久田 文

Background: International guidelines recommend targeted screening to identify gestational thyroid dysfunction. However, currently used risk factors have questionable discriminative ability. We quantified the risk for thyroid function test abnormalities for a subset of risk factors currently used in international guidelines. Methods: We included prospective cohort studies with data on gestational maternal thyroid function and potential risk factors (maternal age, body mass index [BMI], parity, smoking status, pregnancy through in vitro fertilization, twin pregnancy, gestational age, maternal education, and thyroid peroxidase antibody [TPOAb] or thyroglobulin antibody [TgAb] positivity). Exclusion criteria were pre-existing thyroid disease and use of thyroid interfering medication. We analyzed individual participant data using mixed-effects regression models. Primary outcomes were overt and subclinical hypothyroidism and a treatment indication (defined as overt hypothyroidism, subclinical hypothyroidism with thyrotropin >10 mU/L, or subclinical hypothyroidism with TPOAb positivity). Results: The study population comprised 65,559 participants in 25 cohorts. The screening rate in cohorts using risk factors currently recommended (age >30 years, parity ≥2, BMI ≥40) was 58%, with a detection rate for overt and subclinical hypothyroidism of 59%. The absolute risk for overt or subclinical hypothyroidism varied <2% over the full range of age and BMI and for any parity. Receiver operating characteristic curves, fitted using maternal age, BMI, smoking status, parity, and gestational age at blood sampling as explanatory variables, yielded areas under the curve ranging from 0.58 to 0.63 for the primary outcomes. TPOAbs/TgAbs positivity was associated with overt hypothyroidism (approximate risk for antibody negativity 0.1%, isolated TgAb positivity 2.4%, isolated TPOAb positivity 3.8%, combined antibody positivity 7.0%; p < 0.001), subclinical hypothyroidism (risk for antibody negativity 2.2%, isolated TgAb positivity 8.1%, isolated TPOAb positivity 14.2%, combined antibody positivity 20.0%; p < 0.001) and a treatment indication (risk for antibody negativity 0.2%, isolated TgAb positivity 2.2%, isolated TPOAb positivity 3.0%, and combined antibody positivity 5.1%; p < 0.001). Twin pregnancy was associated with a higher risk of overt hyperthyroidism (5.6% vs. 0.7%; p < 0.001). Conclusions: The risk factors assessed in this study had poor predictive ability for detecting thyroid function test abnormalities, questioning their clinical usability for targeted screening. As expected, TPOAb positivity (used as a benchmark) was a relevant risk factor for (subclinical) hypothyroidism. These results provide insights into different risk factors for gestational thyroid dysfunction.

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.

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.

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: Adequate maternal thyroid function is important for an uncomplicated pregnancy. Although multiple observational studies have evaluated the association between thyroid dysfunction and hypertensive disorders of pregnancy, the methods and definitions of abnormalities in thyroid function tests were heterogeneous, and the results were conflicting. We aimed to examine the association between abnormalities in thyroid function tests and risk of gestational hypertension and pre-eclampsia. METHODS: In this systematic review and meta-analysis of individual-participant data, we searched MEDLINE (Ovid), Embase, Scopus, and the Cochrane Database of Systematic Reviews from date of inception to Dec 27, 2019, for prospective cohort studies with data on maternal concentrations of thyroid-stimulating hormone (TSH), free thyroxine (FT4), thyroid peroxidase (TPO) antibodies, individually or in combination, as well as on gestational hypertension, pre-eclampsia, or both. We issued open invitations to study authors to participate in the Consortium on Thyroid and Pregnancy and to share the individual-participant data. We excluded participants who had pre-existing thyroid disease or multifetal pregnancy, or were taking medications that affect thyroid function. The primary outcomes were documented gestational hypertension and pre-eclampsia. Individual-participant data were analysed using logistic mixed-effects regression models adjusting for maternal age, BMI, smoking, parity, ethnicity, and gestational age at blood sampling. The study protocol was registered with PROSPERO, CRD42019128585. FINDINGS: We identified 1539 published studies, of which 33 cohorts met the inclusion criteria and 19 cohorts were included after the authors agreed to participate. Our study population comprised 46 528 pregnant women, of whom 39 826 (85·6%) women had sufficient data (TSH and FT4 concentrations and TPO antibody status) to be classified according to their thyroid function status. Of these women, 1275 (3·2%) had subclinical hypothyroidism, 933 (2·3%) had isolated hypothyroxinaemia, 619 (1·6%) had subclinical hyperthyroidism, and 337 (0·8%) had overt hyperthyroidism. Compared with euthyroidism, subclinical hypothyroidism was associated with a higher risk of pre-eclampsia (2·1% vs 3·6%; OR 1·53 [95% CI 1·09-2·15]). Subclinical hyperthyroidism, isolated hypothyroxinaemia, or TPO antibody positivity were not associated with gestational hypertension or pre-eclampsia. In continuous analyses, both a higher and a lower TSH concentration were associated with a higher risk of pre-eclampsia (p=0·0001). FT4 concentrations were not associated with the outcomes measured. INTERPRETATION: Compared with euthyroidism, subclinical hypothyroidism during pregnancy was associated with a higher risk of pre-eclampsia. There was a U-shaped association of TSH with pre-eclampsia. These results quantify the risks of gestational hypertension or pre-eclampsia in women with thyroid function test abnormalities, adding to the total body of evidence on the risk of adverse maternal and fetal outcomes of thyroid dysfunction during pregnancy. These findings have potential implications for defining the optimal treatment target in women treated with levothyroxine during pregnancy, which needs to be assessed in future interventional studies. FUNDING: Arkansas Biosciences Institute and Netherlands Organization for Scientific Research.

