by acrodysostosis.

Background: Heavy metals such as lead (Pb) and cadmium (Cd) have been associated with adverse pregnancy and developmental outcomes, including congenital abnormalities. This study investigated the association between exposure to heavy metals and trace elements during fetal life and congenital limb abnormalities in infants. Methods: This study is based on a prospective ongoing nationwide birth cohort from the Japan Environment and Children’s Study (JECS). The concentrations of Cd, Pb, mercury (Hg), selenium (Se), and manganese (Mn) were measured in maternal blood collected during the mid–late trimesters. Inclusion criteria were available from questionnaires filled in during pregnancy, including information about congenital limb abnormalities at birth or at one month. To examine the associations with limb anomalies and individual chemicals, logistic regression models were applied following log-transformation or division into quartiles of Cd, Pb, Hg, Se, and Mn concentrations. To assess the associations with the heavy metals and trace elements mixture, quantile g-computation was employed. All models were adjusted for age, maternal smoking history, maternal alcohol intake, history of smoking, and infant sex. Results: Data from 90,163 participants were included in the analysis, of whom 369 had congenital limb abnormalities in any of the collected information, and 89,794 had none. Among the 369 cases of congenital limb abnormalities, there were 185 and 142 cases of polydactyly and syndactyly, respectively. The median concentrations of Pb, Cd, Hg, Se, and Mn were 5.85, 0.66, 3.64, 168, and 15.3 ng/g, respectively. There were no associations between maternal blood concentrations of Pb [adjusted odd ratio = 0.83; 95% confidence interval = 0.61, 1.11], Cd [0.87; 0.68, 1.10], Hg [0.88; 0.73, 1.07], Se [1.07; 0.44, 2.59], and Mn [0.91; 0.64, 1.30] with congenital limb abnormalities. No significant association was observed between the mixture of heavy metals and trace elements [0.85; 0.72, 1.02] and any congenital limb abnormalities. Moreover, there was no association with all polydactylies and all syndactylies, or any type of abnormality as a subdivision. Conclusion: At the maternal exposure levels of Cd, Pb, Hg, Se, and Mn assessed in the present study, no association was identified with the risk of developing congenital limb abnormalities in children.

BackgroundChildhood asthma is known to be affected by a range of factors, including conditions in the indoor environment. While flooring material influences indoor air conditions, the potential association between flooring materials and childhood asthma remains poorly understood in Japan.ObjectiveThe present study aims to assess the association between childhood asthma incidence and the primary flooring material with the ongoing prospective nationwide birth cohort data of the Japan Environment and Children's Study (JECS).MethodsThe JECS gathered data on mothers and children through 15 Regional Centres across Japan. The present study assessed flooring materials used in the home and asthma incidence at age four among children born between 2011 and 2014. We implemented logistic regressions, setting asthma incidence among the children as the outcome and home floor type as the exposure. Additional analyses were conducted, stratifying the home's age as a proxy for tatami age, to assess whether the potential effect of tatami flooring on asthma risk is influenced by its age.ResultsThe present study included total of 75,629 infants. For tatami flooring, the main multivariable regression and additional sub-group regression for homes over ten years old produced odds ratios of 1.09; 95% Confidence Interval (CI) [1.01-1.17] and 1.10; 95% CI [1.00-1.21] compared with flooring, respectively.ConclusionThese results imply that exposure to tatami flooring, particularly in older homes, may be associated with childhood asthma incidence. Moreover, our study highlights the importance of evaluating the relationship between regional and cultural differences between asthma and flooring materials.

