Risk Factors for Thyroid Dysfunction in Pregnancy: An Individual Participant Data Meta-Analysis.

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.

Effect of nausea and vomiting during pregnancy on mother-to-infant bonding and the mediation effect of postpartum depression: the Japan Environment and Children's Study.

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.

Investigation of umbilical cord serum miRNAs associated with childhood obesity: A pilot study from a birth cohort study.

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.

Maternal Iodine Intake and Neurodevelopment of Offspring: The Japan Environment and Children's Study.

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.

Association between maternal thyroid function and risk of gestational hypertension and pre-eclampsia: a systematic review and individual-participant data meta-analysis.

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.

Association between Total and Individual PCB Congener Levels in Maternal Serum and Birth Weight of Newborns: Results from the Chiba Study of Mother and Child Health Using Weighted Quantile Sum Regression.

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.

Decreased head circumference at birth associated with maternal tobacco smoke exposure during pregnancy on the Japanese prospective birth cohort study.

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.

Urinary neonicotinoids level among pregnant women in Japan.

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.

Associations between prenatal exposure to volatile organic compounds and neurodevelopment in 12-month-old children: The Japan Environment and Children's Study (JECS).

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.

Study of the Correlation Between Multiple Chemical Sensitivity and Personality Using the Quick Environmental Exposure Sensitivity Inventory Questionnaire and the Temperament and Character Inventory.

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.

Association of maternal thyroid function with birthweight: a systematic review and individual-participant data meta-analysis.

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).

Association of Thyroid Function Test Abnormalities and Thyroid Autoimmunity With Preterm Birth: A Systematic Review and Meta-analysis.

Importance: Maternal hypothyroidism and hyperthyroidism are risk factors for preterm birth. Milder thyroid function test abnormalities and thyroid autoimmunity are more prevalent, but it remains controversial if these are associated with preterm birth. Objective: To study if maternal thyroid function test abnormalities and thyroid autoimmunity are risk factors for preterm birth. Data Sources and Study Selection: Studies were identified through a search of the Ovid MEDLINE, EMBASE, Web of Science, the Cochrane Central Register of Controlled Trials, and Google Scholar databases from inception to March 18, 2018, and by publishing open invitations in relevant journals. Data sets from published and unpublished prospective cohort studies with data on thyroid function tests (thyrotropin [often referred to as thyroid-stimulating hormone or TSH] and free thyroxine [FT4] concentrations) or thyroid peroxidase (TPO) antibody measurements and gestational age at birth were screened for eligibility by 2 independent reviewers. Studies in which participants received treatment based on abnormal thyroid function tests were excluded. Data Extraction and Synthesis: The primary authors provided individual participant data that were analyzed using mixed-effects models. Main Outcomes and Measures: The primary outcome was preterm birth (<37 weeks' gestational age). Results: From 2526 published reports, 35 cohorts were invited to participate. After the addition of 5 unpublished data sets, a total of 19 cohorts were included. The study population included 47 045 pregnant women (mean age, 29 years; median gestational age at blood sampling, 12.9 weeks), of whom 1234 (3.1%) had subclinical hypothyroidism (increased thyrotropin concentration with normal FT4 concentration), 904 (2.2%) had isolated hypothyroxinemia (decreased FT4 concentration with normal thyrotropin concentration), and 3043 (7.5%) were TPO antibody positive; 2357 (5.0%) had a preterm birth. The risk of preterm birth was higher for women with subclinical hypothyroidism than euthyroid women (6.1% vs 5.0%, respectively; absolute risk difference, 1.4% [95% CI, 0%-3.2%]; odds ratio [OR], 1.29 [95% CI, 1.01-1.64]). Among women with isolated hypothyroxinemia, the risk of preterm birth was 7.1% vs 5.0% in euthyroid women (absolute risk difference, 2.3% [95% CI, 0.6%-4.5%]; OR, 1.46 [95% CI, 1.12-1.90]). In continuous analyses, each 1-SD higher maternal thyrotropin concentration was associated with a higher risk of preterm birth (absolute risk difference, 0.2% [95% CI, 0%-0.4%] per 1 SD; OR, 1.04 [95% CI, 1.00-1.09] per 1 SD). Thyroid peroxidase antibody-positive women had a higher risk of preterm birth vs TPO antibody-negative women (6.6% vs 4.9%, respectively; absolute risk difference, 1.6% [95% CI, 0.7%-2.8%]; OR, 1.33 [95% CI, 1.15-1.56]). Conclusions and Relevance: Among pregnant women without overt thyroid disease, subclinical hypothyroidism, isolated hypothyroxinemia, and TPO antibody positivity were significantly associated with higher risk of preterm birth. These results provide insights toward optimizing clinical decision-making strategies that should consider the potential harms and benefits of screening programs and levothyroxine treatment during pregnancy.

Maternal Exposure to Pyrethroid Insecticides during Pregnancy and Infant Development at 18 Months of Age.

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.