Maternal exposure to polychlorinated biphenyls (PCBs) during pregnancy is associated with a low birth weight; however, the congener-specific effects of PCB congeners are not well defined. In this study, we used maternal serum samples from the Chiba Study of Mother and Child Health (C-MACH) cohort, collected at 32 weeks of gestational age, to analyze the effects of PCB congener exposure on birth weight by examining the relationship between newborn birth weight and individual PCB congener levels in maternal serum (n = 291). The median total PCB level in the serum of mothers of male and female newborns at approximately 32 weeks of gestation was 39 and 37 ng g-1 lipid wt, respectively. The effect of the total PCB levels and the effects of PCB congener mixtures were analyzed using a linear regression model and a generalized weighted quantile sum regression model (gWQS). The birth weight of newborns was significantly associated with maternal exposure to PCB mixtures in the gWQS model. The results suggest that exposure to PCB mixtures results in low newborn birth weight. However, specific impacts of individual PCB congeners could not be related to newborn birth weight.

<title>Abstract</title>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.

In recent years, there has been an increase in the number of problems associated with neurodevelopmental disorders in children, and there has been a growing interest in the relationship between environmental chemicals and children's health. The objective of this study was to examine whether an association exists between occupational or environmental prenatal maternal exposure to volatile organic compounds and the risk of neurodevelopmental disorders in children using Japanese translations of the Ages & Stages Questionnaires, Third Edition (J-ASQ-3). An increase in the risk of neurodevelopmental delay in 12-month-old children associated with maternal exposure to formalin or formaldehyde was identified in terms of problem-solving (odds ratio (OR): 1.76, 95% confidence interval (CI): 0.99-3.12) and personal-social skills (OR: 3.32, 95% CI: 1.46-7.55). It is not clear whether or not this tendency is reversible, and whether it is observed past 12 months of age. Further research and a preventive approach are needed. (c) 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Neonicotinoids (NEOs) are the most important globally available class of chemical insecticides since the introduction of synthetic pyrethroids. The adverse effects of NEOs for early development have been reported via in vivo and epidemiological studies. Therefore, prenatal NEOs exposure is highly concerning. This study aimed to determine the level of NEOs exposure during daily life among pregnant women in Japan, as well as the sources of exposure. Spot urine samples were collected during the first, second, and third trimesters from 109 pregnant women who delivered their infants at obstetrics and gynecology clinics in Kumamoto city, Japan, between 2014 and 2016. Additional data were obtained from medical records and self-administered questionnaires. thiamethoxam and clothianidin (CLO) were detected in most participants (83.4% and 80.9%, respectively), and at higher concentrations than those in other areas of Japan. Multiple logistic regression analysis showed a statistical significant association of pulses in CLO (1.01 [1.00-1.02]). In conclusion, pregnant women in Japan appear to be exposed to NEOs in their daily lives, and pulses intake may be a source of NEOs exposure. These findings may further the assessment of human NEOs exposure risk.

