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1.  Rationale and study design of the Japan environment and children’s study (JECS) 
BMC Public Health  2014;14:25.
There is global concern over significant threats from a wide variety of environmental hazards to which children face. Large-scale and long-term birth cohort studies are needed for better environmental management based on sound science. The primary objective of the Japan Environment and Children’s Study (JECS), a nation-wide birth cohort study that started its recruitment in January 2011, is to elucidate environmental factors that affect children’s health and development.
Approximately 100,000 expecting mothers who live in designated study areas will be recruited over a 3-year period from January 2011. Participating children will be followed until they reach 13 years of age. Exposure to environmental factors will be assessed by chemical analyses of bio-specimens (blood, cord blood, urine, breast milk, and hair), household environment measurements, and computational simulations using monitoring data (e.g. ambient air quality monitoring) as well as questionnaires. JECS’ priority outcomes include reproduction/pregnancy complications, congenital anomalies, neuropsychiatric disorders, immune system disorders, and metabolic/endocrine system disorders. Genetic factors, socioeconomic status, and lifestyle factors will also be examined as covariates and potential confounders. To maximize representativeness, we adopted provider-mediated community-based recruitment.
Through JECS, chemical substances to which children are exposed during the fetal stage or early childhood will be identified. The JECS results will be translated to better risk assessment and management to provide healthy environment for next generations.
PMCID: PMC3893509  PMID: 24410977
Birth cohort; Children; Growth and development; Environmental chemicals; Pregnant women
2.  Short Sleep Duration and Poor Sleep Quality Increase the Risk of Diabetes in Japanese Workers With No Family History of Diabetes 
Diabetes Care  2012;35(2):313-318.
To investigate whether a difference in the risk for diabetes exists in Japanese workers with regard to sleep duration/quality and the presence or absence of a family history of diabetes (FHD).
The researchers conducted a prospective, occupational-based study of local government employees in Sapporo, Japan. Between April 2003 and March 2004, 3,570 nondiabetic participants, aged 35–55 years, underwent annual health checkups and completed a self-administered questionnaire that included information on sleep duration/quality and FHD at baseline. Having diabetes was defined as taking medication for diabetes or a fasting plasma glucose level of ≥126 mg/dL at follow-up (2007–2008).
A total of 121 (3.4%) new cases of diabetes were reported. In multivariate logistic regression models of workers without an FHD, and after adjustment for potential confounding factors, the odds ratio (95% CI) for developing diabetes was 5.37 (1.38–20.91) in those with a sleep duration of ≤5 h compared with those with a sleep duration of >7 h. Other risk factors were awakening during the night (5.03 [1.43–17.64]), self-perceived insufficient sleep duration (6.76 [2.09–21.87]), and unsatisfactory overall quality of sleep (3.71 [1.37–10.07]). In subjects with an FHD, these associations were either absent or weaker.
The current study shows that poor sleep is associated with a higher risk of developing diabetes in workers without an FHD. Promoting healthy sleeping habits may be effective for preventing the development of diabetes in people without an FHD.
PMCID: PMC3263910  PMID: 22210572
3.  Brachial-ankle pulse wave velocity is an independent predictor of incident hypertension in Japanese normotensive male subjects 
Cardiovascular morbidity and mortality are closely associated with hypertension, however, predictors of incident hypertension have not been fully established. We have conducted a study aimed at evaluating whether brachial-ankle pulse wave velocity (baPWV) is a predictor of incident hypertension.
The relation between baPWV, a noninvasive index of aortic stiffness, and incident hypertension was evaluated in a cohort of 2,278 Japanese normotensive male subjects with a follow-up of 3 years.
Of the 2, 278 study participants, 151 (6.6%) had incident hypertension during the follow-up. After adjustment for variables, including age, gender, body mass index (BMI), smoking habit, alcohol consumption, diabetes mellitus, hyperlipidemia, family history of hypertension, heart rate, systolic blood pressure, low-density lipoprotein cholesterol, triglyceride, and fasting plasma glucose, multiple logistic regression analysis revealed that baPWV was a significant and independent predictor of incident hypertension with an adjusted odds ratio 1.45 (95% confidence interval 1.17–1.79, P < 0.01). In addition, baPWV values >1,380 cm/s indicated a high risk for incident hypertension.