Kawasaki disease (KD) is common among pediatric patients and is associated with an increased risk of later cardiovascular complications, though the precise pathophysiology of KD remains unknown. Per- and polyfluoroalkyl substances (PFAS) have gathered notoriety as the causal pathogens of numerous diseases as well as for their immunosuppressive effects. The present epidemiological study aims to assess whether PFAS may affect KD risk. We evaluated research participants included in the ongoing prospective nationwide birth cohort of the Japan Environment and Children’s Study (JECS). Among the over 100,000 pregnant women enrolled in the JECS study, 28 types of PFAS were measured in pregnancy in a subset of participants (N = 25,040). The JECS followed their children born between 2011 and 2014 (n total infants = 25,256; n Kawasaki disease infants = 271), up to age four. Among the 28 types of PFAS, those which were detected in >60 % of participants at levels above the method reporting limit (MRL) were eligible for analyses. Multivariable logistic regressions were implemented on the seven eligible PFAS, adjusting for multiple comparison effects. Finally, we conducted Weighted Quantile Sum (WQS) and Bayesian kernel machine regression (BKMR) to assess the effects of the PFAS mixture on KD. Therefore, we ran the BKMR model using kernel mechanical regression equations to examine PFAS exposure and the outcomes of KD. Upon analysis, the adjusted multivariable regression results did not reach statistical significance for the seven eligible substances on KD, while odds ratios were all under 1.0. WQS regression was used to estimate the mixture effect of the seven eligible PFAS, revealing a negative correlation with KD incidence; similarly, BKMR implied an inverse association between the PFAS mixture effect and KD incidence. In conclusion, PFAS exposure was not associated with increased KD incidence.

Background: Lower respiratory tract infections (LRTIs) are a cause of inpatient and outpatient care among children. Although orofacial clefts seem to be associated with LRTIs, epidemiological studies are scarce on this topic. This study aimed to examine whether infants with orofacial clefts were associated with LRTIs. Methods: This prospective cohort study used data from the Japan Environment and Children’s Study, for which baseline recruitment was conducted during 2011–2014. This study included 81,535 participants. The number of infants with cleft lip and palate (CLP), cleft lip (CL), and cleft palate only (CP) was 67, 49, and 36, respectively. We defined history of LRTIs until 12 months’ age reported by their mothers as the dependent variable. Accumulated breastfeeding duration was used as a potential mediator. Results: The incidence proportion of LRTIs among the control group was 6.0%. The incidence proportion among infants with CLP, CL, and CP were 11.9%, 14.3%, and 5.6%, respectively. After adjusting for covariates, compared with the control group, infants with CLP and CL were associated with risk of LRTIs (incidence risk ratio [IRR] of CLP, 2.38; 95% confidence interval [CI], 1.30–4.36 and IRR of CL, 2.73; 95% CI, 1.40–5.33), but not ones with CP (IRR 1.08; 95% CI, 0.28–4.15). Accumulated breastfeeding duration decreased the IRR of CLP only (IRR of CLP, 2.16; 95% CI, 1.19–3.93). Conclusion: Infants with orofacial clefts aged 1 year have a potentially high incidence proportion of LRTIs. Accumulated breastfeeding duration might mediate the associations of CLP.

Here we propose a new method to generate Kirigami honeycomb for complicated structures. Although commercially available honeycombs have the same cross-section as standard, Nojima and Saito firstly showed honeycombs could be curved by using the Kirigami operation. By this, the Kirigami honeycomb has become a mighty treasure trove of metamaterial creation, so Kirigami has been an international language like Origami and it has been a hot topic in the Origami engineering community. So far, there is an overlap in the development view of the honeycomb core with a non-convex curved surface and the development view cannot be used for the construction of the core with a non-convex curved surface. Moreover, with conventional methods, STL(Stereolithography) data which are often used by the additive 3D printer can be used only after the formulas on the upper and lower surfaces are obtained. Since with the conventional methods, only the structure that can be completed by the information of the upper and lower surface formulas can be handled, they cannot treat a structure with a non-uniform shape between the upper and lower surfaces, and also curvature and thickness can only change in one axis. With this proposed method, firstly the target structure expressed in CAD and/or STL data is covered with a honeycomb core of any shape in any direction. Secondly, the intersections of the two are obtained and at last it is obtained the honeycomb core peculiar to the structure of the prepared honeycomb base. That is, the proposed one is extremely general like the present additive 3D printer. The biggest drawback of the Kirigami honeycomb is that the material yield is not always good for which this proposed method is also advantageous because it can select the orientation of the honeycomb cell in which material yield is maximized.