OBJECTIVE: We conducted an analysis using the Quick Environmental Exposure Sensitivity Inventory to examine the correlation between multiple chemical sensitivity (MCS) and personality traits by using temperament and character inventory, and environmental exposures. METHODS: An anonymous questionnaire was distributed to 667 employees working at an IT manufacturing plant in Japan. Variables including chemically sensitive population (CSP), personality, and environmental chemical exposure were individually evaluated using U-test, chi-squared test, and correlation analyses. We also did covariance structure analysis to build a structural equation model. RESULTS: There was little direct impact of temperament on the CSP, while there was a significant impact of character on the CSP. Women were more likely to exhibit symptoms of CSP. CONCLUSION: MCS is correlated with personality, impacted more by character acquired later in life than innate temperament. There were sex differences in the incidence of MCS.

BACKGROUND: Adequate transplacental passage of maternal thyroid hormone is important for normal fetal growth and development. Maternal overt hypothyroidism and hyperthyroidism are associated with low birthweight, but important knowledge gaps remain regarding the effect of subclinical thyroid function test abnormalities on birthweight-both in general and during the late second and third trimester of pregnancy. The aim of this study was to examine associations of maternal thyroid function with birthweight. METHODS: In this systematic review and individual-participant data meta-analysis, we searched MEDLINE (Ovid), Embase, Web of Science, the Cochrane Central Register of Controlled Trials, and Google Scholar from inception to Oct 15, 2019, for prospective cohort studies with data on maternal thyroid function during pregnancy and birthweight, and we issued open invitations to identify study authors to join the Consortium on Thyroid and Pregnancy. We excluded participants with multiple pregnancies, in-vitro fertilisation, pre-existing thyroid disease or thyroid medication usage, miscarriages, and stillbirths. The main outcomes assessed were small for gestational age (SGA) neonates, large for gestational age neonates, and newborn birthweight. We analysed individual-participant data using mixed-effects regression models adjusting for maternal age, BMI, ethnicity, smoking, parity, gestational age at blood sampling, fetal sex, and gestational age at birth. The study protocol was pre-registered at the International Prospective Register of Systematic Reviews, CRD42016043496. FINDINGS: We identified 2526 published reports, from which 36 cohorts met the inclusion criteria. The study authors for 15 of these cohorts agreed to participate, and five more unpublished datasets were added, giving a study population of 48 145 mother-child pairs after exclusions, of whom 1275 (3·1%) had subclinical hypothyroidism (increased thyroid stimulating hormone [TSH] with normal free thyroxine [FT4]) and 929 (2·2%) had isolated hypothyroxinaemia (decreased FT4 with normal TSH). Maternal subclinical hypothyroidism was associated with a higher risk of SGA than was euthyroidism (11·8% vs 10·0%; adjusted risk difference 2·43%, 95% CI 0·43 to 4·81; odds ratio [OR] 1·24, 1·04 to 1·48; p=0·015) and lower mean birthweight (mean difference -38 g, -61 to -15; p=0·0015), with a higher effect estimate for measurement in the third trimester than in the first or second. Isolated hypothyroxinaemia was associated with a lower risk of SGA than was euthyroidism (7·3% vs 10·0%, adjusted risk difference -2·91, -4·49 to -0·88; OR 0·70, 0·55 to 0·91; p=0·0073) and higher mean birthweight (mean difference 45 g, 18 to 73; p=0·0012). Each 1 SD increase in maternal TSH concentration was associated with a 6 g lower birthweight (-10 to -2; p=0·0030), with higher effect estimates in women who were thyroid peroxidase antibody positive than for women who were negative (pinteraction=0·10). Each 1 SD increase in FT4 concentration was associated with a 21 g lower birthweight (-25 to -17; p<0·0001), with a higher effect estimate for measurement in the third trimester than the first or second. INTERPRETATION: Maternal subclinical hypothyroidism in pregnancy is associated with a higher risk of SGA and lower birthweight, whereas isolated hypothyroxinaemia is associated with lower risk of SGA and higher birthweight. There was an inverse, dose-response association of maternal TSH and FT4 (even within the normal range) with birthweight. These results advance our understanding of the complex relationships between maternal thyroid function and fetal outcomes, and they should prompt careful consideration of potential risks and benefits of levothyroxine therapy during pregnancy. FUNDING: Netherlands Organization for Scientific Research (grant 401.16.020).