Among the Japanese normotensive male subjects participating in this study, BaPWV was a significant and independent predictor of incident hypertension. This result suggests that BaPWV could be a useful screening method to identify normotensive individuals who should be targeted for interventions aimed at preventing the incident hypertension.
PMCID: PMC3117209  PMID: 21431793
Arterial stiffness; Hypertension; Pulse wave velocity; Cohort studies; Japanese male subjects
4.  Effects of Maternal 5,10-Methylenetetrahydrofolate Reductase C677T and A1298C Polymorphisms and Tobacco Smoking on Infant Birth Weight in a Japanese Population 
Journal of Epidemiology  2012;22(2):91-102.
Intracellular folate hemostasis depends on the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene. Because 5,10-MTHFR 677TT homozygosity and tobacco smoking are associated with low folate status, we tested the hypothesis that smoking in mothers with 5,10-MTHFR C677T or A1298C polymorphisms would be independently associated with lower birth weight among their offspring.
We assessed 1784 native Japanese mother-child pairs drawn from the ongoing birth cohort of The Hokkaido Study on Environment and Children’s Health. Data (demographic information, hospital birth records, and biological specimens) were extracted from recruitments that took place during the period from February 2003 to March 2006. Maternal serum folate were assayed by chemiluminescent immunoassay, and genotyping of 5,10-MTHFR C677T/A1298C polymorphisms was done using a TaqMan allelic discrimination assay.
The prevalence of folate deficiency (<6.8 nmol/L) was 0.3%. The 5,10-MTHFR 677CT genotype was independently associated with an increase of 36.40 g (95% CI: 2.60 to 70.30, P = 0.035) in mean infant birth weight and an increase of 90.70 g (95% CI: 6.00 to 175.50, P = 0.036) among male infants of nonsmokers. Female infants of 677TT homozygous passive smokers were 99.00 g (95% CI: −190.26 to −7.56, P = 0.034) lighter. The birth weight of the offspring of smokers with 5,10-MTHFR 1298AA homozygosity was lower by 107.00 g (95% CI: −180.00 to −33.90, P = 0.004).
The results suggest that, in this population, maternal 5,10-MTHFR C677T polymorphism, but not the 5,10-MTHFR A1298C variant, is independently associated with improvement in infant birth weight, especially among nonsmokers. However, 5,10-MTHFR 1298AA might be associated with folate impairment and could interact with tobacco smoke to further decrease birth weight.
PMCID: PMC3798587  PMID: 22277790
birth weight; tobacco smoking; MTHFR SNPs; folate; Japan
5.  Inflammation as a cardiovascular risk factor and pulse wave velocity as a marker of early-stage atherosclerosis in the Japanese population 
Inflammation and pulse wave velocity (PWV) are a potential risk factor and marker, respectively, for atherosclerosis in the primary prevention setting. Atherosclerosis is now generally accepted to be an inflammatory disorder of the arterial wall, and the high-sensitivity C-reactive protein (hs-CRP) level has been reported to be a strong predictor of cardiovascular events. High-sensitivity-CRP is associated with two factors related to inflammation: (1) the local production of CRP by atheromatous tissue or coronary artery smooth muscle cells and (2) adipose tissue as a potent source of inflammatory cytokines. Based on studies in North America and Europe, hs-CRP has been established as a cardiovascular risk factor and a cut-off value has been recommended. However, Japanese have lower hs-CRP values than their Western counterparts, partly because Japanese have a lower body mass index (BMI), which correlates positively to hs-CRP, and partly because lifestyle and genetic factors can affect hs-CRP values. Therefore, a cut-off value needs to be established by cohort studies for the Japanese population. Carotid-femoral PWV is most commonly measured by applanation tonometry, particularly in Europe, but this method is critically dependent upon the accurate placing of transducers over the arteries and is both time-consuming and complex. A novel device has been recently developed in Japan that measures brachial-ankle PWV (baPWV) using a volume-rendering method. Brachian-ankle PWV is a suitable screening method because of its technical simplicity and shorter measurement time. It is associated not only with conventional cardiovascular risk factors but also with new risk factors, such as inflammation, γ-glutamyltransferase, chronic kidney disease, and psychosocial factors. However, a suitable cut-off value has yet to be established.