Abstract Numerous genetic variants associated with hypertension and blood pressure are known, but there is a paucity of evidence from genetic studies of resistant hypertension, especially in Asian populations. To identify novel genetic loci associated with resistant hypertension in the Japanese population, we conducted a genome-wide association study with 2705 resistant hypertension cases and 21,296 mild hypertension controls, all from BioBank Japan. We identified one novel susceptibility candidate locus, rs1442386 on chromosome 18p11.3 (DLGAP1), achieving genome-wide significance (odds ratio (95% CI) = 0.85 (0.81–0.90), P = 3.75 × 10−8) and 18 loci showing suggestive association, including rs62525059 of 8q24.3 (CYP11B2) and rs3774427 of 3p21.1 (CACNA1D). We further detected biological processes associated with resistant hypertension, including chemical synaptic transmission, regulation of transmembrane transport, neuron development and neurological system processes, highlighting the importance of the nervous system. This study provides insights into the etiology of resistant hypertension in the Japanese population.

Neurodevelopmental delay is associated with neurodevelopmental disorders. Prenatal metal exposure can potentially cause neurodevelopmental delays in children. This study examines whether prenatal exposure to mercury (Hg) and selenium (Se) is associated with the risk of neurodevelopmental delays in children up to 4 years of age. Children enrolled in a prospective birth cohort of the Japan Environment and Children’s Study were examined. Hg and Se levels in maternal (nchild = 48,731) and cord (nchild = 3,083) blood were analyzed by inductively coupled plasma-mass spectrometry. Neurodevelopmental delays were assessed in children between the ages of 0.5 to 4 years using the Ages and Stages Questionnaires, Third Edition. The association between exposure and outcomes was examined using the generalized estimation equation models. In maternal blood, compared to participants with Se levels in the first quartile (83.0 to

Abstract Background The influence of maternal psychological distress on infant congenital heart defects (CHDs) has not been thoroughly investigated. Furthermore, there have been no reports on the combined effect of maternal psychological distress and socioeconomic status on infant CHDs. This study aimed to examine whether maternal psychological distress, socioeconomic status, and their combinations were associated with CHD. Methods We conducted a prospective cohort study using data from the Japan Environment and Children’s Study, which recruited pregnant women between 2011 and 2014. Maternal psychological distress was evaluated using the Kessler Psychological Distress Scale in the first trimester, while maternal education and household income were evaluated in the second and third trimesters. The outcome of infant CHD was determined using the medical records at 1 month of age and/or at birth. Crude- and confounder-adjusted logistic regression analyses were performed to evaluate the association between maternal psychological distress and education and household income on infant CHD. Results A total of 93,643 pairs of mothers and infants were analyzed, with 1.1% of infants having CHDs. Maternal psychological distress had a significantly higher odds ratio in the crude analysis but not in the adjusted analysis, while maternal education and household income were statistically insignificant. In the analysis of the combination variable of lowest education and psychological distress, the P for trend was statistically significant in the crude and multivariate model excluding anti-depressant medication, but the significance disappeared in the full model (P = 0.050). Conclusions The combination of maternal psychological distress and lower education may be a possible indicator of infant CHD.