OBJECTIVE: We conducted an analysis using the Quick Environmental Exposure Sensitivity Inventory to examine the correlation between multiple chemical sensitivity (MCS) and personality traits by using temperament and character inventory, and environmental exposures. METHODS: An anonymous questionnaire was distributed to 667 employees working at an IT manufacturing plant in Japan. Variables including chemically sensitive population (CSP), personality, and environmental chemical exposure were individually evaluated using U-test, chi-squared test, and correlation analyses. We also did covariance structure analysis to build a structural equation model. RESULTS: There was little direct impact of temperament on the CSP, while there was a significant impact of character on the CSP. Women were more likely to exhibit symptoms of CSP. CONCLUSION: MCS is correlated with personality, impacted more by character acquired later in life than innate temperament. There were sex differences in the incidence of MCS.

The possible association between maternal exposure to pyrethroid insecticides (PYRs) during pregnancy and infant development was explored. Levels of exposure to PYRs was assessed by metabolite (3-phenoybenzoic acid, 3-PBA) concentration in maternal spot urine sampled in the first trimester of index pregnancy, and infant development was assessed at 18 months of age using the Kinder Infants Development Scale (KIDS), which is based on a questionnaire to the caretaker. The relationship between KIDS score and maternal urinary 3-PBA levels was examined by a stepwise multiple regression analysis using biological attributes of the mother and infant, breast feeding, and nursing environment as covariates. The analysis extracted 3-PBA and the nursing environment as significant to explain the KIDS score at 18 months of age with positive partial regression coefficients. Inclusion of fish consumption frequency of the mother during pregnancy as an independent variable resulted in the selection of fish consumption as significant, while the two variables were marginally insignificant but still with a positive coefficient with the KIDS score. The result suggested a positive effect of maternal PYR exposure on infant development, the reason for which is not clear, but an unknown confounding factor is suspected.

The possible association between maternal exposure to pyrethroid insecticides (PYRs) during pregnancy and infant development was explored. Levels of exposure to PYRs was assessed by metabolite (3-phenoybenzoic acid, 3-PBA) concentration in maternal spot urine sampled in the first trimester of index pregnancy, and infant development was assessed at 18 months of age using the Kinder Infants Development Scale (KIDS), which is based on a questionnaire to the caretaker. The relationship between KIDS score and maternal urinary 3-PBA levels was examined by a stepwise multiple regression analysis using biological attributes of the mother and infant, breast feeding, and nursing environment as covariates. The analysis extracted 3-PBA and the nursing environment as significant to explain the KIDS score at 18 months of age with positive partial regression coefficients. Inclusion of fish consumption frequency of the mother during pregnancy as an independent variable resulted in the selection of fish consumption as significant, while the two variables were marginally insignificant but still with a positive coefficient with the KIDS score. The result suggested a positive effect of maternal PYR exposure on infant development, the reason for which is not clear, but an unknown confounding factor is suspected.

九州地方都市に工場がある企業2社の従業員737名(男性551名、女性186名)にアンケートを行い、「対象者特性」5項目(年齢、性別、最終学歴、婚姻状態、子どもの有無)と、「遺伝子検査への意識」7項目(遺伝子検査を知っているか、遺伝子検査を受けたいか等)について調査し、「対象者特性」が「意識」に与えている影響について統計学的に検討した。結果、遺伝子検査を知っている人の特性として[高年齢(40代以上)]が抽出され、遺伝子検査を受けたい人の特性として[女性][高学歴][遺伝子検査を知っている]が抽出された。

OBJECTIVES: The objectives of this study were to assess the possibility of utilization of genetic testing and to determine the effect of participant characteristics on genetic testing awareness in Japanese workers. METHODS: The subjects of this study consisted of 998 workers from two companies located in Kyusyu, Japan, from June to July, 2014. We examined the participant characteristics and genetic testing awareness using paper questionnaires. Ultimately, the data from 737 subjects (73.8%) was included in our analysis. RESULTS: Regarding participant characteristics, the percentage of respondents who replied "I have heard of genetic testing" (including knowledge about genetic testing) and "I would like to have genetic testing" were 82.5% and 58.2%, respectively. A significant age difference in genetic testing awareness was also observed in our study. Logistic regression analysis revealed both significant adjust odds ratios (ORs) of 3.02 (95% CI 1.67-5.46) and 3.82 (95% CI 1.71-8.53) in the 40-49-year-old group and the over 50 year old group, respectively, compared with the 20-29-year-old group. In addition, females and the participants who graduated from graduate schools showed greater interest in genetic testing. CONCLUSIONS: This survey showed that about 80% of Japanese workers know about genetic testing and about 60% would like to have a test. The results of our survey also suggest that the awareness of genetic testing is influenced by participant characteristics, namely age, sex, and education.