PMCID: PMC2684804  PMID: 19568843
Arterial stiffness; Atherosclerosis; C-reactive protein; Inflammation; Pulse wave velocity
6.  Survival Prognosis of Japanese With Severe Motor and Intellectual Disabilities Living in Public and Private Institutions Between 1961 and 2003 
Journal of Epidemiology  2010;20(1):77-81.
Although the prognosis for survival in people with severe functional disabilities is a serious concern for their families and health care practitioners, there have been few reports on survival rates for this population. Every year, the Japanese Association of Welfare for Persons with Severe Motor and Intellectual Disability collects anonymous records of individual registrations and deaths from all private and public institutions, excepting national institutions. We used these data to estimate the prognosis for survival.
We reviewed the records of 3221 people with severe motor and intellectual disabilities (SMID); all subjects had lived in one of 119 public or private institutions in Japan between 1961 and 2003. Kaplan–Meier survival estimates were calculated according to disability type and birth year range.
Of the 3221 persons, 2645 were alive and 576 had died. The survival rate at the age of 20 for all subjects was 79% (95% confidence interval, 78%–81%). Among people who were unable to sit, those with lower intelligence quotients had lower survival rates.
The survival rate among people with SMID housed in public and private institutions in Japan was much worse than that of the general population, and has not improved since the 1960s.
PMCID: PMC3900783  PMID: 19946176
prognosis for survival; severe motor and intellectual disabilities; survival analysis
7.  Correlations between Prenatal Exposure to Perfluorinated Chemicals and Reduced Fetal Growth 
Environmental Health Perspectives  2008;117(4):660-667.
Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) are man-made, ubiquitous, and persistent contaminants in the environment, wildlife, and humans. Although recent studies have shown that these chemicals interfere with fetal growth in humans, the results are inconsistent.
Our goal was to investigate the correlation between relatively low levels of PFOS and PFOA in maternal serum and birth weight and birth size.
We conducted a hospital-based prospective cohort study between July 2002 and October 2005 in Sapporo, Japan. A total of 428 women and their infants were involved in the study. We obtained characteristics of the mothers and infants from self-administered questionnaire surveys and from medical records. We analyzed maternal serum samples for PFOS and PFOA by liquid chromatography–tandem mass spectrometry (LC/MS/MS).
After adjusting for confounding factors, PFOS levels negatively correlated with birth weight [per log10 unit: β = −148.8 g; 95% confidence interval (CI), −297.0 to −0.5 g]. In addition, analyses stratified by sex revealed that PFOS levels negatively correlated with birth weight only in female infants (per log10 unit: β = −269.4 g; 95% CI, −465.7 to −73.0 g). However, we observed no correlation between PFOA levels and birth weight.
Our results indicate that in utero exposure to relatively low levels of PFOS was negatively correlated with birth weight.
PMCID: PMC2679613  PMID: 19440508
birth weight; chest circumference; fetal growth; head circumference; length; perfluorinated chemicals; perfluorooctane sulfonate; perfluorooctanoate; prenatal exposure
8.  Cancer Mortality in Workers Exposed to Organochlorine Compounds in the Pulp and Paper Industry: An International Collaborative Study 
Environmental Health Perspectives  2006;114(7):1007-1012.
The objective of this study was to evaluate cancer mortality in pulp and paper industry workers exposed to chlorinated organic compounds. We assembled a multinational cohort of workers employed between 1920 and 1996 in 11 countries. Exposure to both volatile and nonvolatile organochlorine compounds was estimated at the department level using an exposure matrix. We conducted a standardized mortality ratio (SMR) analysis based on age and calendar-period–specific national mortality rates and a Poisson regression analysis. The study population consisted of 60,468 workers. Workers exposed to volatile organochlorines experienced a deficit of all-cause [SMR = 0.91; 95% confidence interval (CI), 0.89–0.93] and all-cancer (SMR = 0.93; 95% CI, 0.89–0.97) mortality, with no evidence of increased risks for any cancer of a priori interest. There was a weak, but statistically significant, trend of increasing risk of all-cancer mortality with increasing weighted cumulative exposure. A similar deficit in all-cause (SMR = 0.94; 95% CI, 0.91–0.96) and all-cancer (SMR = 0.94; 95% CI, 0.89–1.00) mortality was observed in those exposed to non-volatile organochlorines. No excess risk was observed in cancers of a priori interest, although mortality from Hodgkin disease was elevated (SMR = 1.76; 95% CI, 1.02–2.82). In this study we found little evidence that exposure to organochlorines at the levels experienced in the pulp and paper industry is associated with an increased risk of cancer, apart from a weak but significant association between all-cancer mortality and weighted cumulative volatile organochlorine exposure.