Abstract Background The Hokkaido Study on Environment and Children’s Health is an ongoing study consisting of two birth cohorts of different population sizes: the Sapporo cohort and the Hokkaido cohort. Our primary objectives are to (1) examine the effects that low-level environmental chemical exposures have on birth outcomes, including birth defects and growth retardation; (2) follow the development of allergies, infectious diseases, and neurobehavioral developmental disorders, as well as perform a longitudinal observation of child development; (3) identify high-risk groups based on genetic susceptibility to environmental chemicals; and (4) identify the additive effects of various chemicals, including tobacco. Methods The purpose of this report is to provide an update on the progress of the Hokkaido Study, summarize recent results, and suggest future directions. In particular, this report provides the latest details from questionnaire surveys, face-to-face examinations, and a collection of biological specimens from children and measurements of their chemical exposures. Results The latest findings indicate different risk factors of parental characteristics on birth outcomes and the mediating effect between socioeconomic status and children that are small for the gestational age. Maternal serum folate was not associated with birth defects. Prenatal chemical exposure and smoking were associated with birth size and growth, as well as cord blood biomarkers, such as adiponectin, leptin, thyroid, and reproductive hormones. We also found significant associations between the chemical levels and neuro development, asthma, and allergies. Conclusions Chemical exposure to children can occur both before and after birth. Longer follow-up for children is crucial in birth cohort studies to reinforce the Developmental Origins of Health and Disease hypothesis. In contrast, considering shifts in the exposure levels due to regulation is also essential, which may also change the association to health outcomes. This study found that individual susceptibility to adverse health effects depends on the genotype. Epigenome modification of DNA methylation was also discovered, indicating the necessity of examining molecular biology perspectives. International collaborations can add a new dimension to the current knowledge and provide novel discoveries in the future.

Background: Population impact of modifiable risk factors on orofacial clefts is still unknown. This study aimed to estimate population attributable fractions (PAFs) of modifiable risk factors for nonsyndromic cleft lip with or without cleft palate (CL±P) and cleft palate only (CP) in Japan. Methods: We conducted a prospective cohort study using data from the Japan Environment and Children’s Study, which recruited pregnant women from 2011 to 2014. We estimated the PAFs of maternal alcohol consumption, psychological distress, maternal active and passive smoking, abnormal body mass index (BMI) (

Background: Concerns have been raised about the adverse health impacts of mobile device usage. The objective of this cross-sectional study was to examine the association between a child’s age at the first use of a mobile device and the duration of use as well as associated behavioral problems among school-aged children. Methods: This study focused on children aged 7–17 years participating in the Hokkaido Study on Environment and Children’s Health. Between October 2020 and October 2021, the participants (n = 3,021) completed a mobile device use-related questionnaire and the strengths and difficulties questionnaire (SDQ). According to the SDQ score (normal or borderline/high), the outcome variable was behavioral problems. The independent variable was child’s age at first use of a mobile device and the duration of use. Covariates included the child’s age at the time of survey, sex, sleep problems, internet addiction, health-related quality of life, and history of developmental concerns assessed at health checkups. Logistic regression analysis was performed for all children; the analysis was stratified based on the elementary, junior high, and senior high school levels. Results: According to the SDQ, children who were younger at their first use of a mobile device and used a mobile device for a longer duration represented more problematic behaviors. This association was more pronounced among elementary school children. Moreover, subscale SDQ analysis showed that hyperactivity, and peer and emotional problems among elementary school children, emotional problems among junior high school children, and conduct problems among senior high school children were related to early and long usage of mobile devices. Conclusions: Elementary school children are more sensitive to mobile device usage than older children, and early use of mobile devices may exacerbate emotional instability and oppositional behaviors in teenagers. Longitudinal follow-up studies are needed to clarify whether these problems disappear with age.

Summary: The killer cell immunoglobulin-like receptor (KIR) recognizes human leukocyte antigen (HLA) class I molecules and modulates the function of natural killer cells. Despite its role in immunity, the complex genomic structure has limited a deep understanding of the KIR genomic landscape. Here we conduct deep sequencing of 16 KIR genes in 1,173 individuals. We devise a bioinformatics pipeline incorporating copy number estimation and insertion or deletion (indel) calling for high-resolution KIR genotyping. We define 118 alleles in 13 genes and demonstrate a linkage disequilibrium structure within and across KIR centromeric and telomeric regions. We construct a KIR imputation reference panel (nreference = 689, imputation accuracy = 99.7%), apply it to biobank genotype (ntotal = 169,907), and perform phenome-wide association studies of 85 traits. We observe a dearth of genome-wide significant associations, even in immune traits implicated previously to be associated with KIR (the smallest p = 1.5 × 10−4). Our pipeline presents a broadly applicable framework to evaluate innate immunity in large-scale datasets.