This study was designed to determine the correlation between mental health and multiple chemical sensitivity (MCS). The present study was conducted at two companies in 2011; both in Kyushu, Japan. The "subjective symptoms" subscale of the "Self-diagnosis Checklist for Assessment of Workers' Accumulated Fatigue" was used as a mental health subscale. To determine if multiple chemical exposure has an impact on mental health, we composed an original path model using structural equation analysis. Our final path model can be regarded as good: CMIN/DF = 1.832, CFI = 0.996, and RMSEA = 0.038, AIC = 71.158. As expected, chemical sensitivity and other chemical sensitivity scores predicted the health effects of multiple chemical exposure (beta = 0.19, 0.64). Mental health was predicted by symptom severity and life impact (beta = 0.56 and 0.12), which were both affected by multiple chemical exposure (beta = 0.38 and 0.89, respectively). As far as we are aware, this is the first study using path analysis to explore whether MCS can indicate mental health in worker populations worldwide, and we found a significant causal relationship between them. This could indicate that more focus should be placed on the impact of MCS on mental health in future investigations.

Objective Chronic obstructive pulmonary disease (COPD) is often associated with concomitant systemic manifestations and comorbidities, such as cardiovascular disease. There are limited data regarding airflow limitation (AL) and atherosclerosis in Japanese patients, and the potential association between AL and arterial stiffness has not yet been investigated in Japanese patients. Therefore, the purpose of this study was to investigate the association between AL severity and arterial stiffness using the brachial-ankle pulse wave velocity (baPWV).<br> Methods This cross-sectional study included 1,356 subjects aged 40-79 years without clinical cardiovascular diseases who underwent a comprehensive health screening that included spirometry, the baPWV measurement, and blood sampling during medical check-ups in 2009 at the Japanese Red Cross Kumamoto Health Care Center. AL was defined in accordance with the Global Initiative for COPD criteria (forced expiratory volume in one second / forced vital capacity of < 0.7). A cut-off baPWV value of >1,400 cm/s was used for risk prediction and screening.<br> Results The average baPWV (SD) results were 1,578.0 (317.9), 1,647.3 (374.4), and 1,747.3 (320.1) cm/s in the patients with a normal pulmonary function, mild AL, and moderate-to-severe AL, respectively (p< 0.001). Using logistic regression models adjusted for the age, body mass index, smoking status, hypersensitive C-reactive protein levels, hypertension, hyperglycemia, and dyslipidemia, an increased baPWV (>1,400 cm/s) was significantly associated with moderate-to-severe AL compared with a normal pulmonary function (odds ratio=2.76; 95% confidence intervals, 1.37-5.55; p=0.004).<br> Conclusion Our results indicated an association between AL and increased arterial stiffness. Arterial stiffness may therefore worsen with an increase in the severity of AL.<br>

Pyrethroid insecticides have been shown to possess thyroid hormone disrupting properties in previous animal studies. In this study, the relationship between maternal exposure to pyrethroid insecticides during pregnancy and neonatal thyroid hormone status (free thyroxine (fT4) and thyroid stimulating hormone (TSH) in whole blood) and birth sizes were explored in 147 mother-neonate pairs in Tokyo. The concentration of 3-phenoxybenzoic acid (3-PBA) in maternal urine, sampled in the first trimester of gestation, was used for pyrethroid exposure assessment Neonatal fT4 and TSH were within the normal range except for one elevated TSH (but normal fT4) in a neonate. Multiple regression analyses with stepwise variable selection did not extract maternal 3-PBA as significant for neonatal fT4 and TSH, indicating that maternal pyrethroid exposure had no apparent effect on the neonatal thyroid hormone status of the neonate subjects. For birth weight and head circumference, maternal 3-PBA was selected as significant with a positive partial regression coefficient along with other factors known to increase birth sizes of neonates (gestational weeks or maternal BMI). It was not clear if this was causal because no biological mechanism was apparent (C) 2014 Elsevier B.V. All rights reserved.