Survey on the Awareness of Genetic Testing in Japanese Workers: The Effect of Participant Characteristics on Awareness.

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.

[Application of Metabolomics to Multiple Chemical Sensitivity Research].

Multiple chemical sensitivity (MCS) is an acquired chronic disorder characterized by nonspecific symptoms in multiple organ systems associated with exposure to low-level chemicals. Diagnosis of MCS can be difficult because of the inability to assess the causal relationship between exposure and symptoms. No standardized objective measures for the identification of MCS and no precise definition of this disorder have been established. Recent technological advances in mass spectrometry have significantly improved our capacity to obtain more data from each biological sample. Metabolomics comprises the methods and techniques that are used to determine the small-level molecules in biofluids and tissues. The metabolomic profile-the metabolome-has multiple applications in many biological sciences, including the development of new diagnostic tools for medicine. We performed metabolomics to detect the difference between 9 patients with MCS and 9 controls. We identified 183 substances whose levels were beyond the normal detection limit. The most prominent differences included significant increases in the levels of both hexanoic acid and pelargonic acid, and also a significant decrease in the level of acetylcarnitine in patients with MCS. In conclusion, using metabolomics analysis, we uncovered a hitherto unrecognized alteration in the levels of metabolites in MCS. These changes may have important biological implications and may have a significant potential for use as biomarkers.

Associations between aldehyde dehydrogenase 2 (ALDH2) genetic polymorphisms, drinking status, and hypertension risk in Japanese adult male workers: a case-control study.

OBJECTIVES: We sought to identify associations between aldehyde dehydrogenase 2 (ALDH2), alcohol consumption, and hypertension in Japanese men. METHODS: The study participants were 1,225 male Japanese workers. We collected lifestyle information, body measurements, blood biochemical parameters, blood pressure measurements, and ALDH2 genotyping data during medical examinations conducted between March 2004 and January 2005 at a work facility and an affiliated company. Lifestyle data on alcohol intake and smoking were collected using self-administered questionnaires at the same time as when the aforementioned measurements were obtained. RESULTS: The genotype frequencies of ALDH2 genetic polymorphisms were 62.6, 32.7, and 4.7% for *1/*1, *1/*2, and *2/*2, respectively. Systolic blood pressure and diastolic blood pressure in the *1/*2 or *2/*2 group were significantly lower than those in the *1/*1 group (P < 0.001). Multiple regression analysis (stepwise method) for blood pressure according to ALDH2 genetic polymorphism revealed that the amount of daily alcohol intake affected systolic blood pressure in participants who harbored the ALDH2 genetic polymorphism *1/*2 or *2/*2. CONCLUSIONS: The interaction between alcohol intake and ALDH2 genetic polymorphisms might affect systolic blood pressure in adult male workers.

Association between airflow limitation severity and arterial stiffness as determined by the brachial-ankle pulse wave velocity: a cross-sectional study.

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). 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. 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). 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.

Associations between estrogen receptor genetic polymorphisms, smoking status, and prostate cancer risk: a case-control study in Japanese men.

OBJECTIVE: Prostate cancer (PCa) is one of the major causes of death among men. Our study investigated the association of ESR1 and ESR2 genotypes with susceptibility to PCa in relation to smoking status in Japanese. METHOD: A case-control study was performed with 750 Japanese prostate cancer patients and 870 healthy controls. After age-matching in case-controls, 352 controls and 352 cases were enrolled in this study. By using logistic regression analysis, the different genotypes from ESR1 and ESR2 were analyzed according to case/control status. RESULT: ESR2 rs4986938 AG and AG + AA genotypes were associated with significantly decreased risk of PCa (AG: OR = 0.68, 95 % CI 0.47-0.97, P < 0.05 and AG + AA: OR = 0.67, 95 % CI 0.47-0.94, P < 0.05). However, there was no significant association between ESR1 rs2234693 and PCa risk. When patients were grouped according to smoking status, the ESR2 rs1256049 AA genotype (OR = 0.48, 95 % CI 0.25-0.95, P < 0.05) and ESR2 rs4986938 AG + AA genotype (OR = 0.64, 95 % CI 0.41-1.00, P < 0.05) showed significantly decreased PCa risk in the ever-smoker group. CONCLUSION: Our results suggest that the estrogen receptor ESR2 has a very important function to predict PCa and that different SNPs have different predictive values. Smoking may influence estrogenic activity and may influence PCa together with the estrogen receptor.

The correlation between mental health and multiple chemical sensitivity: a survey study in Japanese workers.

OBJECTIVE: This study was designed to determine the correlation between mental health and multiple chemical sensitivity (MCS). METHOD: 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. RESULT: 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 (ß = 0.19, 0.64). Mental health was predicted by symptom severity and life impact (ß = 0.56 and 0.12), which were both affected by multiple chemical exposure (ß = 0.38 and 0.89, respectively). CONCLUSION: 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.

Inter- and intra-individual variation in urinary excretion of daidzein and equol in female Japanese.

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 µg/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.