Background: Disruption of thyroid hormone (TH) levels during pregnancy contributes to attention deficit hyperactivity disorder (ADHD). Exposure to perfluoroalkyl substances (PFAS) during gestation may affect levels of maternal and neonatal TH; however, little is known about the effect of PFAS on ADHD mediated by TH. Objectives: We investigated the impact of maternal PFAS exposure on children’s ADHD symptoms with the mediating effect of TH. Methods: In a prospective birth cohort (the Hokkaido study), we included 770 mother–child pairs recruited between 2002 and 2005 for whom both prenatal maternal and cord blood samples were available. Eleven PFAS were measured in maternal serum obtained at 28–32 weeks of gestation using ultra-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry. TH and thyroid antibody, including thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb) were measured in maternal blood during early pregnancy (median 11 gestational weeks) and in cord blood at birth. ADHD symptoms in the children at 8 years of age were rated by their parents using the ADHD-Rating Scale (ADHD-RS). The cut-off value was set at the 80th percentile for each sex. Results: Significant inverse associations were found between some PFAS in maternal serum and ADHD symptoms among first-born children. Assuming causality, we found only one significant association: maternal FT4 mediated 17.6% of the estimated effect of perfluoroundecanoic acid exposure on hyperactivity–impulsivity among first-born children. Discussion: Higher PFAS levels in maternal serum during pregnancy were associated with lower risks of ADHD symptoms at 8 years of age. The association was stronger among first-born children in relation to hyperactivity–impulsivity than with regard to inattention. There was little mediating role of TH during pregnancy in the association between maternal exposure to PFAS and reduced ADHD symptoms at 8 years of age.

Abstract Background There have been inconsistent findings reported on maternal passive smoking during pregnancy and child risk of ADHD. In this study, ADHD symptoms at pre-school age children in association with prenatal passive and active tobacco smoke exposure determined by maternal plasma cotinine levels in the third trimester were investigated. Methods This was a follow-up study of the birth cohort: the Hokkaido Study on Environment and Children’s Health. Children whose parents answered Strengths and Difficulties Questionnaire (SDQ) to identify child ADHD symptoms (hyperactivity/inattention and conduct problems) and total difficulties at age 5 years with available maternal plasma cotinine level at the third trimester were included (n = 3216). Cotinine levels were categorized into 4 groups; ≦ 0.21 ng/ml (non-smoker), 0.22–0.51 ng/ml (low-passive smoker), 0.52–11.48 ng/ml (high-passive smoker), and ≧ 11.49 ng/ml (active smoker). Results Maternal cotinine levels of active smokers were significantly associated with an increased risk of total difficulties (OR = 1.67) and maternal low- and high-passive smoking also increased the risk (OR = 1.11, 1.25, respectively) without statistical significance. Similarly, maternal cotinine levels of active smokers were associated with an increased risk of hyperactivity/inattention (OR = 1.49). Maternal low- and high-passive smoking and active smoking increased the risk of hyperactivity/inattention (OR = 1.45, 1.43, and OR = 1.59, respectively) only in boys. Conclusion Our findings suggested that maternal active smoking during pregnancy may contribute to the increased risk of child total difficulties and hyperactivity/inattention at pre-school age. Pregnant women should be encouraged to quit smoking and avoid exposure to tobacco smoke.