Objective: To evaluate the representativeness of single measurement of urinary soy-isoflavone concentrations for the assessment of long-term intake levels. Methods: Five urine samples taken from 14 Japanese female subjects over 2-3 months were measured for daidzein and equol by gas chromatography-mass spectrometry (GC-MS). Results: Geometric mean daidzein and equol concentrations of 14 subjects were 582 and 2.66 mu g/g creatinine, respectively. Intra-class correlation coefficients for daidzein and equol were 0.355 (95% CI: 0.130-0.649) and 0.741 (0.551-0.891), respectively. Conclusion: Single measurement of urinary equol is effective for the assessment of long-term equol status of Japanese subject while that of daidzein is not.

We aimed to evaluate the prevalence rates and interannual fluctuations in multiple chemical sensitivity (MCS) in Japanese workers. We assessed MCS using the Quick Environmental Exposure and Sensitivity Inventory, employing both Miller and Japanese criteria. Workers of two manufacturing companies located in Kyushu, Japan, were assessed, with company A surveyed in 2003, 2006 and 2011, and company B in 2003 and 2011. In company A, the Miller criteria-based MCS prevalence rate was higher in 2011 than in 2003, and according to the Japanese criteria, it was higher in 2011 than 2006. In company B, the Miller criteria-based MCS prevalence rate was lower in 2011 than in 2003. The results indicated that MCS exists among industrial workers in Japan. We found no statistically significant interannual changes in MCS rates.

The purpose of this study was to investigate possible associations between concentrations of hydroxylated PCBs (OH-PCBs) and PCBs in the serum of women in the first trimester of pregnancy and thyroid hormone levels and body size of newborn infants in 79 mother-neonate pairs. We measured 16 OH-PCB isomers and 29 PCB isomers in the serum of Japanese women sampled at 11.1 +/- 1.9 weeks of gestation. The concentrations Of free thyroxine (fT4) and thyroid stimulating hormone (TSH) were measured in whole blood spots on filter papers sampled from the neonates. Dietary and lifestyle information of the mothers were obtained by self-administered questionnaires. Geometric mean (GM) concentrations of the sum of 16 OH-PCB isomers and of 29 PCB isomers were 1.2 x 10(2) pg/g wet wt. and 69 ng/g lipid wt., respectively, in maternal serum. The GM concentrations of neonatal fT4 and TSH were 2.21 ng/dL and 1.37 mu IU/mL, respectively. Multiple regression analysis was performed using measures of neonatal thyroid hormones as dependent variable and serum levels of OH-PCBs/PCBs and other potential covariates (age, pre-pregnancy weight, smoking status, etc.) as independent variables. The results demonstrated a significant positive association between the concentrations of some OH-PCB isomers and that of neonatal TSH. There were no significant associations between levels of PCBs and neonatal fT4, or between OH-PCBs/PCBs and body size of neonates. We conclude that exposure to/body burden of OH-PCBs, but not PCBs, at environmental levels during the first trimester of pregnancy can affect neonatal thyroid hormone status. (c) 2013 Elsevier GmbH. All rights reserved.