PMCID: PMC1513323  PMID: 16835051
epidemiology; mortality; neoplasms; organochlorines; pulp and paper industry
9.  Indoor airborne mold spores in newly built dwellings 
To investigate the relationships between sick building syndrome and mold in newly-built dwellings.
Symptoms of 61 residents in 18 dwellings were surveyed by standardized questionnaires. Mold sampling was done by gravity sampling using an open Petri dish. Potato dextrose agar (PDA) and dichloran-18% glycerol agar (DG-18) were used as the culture medium.
There were 6 dwellings in which at least one inhabitant complained of one or more symptoms and 12 dwellings in which none of the inhabitants complained of symptoms. There was a tendency for the dwellings with inhabitants reporting symptoms to have larger colony forming units (CFU) on PDA than those without inhabitants reporting symptoms (p=0.1), but there was no difference in DG-18 result. There was a tendency for the dwellings with inhabitants reporting symptoms to have larger CFU ofCladosporium on PDA than those without (p=0.08), but there was no difference in DG-18 result. Significantly moreUlocladium sp. was detected in the dwellings with inhabitants reporting symptoms than in those without (p=0.03).Cladosporium cladosporioides was detected in all the dwellings with inhabitants reporting symptoms and 75% of the dwellings without.Cladosporium macrocarpum andCladosporium herbarum were detected in 33% of the dwellings with inhabitants reporting e symptoms and none of the dwellings without (p=0.1).
Cladosporium was dominant in the Japanese newly-built dwellings studied, andCladosporium andUlocladium were probably associated with the residents’ symptoms in these newly-built dwellings.
PMCID: PMC2723256  PMID: 21432155
mold; sick building syndrome; Cladosporium; Ulocladium
10.  Effects of Prenatal Exposure to Polychlorinated Biphenyls and Dioxins on Mental and Motor Development in Japanese Children at 6 Months of Age 
Environmental Health Perspectives  2005;114(5):773-778.
Several studies have shown that prenatal and/or postnatal background-level exposure to environmental chemicals, such as polychlorinated biphenyls (PCBs) and dioxins, induces adverse effects on the neurodevelopment of children. However, other studies have not detected any harmful influences on neurodevelopment. Furthermore, except in western countries, no developmental tests have been carried out in relation to detailed assessment of exposure to PCBs and dioxins. In this study (the Hokkaido Study on Environment and Children’s Health), the effect of prenatal exposure to background levels of PCBs and dioxins on infant neurodevelopment in Japan/Sapporo was elucidated. The associations between the total or individual isomer level of PCBs and dioxins in 134 Japanese pregnant women’s peripheral blood and the mental or motor development of their 6-month-old infants were evaluated using the second edition of the Bayley Scales of Infant Development. The mean level of total toxicity equivalency quantity (TEQ) was 18.8 (4.0–51.2) pg/g lipid in blood of 134 mothers. After adjustment for potential confounding variables, the total TEQ value was shown not to be significantly associated with mental developmental index (MDI) or psychomotor developmental index (PDI). However, the levels of one polychlorinated dibenzo-p-dioxin (PCDD) isomer, total PCDDs, and total PCDDs/polychlorinated dibenzofurans (PCDFs) were significantly negatively associated with MDI, and the levels of two PCDD isomers and three PCDF isomers were significantly negatively associated with the PDI. In conclusion, the background-level exposure of several isomers of dioxins during the prenatal period probably affects the motor development of 6-month-old infants more than it does their mental development.