Abstract Background The aim of this study was to investigate the association between statin use and new-onset diabetes in clinical settings and to assess its effect modification (heterogeneity) among patients with various medical histories and current medications. Methods In a total of 12,177 Japanese patients without diabetes, from December 2004 to November 2012, we identified 500 statin users and 500 matched non-users using propensity-score matching. Patients were followed until December 2017. We estimated the hazard ratios of new-onset diabetes associated with statin use. We also tested the heterogeneity of the treatment effect by evaluating subgroup interactions in subgroups according to sex, age, medical history, and current medication. Results New-onset diabetes had occurred in 71 patients (13.6%) with statin use and 43 patients (8.3%) with non-use at 5 years (hazard ratio, 1.66; 95% confidence interval [CI], 1.11 to 2.48; P = 0.0143), and in 78 patients (15.6%) with statin use and 48 patients (9.6%) with non-use at 10 years (hazard ratio, 1.61; 95% CI, 1.10 to 2.37; P = 0.0141). There were no significant treatment-by-subgroup interactions in all subgroups defined according to sex, age, medical history, and current medication. Conclusions In patients with various clinical backgrounds, those who received statin therapy had a higher risk of new-onset diabetes at 5 and 10 years than those who did not receive it. Effect modification of statins on new-onset diabetes was not found in patient populations defined according to various comorbid diseases or concomitant drugs.

Background: It is necessary to determine whether there are adverse health effects of prenatal exposure to long-term, low levels of mercury and selenium. However, there are limited that reports on the association between mercury levels by selenium levels and birth size. Therefore, we examined whether maternal mercury levels during pregnancy had any effect on infant birth size, and size, and whether selenium levels influenced this relationship. Objectives: To examine the association between mercury and selenium levels during pregnancy with infant birth size. Methods: The Japan Environment and Children's Study is a prospective birth cohort conducted between 2011 and 2014. Total mercury levels and total selenium levels in maternal blood during the second and third trimesters were measured using Inductively Coupled Plasma-Mass Spectrometry. Birth weight and small-for-gestational-age were confirmed by medical records. Small-for-gestational-age was defined as birth weight below the 10th percentile according to standard percentile for gender, parity, and gestational age. Multiple linear and logistic regression analyses were used to examine the association between maternal mercury exposure and birth weight or small-for-gestational-age adjusted for confounders (including maternal age and body mass index pregnancy). Results: Overall, 15,444 pregnant women were included in this study. Median (inter-quartile range) of blood mercury and selenium levels were 3.66 (2.59–5.18) ng/g and 170.0 (158.0–183.0) ng/g, respectively. Compared to infants of mothers with the highest blood selenium level, those of mothers with the lowest blood selenium level had neither a significant birth weight increase (9 g, 95% confidence interval: −6, 25) nor a significant odds ratio for small-for-gestational-age (0.903, 95% confidence interval: 0.748, 1.089). Compared to infants of mothers with the lowest blood mercury level, those of mothers with the highest blood mercury level had neither a significant birth weight reduction (−12 g, 95% confidence interval: −27, 4) nor a significant odds ratio for small-for-gestational-age (0.951, 95% confidence interval: 0.786, 1.150). Compared to infants of mothers with the lowest quartile of maternal blood mercury level, all infants of mothers with the highest quartile of maternal blood mercury level had a reduced birth head circumference of 0.073 cm (95% confidence interval: −0.134, −0.011). Conclusions: There was no association between maternal blood mercury levels and small-for-gestational-age and birth weight among 15,444 pregnant women. In a Japanese population, which has a relatively higher blood mercury level than reported in Western population, reduced birth size was not found to be associated with blood mercury levels, with the exception of birth head circumference. Keywords: Mercury, Selenium, Pregnancy, Birth weight, Small-for-gestational-age, The Japan Environment and Children's Study

Japanese traditional fan has the variety of three-dimensional expression that differs from two-dimensional expression. The image painted on the fan deforms, when it is folded into convex-concave configuration and fixed to the bamboo bones，due to the difference between the shrinking percentage of the outer arc and the inner arc. Many of the fans made until the Edo era are thought to be painted in consideration of the deformation, but this idea is not recognized in the field of traditional Japanese art. Therefore, many culturally valuable fans, which are more or less damaged due to aging, have lost their bones and damaged edges, and stretched flat like paintings. The fan surface is preserved but the original value of the fan is lost. In this study, we create a digital fan model by proposing approximate formulas for clarifying the deformation on the fan face according to parameters such as length of the bamboo bones, to support the opinion that three-dimensional configuration is essential for folding fans. We then validate the digital model with an actual fan. Regarding shape and area, there was good results, although further study is necessary to improve it. Furthermore, we obtain the original plan view from images of the folded fan as a reverse problem, which is useful for product development that makes use of the characteristics of folding fans.In future study, we would like to upgrade this model to the tool that assists the difficult task of reproducing folding fan without its original configuration. Also we would like to capture precious folding fans in three-dimensional space applying this model and to exhibit those fans in a digital museum, to give opportunities not only to enjoy the value of them but also to encourage the research of the Japanese traditional culture.