Background: An increased leukocyte count is an independent risk factor for cardiovascular events, but the association between leukocyte subtype counts and carotid atherosclerosis in patients with diabetes has not been determined. We therefore investigated the correlation between leukocyte subtype counts and intima-media thickness of the common carotid artery (CCA-IMT) in subjects with type 2 diabetes. Methods: This cross-sectional study involved 484 in-patients with type 2 diabetes (282 males and 202 females), who were hospitalized for glycemic control and underwent carotid ultrasonography at Kumamoto University Hospital between 2005 and 2011. Mean and maximum CCA-IMT was measured by high-resolution B-mode ultrasonography. Results: Univariate analyses revealed that mean CCA-IMT was positively correlated with age, systolic blood pressure, brachial-ankle pulse wave velocity (PWV), urinary albumin excretion and duration of diabetes, but was negatively correlated with diastolic blood pressure and fasting plasma glucose. Maximum CCA-IMT was positively and negatively correlated with the same factors as mean CCA-IMT except for fasting plasma glucose. Mean CCA-IMT was positively correlated with total leukocyte (r = 0.124, p = 0.007), monocyte (r = 0.373, p < 0.001), neutrophil (r = 0.139, p = 0.002) and eosinophil (r = 0.107, p = 0.019) counts. Maximum CCA-IMT was positively correlated with total leukocyte (r = 0.154, p < 0.001), monocyte (r = 0.398, p < 0.001), neutrophil (r = 0.152, p < 0.001) and basophil counts (r = 0.102, p = 0.027). Multiple regression analyses showed that monocyte count, age and PWV were significant and independent factors associated with mean CCA-IMT (adjusted R2 = 0.239, p < 0.001), and that monocyte count, age and urinary albumin excretion were significant and independent factors associated with maximum CCA-IMT (adjusted R2 = 0.277, p < 0.001).Conclusions: Monocyte counts were positively correlated with both mean CCA-IMT and maximum CCA-IMT in patients with type 2 diabetes. Monocyte count may be a useful predictor of macrovascular complications in patients with type 2 diabetes.Trial registration: Trial registry no: UMIN000003526. © 2013 Matsumura et al.; licensee BioMed Central Ltd.

Possible association between environmental exposure to pyrethroid insecticides and serum thyroid-related measures was explored in 231 pregnant women of 10-12 gestational weeks recruited at a university hospital in Tokyo during 2009-2011. Serum levels of free thyroxine (fT4), thyroid stimulating hormone (TSH) and thyroid biding globulin (TBG) and urinary pyrethroid insecticide metabolite (3-phenoxybenzoic acid, 3-PBA) were measured. Obstetrical information was obtained from Medical records and dietary and lifestyle information was collected by self-administered questionnaire. Geometric mean concentration of creatinine-adjusted urinary 3-PBA was 0.363 (geometric standard deviation: 3.06) mu g/g cre, which was consistent with the previously reported levels for non-exposed Japanese adult females. The range of serum fT4, TSH and TBG level was 0.83-3.41 ng/dL, 0.01-27.4 mu IU/mL and 16.4-54.4 mu g/mL, respectively. Multiple regression analysis was carried out by using either one of serum levels of thyroid-related measures as a dependent variable and urinary 3-PBA as well as other potential covariates (age, pre-pregnancy BMI, parity, urinary iodine, smoking and drinking status) as independent variables: 3-PBA was not found as a significant predictor of serum level of thyroid-related measures. Lack of association may be due to lower pyrethroid insecticide exposure level of the present subjects. Taking the ability of pyrethroid insecticides and their metabolite to bind to nuclear thyroid hormone (TH) receptor, as well as their ability of placental transfer, into consideration, it is warranted to investigate if pyrethroid pesticides do not have any effect on TH actions in fetus brain even though maternal circulating TH level is not affected. (C) 2013 Elsevier Inc. All rights reserved.

Objectives: The purpose of this study was to investigate the associations between serum concentrations of hydroxylated PCBs (OH-PCBs) and PCBs and measures of thyroid hormone status of Japanese pregnant women. Methods: The concentrations of free thyroxine (fT4), thyroid stimulating hormone (TSH), and thyroxine binding globulin (TBG) as well as 16 OH-PCB isomers and 29 PCB isomers were analyzed in the serum of 129 women sampled in the first trimester of gestation. Dietary and lifestyle information of the subjects was obtained by self-administered questionnaire. Multiple regression analysis was performed using measures of thyroid hormones as the dependent variable and serum levels of OH-PCBs/PCBs, urinary iodine concentration, and other potential covariates (age, BMI, smoking, etc.) as independent variables. Results: Geometric mean (GM) concentration of the sum of 16 isomers of OH-PCBs was 120 pg/g wet wt. and that of 29 isomers of PCBs was 68 ng/g lipid wt., respectively, in the serum of the subjects. Iodine nutrition was considered adequate to high from urinary iodine level (GM, 370 μg/g creatinine). The mean concentration of TSH, fT4 and TBG was 1.34 ± 1.37 μIU/mL, 1.22 ± 0.16 ng/dL and 33.0 ± 6.4 μg/mL, respectively, with a small number of subjects who were outside the reference range. Multiple regression analysis revealed that serum concentrations of OH-PCBs/PCBs were not significantly associated with any of the measures of thyroid hormone status. Conclusions: Exposure/body burden of OH-PCBs and PCBs at environmental levels does not have a measurable effect on thyroid hormones. © 2012 The Japanese Society for Hygiene.