PMCID: PMC1459935  PMID: 16675436
dioxins; infant development; maternal blood; polychlorinated biphenyls (PCBs); prenatal exposure
11.  Perfluorooctane Sulfonate (PFOS) and Related Perfluorinated Compounds in Human Maternal and Cord Blood Samples: Assessment of PFOS Exposure in a Susceptible Population during Pregnancy 
Environmental Health Perspectives  2004;112(11):1204-1207.
Fluorinated organic compounds (FOCs), such as perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), and perfluorooctane sulfonylamide (PFOSA), are widely used in the manufacture of plastic, electronics, textile, and construction material in the apparel, leather, and upholstery industries. FOCs have been detected in human blood samples. Studies have indicated that FOCs may be detrimental to rodent development possibly by affecting thyroid hormone levels. In the present study, we determined the concentrations of FOCs in maternal and cord blood samples. Pregnant women 17–37 years of age were enrolled as subjects. FOCs in 15 pairs of maternal and cord blood samples were analyzed by liquid chromatography–electrospray mass spectrometry coupled with online extraction. The limits of quantification of PFOS, PFOA, and PFOSA in human plasma or serum were 0.5, 0.5, and 1.0 ng/mL, respectively. The method enables the precise determination of FOCs and can be applied to the detection of FOCs in human blood samples for monitoring human exposure. PFOS concentrations in maternal samples ranged from 4.9 to 17.6 ng/mL, whereas those in fetal samples ranged from 1.6 to 5.3 ng/mL. In contrast, PFOSA was not detected in fetal or maternal samples, whereas PFOA was detected only in maternal samples (range, < 0.5 to 2.3 ng/mL, 4 of 15). Our results revealed a high correlation between PFOS concentrations in maternal and cord blood (r2 = 0.876). However, we did not find any significant correlations between PFOS concentration in maternal and cord blood samples and age bracket, birth weight, or levels of thyroid-stimulating hormone or free thyroxine. Our study revealed that human fetuses in Japan may be exposed to relatively high levels of FOCs. Further investigation is required to determine the postnatal effects of fetal exposure to FOCs.
PMCID: PMC1247483  PMID: 15289168
cord blood; fluorinated organic compounds; human; PFOA; PFOS; PFOSA; pregnancy
12.  Mortality from lung cancer in workers exposed to sulfur dioxide in the pulp and paper industry. 
Environmental Health Perspectives  2002;110(10):991-995.
Our objective in this study was to evaluate the mortality of workers exposed to sulfur dioxide in the pulp and paper industry. The cohort included 57,613 workers employed for at least 1 year in the pulp and paper industry in 12 countries. We assessed exposure to SO(2) at the level of mill and department, using industrial hygiene measurement data and information from company questionnaires; 40,704 workers were classified as exposed to SO(2). We conducted a standardized mortality ratio (SMR) analysis based on age-specific and calendar period-specific national mortality rates. We also conducted a Poisson regression analysis to determine the dose-response relations between SO(2) exposure and cancer mortality risks and to explore the effect of potential confounding factors. The SMR analysis showed a moderate deficit of all causes of death [SMR = 0.89; 95% confidence interval (CI), 0.87-0.96] among exposed workers. Lung cancer mortality was marginally increased among exposed workers (SMR = 1.08; 95% CI, 0.98-1.18). After adjustment for occupational coexposures, the lung cancer risk was increased compared with unexposed workers (rate ratio = 1.49; 95% CI, 1.14-1.96). There was a suggestion of a positive relationship between weighted cumulative SO(2) exposure and lung cancer mortality (p-value of test for linear trend = 0.009 among all exposed workers; p = 0.3 among workers with high exposure). Neither duration of exposure nor time since first exposure was associated with lung cancer mortality. Mortality from non-Hodgkin lymphoma and from leukemia was increased among workers with high SO(2) exposure; a dose-response relationship with cumulative SO(2) exposure was suggested for non-Hodgkin lymphoma. For the other causes of death, there was no evidence of increased mortality associated with exposure to SO(2). Although residual confounding may have occurred, our results suggest that occupational exposure to SO(2) in the pulp and paper industry may be associated with an increased risk of lung cancer.
PMCID: PMC1241024  PMID: 12361923

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