BackgroundThe influence of mothers' and fathers' educational levels in separate evaluations of asthma has not been fully investigated. This study aims to examine the associations of the mother's and fathers' educational levels with childhood wheeze and asthma adjusting for crude and pre-and post-natal modifiable risk factors.MethodsWe conducted a prospective cohort study using data from the Japan Environment and Children's Study, which recruited pregnant women from 2011 to 2014. The mother's and father's educational levels were surveyed by a questionnaire during the pregnancy, and childhood wheezing and doctor-diagnosed asthma were estimated using a 3-year questionnaire. Multilevel logistic regression analysis was performed to evaluate the association between the mother's and father's educational levels and childhood wheezing and asthma, adjusted for pre-and post-natal factors.ResultsA total of 69,607 pairs of parents and their single infants were analyzed. We found 17.3% of children had wheezing and 7.7% had asthma. In crude analyses, lower educational level of parents was associated with an increased risk of childhood wheezing and asthma. After full adjustment, a lower educational level of mothers was associated with an increased risk of childhood asthma (junior high school (reference: high school); odds ratio (OR): 1.17, 95% CI, 1.01-1.36), and higher educational level, especially the mother's, was associated with an increased risk of childhood wheezing (technical junior college, technical/vocational college, or associate degree (ECD3); OR: 1.12, 95% CI, 1.06-1.18, bachelor's degree, or postgraduate degree; OR: 1.10, 95% CI, 1.03-1.18), and asthma (ECD3; OR: 1.13, 95% CI, 1.04-1.21).ConclusionsParents' lower educational level was a crude risk factor for childhood wheezing and asthma. However, an increased risk of wheezing due to mothers' higher educational level was found after adjusting for pre-and post-natal factors.

Abstract Background Studies reported adverse behavioral development including internalizing and externalizing problems in association with prenatal exposure to bisphenol A (BPA) and phthalates; however, findings were not sufficient due to using different assessment tools and child ages among studies. This study aimed to examine associations between maternal serum levels of BPA and phthalate metabolites and behavioral problems at preschool age. Methods The Strengths and Difficulties Questionnaire (SDQ) was used to assess behavioral problems at 5 years of age. BPA and phthalate metabolite levels in the first trimester maternal serum was determined by LC-MS/MS for 458 children. Variables used for adjustment were parental ages, maternal cotinine levels, family income during pregnancy, child sex, birth order, and age at SDQ completed. Results The median concentrations of BPA, MnBP, MiBP, MEHP, and MECPP, primary and secondary metabolites of phthalates, were 0.062, 26.0, 7.0, 1.40, and 0.20 ng/ml, respectively. MECPP level was associated with increase conduct problem risk (OR = 2.78, 95% CI 1.36–5.68) overall and the association remained after child sex stratification, and odds ratios were increased with wider confidence interval (OR = 2.85, 95% CI 1.07–7.57 for boys, OR = 4.04, 95% CI 1.31–12.5 for girls, respectively). BPA, ∑DBPm (MnBP + MiBP), and ∑DEHPm (MEHP+MECPP) levels were not associated with any of the child behavioral problems. Conclusions Our analyses found no significant association between BPA or summation of phthalate metabolite levels and any of the behavioral problems at 5 years of age but suggested possible association between MECPP levels and increased risk of conduct problems.