Background/Purpose: We hypothesized that polymorphic differences among individuals might cause variations in the effect that environmental endocrine disruptors (EEDs) have on male genital malformations (MGMs). In this study, individual variation in the genetic response to low-dose bisphenol A (BPA) was investigated in human foreskin fibroblast cells (hFFCs) derived from child cryptorchidism (CO) and hypospadias (HS) patients. Methodology/Principal Findings: hFFCs were collected from control children without MGMs (n = 5) and child CO and HS patients (n = 8 and 21, respectively). BPA exposure (10 nM) was found to inhibit matrix metalloproteinase-11 (MMP11) expression in the HS group (0.74-fold, P = 0.0034) but not in the control group (0.93- fold, P = 0.84) and CO group (0.94-fold, P = 0.70). Significantly lower levels of MMP11 expression were observed in the HS group compared with the control group (0.80-fold, P = 0.0088) and CO group (0.79-fold, P = 0.039) in response to 10 nM BPA. The effect of single-nucleotide polymorphism rs5000770 (G. A), located within the aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) locus, on individual sensitivity to low-dose BPA was investigated in the HS group. A significant difference in neurotensin receptor 1 (NTSR1) expression in response to 10 nM BPA was observed between AA and AG/GG groups (n = 6 and 15, respectively. P = 0.031). However, no significant difference in ARNT2 expression was observed (P = 0.18). Conclusions/Significance: This study advances our understanding of the specificity of low-dose BPA effects on human reproductive health. Our results suggest that genetic variability among individuals affects susceptibility to the effects of EEDs exposure as a potential cause of HS.

Urinary concentrations of inorganic arsenic (iAs) metabolites have been used as biomarker of exposure in the previous studies. However, whether or not iAs and its metabolite concentration in spot urine represents long-term iAs exposure level of the individual has not been extensively studied. The aim of this study was to quantitatively compare inter- and intra-individual variability of urinary iAs metabolites in Japanese subjects for evaluating whether single spot urine is suitable medium for the assessment of long-term iAs exposure. We collected five first morning urine samples from each of 14 healthy female subjects for 4 - 5 months at 2 - 3 weeks interval. Urinary iAs and its metabolites concentrations were determined by liquid chromatography-ICP mass spectrometry with a hydride generation system. The median concentration of iAs + methylarsonic acid in 70 urine samples was 1.90 &micro;g As/g-cre (range: <0.47 - 58.3). The intraclass correlation coefficient of urinary concentration of iAs + methylarsonic acid of the 14 subjects were 0.15, indicating poor reproducibility. It was shown that the concentration of iAs metabolites in single spot urine is not a suitable biomarker of long-term exposure levels of iAs in Japanese at individual level; it was estimated that four spot urine samples were required from a subject for that purpose.

Objectives: To quantitatively assess the intra- and inter-individual variation of urinary iodine concentration in Japanese to determine whether urinary analysis is applicable to assessing habitual iodine intake in subjects on an individual basis.<br> Methods: Five urine samples (first void) were taken from each of the 14 healthy female subjects at 2–3 week intervals over 4–5 months. Information on diet and medication use on the previous day of urine sampling was obtained by a questionnaire during each urine sampling. The concentration of iodine in urine samples was measured by inductively coupled plasma mass spectrometry (ICP-MS). Intra- and inter-individual variation was assessed by intra class correlation coefficient (ICC).<br> Results: The median concentration of iodine in 70 urine samples was 91 μg/g-cre (range: 15–4400 μg/g-cre). The mean iodine concentration in urine samples from subjects who took iodine-rich foods/medications on the day before sampling was statistically significantly higher than that from subjects who did not take such foods/medications (p < 0.01, t-test). The ICC of urinary iodine concentration of the 14 subjects was 0.55, indicating good reproducibility; however, this was 0.28 when one subject who routinely used an iodine-containing gargle was excluded from analysis.<br> Conclusions: Urine sampled on a single occasion is not a suitable medium for the assessment of long-term intake levels of iodine in subjects on an individual basis.<br>