Background: Thyroid antibodies (TAs) are the most common cause of hypothyroidism during gestation. Although previous studies found that prenatal exposure to perfluoroalkyl substances (PFASs) disrupts thyroid hormones (THs) in humans, their effects on TAs during the perinatal period have not been investigated. Objective: To explore the associations between prenatal exposure to eleven different PFASs from two different groups (carboxylates and sulfonates) and the expression of THs and TAs in maternal and cord blood while considering maternal TA status. Methods: In a prospective birth cohort (the Hokkaido Study), we included 701 mother‑neonate pairs recruited in 2002–2005 for whom both prenatal maternal and cord blood samples were available. Eleven PFASs were measured in maternal plasma obtained at 28–32 weeks of gestation using ultra-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry. THs and TAs including thyroid stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb) were measured in maternal blood during early pregnancy (median 11 gestational weeks), and in cord blood at birth. Results: The median levels of TgAb and TPOAb in maternal serum were 15.0 and 6.0 IU/mL, respectively. The median TgAb level in neonates was 38.0 IU/mL, and TPOAb were detected in only 12.3% of samples. Maternal FT3 level was positively associated with PFAS levels in both TA-positive and TA-negative mothers. Maternal perfluorooctanoate was inversely associated with maternal TPOAb. Among boys, some maternal PFASs were associated with higher TSH and lower FT3 levels in maternal TA-negative group, while perfluorodecanoic acid was associated with lower TSH in maternal TA-positive group. Among girls, some PFAS of mothers showed associations with lower TSH and higher FT3 in maternal TA-negative group, while perfluorododecanoic acid was associated with lower FT4 in maternal TA-positive. Maternal PFASs showed associations with boy's TgAb inversely in maternal TA-negative group and with girl's TgAb positively in maternal TA-positive group. Conclusions: Our results suggest thyroid disrupting effects of PFAS exposure and susceptibility vary depending on maternal TA levels. Keywords: Perfluoroalkyl substances, Thyroid antibodies, Thyroid hormones, Prenatal exposure, Birth cohort

Abstract The Hokkaido Study on Environment and Children’s Health is an ongoing study consisting of two birth cohorts of different population sizes: the Sapporo cohort and the Hokkaido cohort. Our primary study goals are (1) to examine the effects of low-level environmental chemical exposures on birth outcomes, including birth defects and growth retardation; (2) to follow the development of allergies, infectious diseases, and neurobehavioral developmental disorders and perform a longitudinal observation of child development; (3) to identify high-risk groups based on genetic susceptibility to environmental chemicals; and (4) to identify the additive effects of various chemicals, including tobacco smoking. The purpose of this report is to update the progress of the Hokkaido Study, to summarize the recent results, and to suggest future directions. In particular, this report provides the basic characteristics of the cohort populations, discusses the population remaining in the cohorts and those who were lost to follow-up at birth, and introduces the newly added follow-up studies and case-cohort study design. In the Sapporo cohort of 514 enrolled pregnant women, various specimens, including maternal and cord blood, maternal hair, and breast milk, were collected for the assessment of exposures to dioxins, polychlorinated biphenyls, organochlorine pesticides, perfluoroalkyl substances, phthalates, bisphenol A, and methylmercury. As follow-ups, face-to-face neurobehavioral developmental tests were conducted at several different ages. In the Hokkaido cohort of 20,926 enrolled pregnant women, the prevalence of complicated pregnancies and birth outcomes, such as miscarriage, stillbirth, low birth weight, preterm birth, and small for gestational age were examined. The levels of exposure to environmental chemicals were relatively low in these study populations compared to those reported previously. We also studied environmental chemical exposure in association with health outcomes, including birth size, neonatal hormone levels, neurobehavioral development, asthma, allergies, and infectious diseases. In addition, genetic and epigenetic analyses were conducted. The results of this study demonstrate the effects of environmental chemical exposures on genetically susceptible populations and on DNA methylation. Further study and continuous follow-up are necessary to elucidate the combined effects of chemical exposure on health outcomes.