Shoji F. Nakayama

Rationale and study design of the Japan environment and children’s study (JECS)

BackgroundThere 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.Methods/DesignApproximately 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.DiscussionThrough 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.

The Japan Environment and Children's Study (JECS): A Preliminary Report on Selected Characteristics of Approximately 10 000 Pregnant Women Recruited During the First Year of the Study

BACKGROUND The Japan Environment and Childrens Study (JECS) is an ongoing nationwide birth cohort study launched in January 2011. In this progress report, we present data collected in the first year to summarize selected maternal and infant characteristics. METHODS In the 15 Regional Centers located throughout Japan, the expectant mothers were recruited in early pregnancy at obstetric facilities and/or at local government offices issuing pregnancy journals. Self-administered questionnaires were distributed to the women during their first trimester and then again during the second or third trimester to obtain information on demographic factors, physical and mental health, lifestyle, occupation, environmental exposure, dwelling conditions, and socioeconomic status. Information was obtained from medical records in the first trimester and after delivery on medical history, including gravidity and related complications, parity, maternal anthropometry, and infant physical examinations. RESULTS We collected data on a total of 9819 expectant mothers (mean age = 31.0 years) who gave birth during 2011. There were 9635 live births. The selected infant characteristics (singleton births, gestational age at birth, sex, birth weight) in the JECS population were similar to those in national survey data on the Japanese general population. CONCLUSIONS Our final birth data will eventually be used to evaluate the national representativeness of the JECS population. We hope the JECS will provide valuable information on the impact of the environment in which our children live on their health and development.Background The Japan Environment and Children’s Study (JECS) is an ongoing nationwide birth cohort study launched in January 2011. In this progress report, we present data collected in the first year to summarize selected maternal and infant characteristics. Methods In the 15 Regional Centers located throughout Japan, the expectant mothers were recruited in early pregnancy at obstetric facilities and/or at local government offices issuing pregnancy journals. Self-administered questionnaires were distributed to the women during their first trimester and then again during the second or third trimester to obtain information on demographic factors, physical and mental health, lifestyle, occupation, environmental exposure, dwelling conditions, and socioeconomic status. Information was obtained from medical records in the first trimester and after delivery on medical history, including gravidity and related complications, parity, maternal anthropometry, and infant physical examinations. Results We collected data on a total of 9819 expectant mothers (mean age = 31.0 years) who gave birth during 2011. There were 9635 live births. The selected infant characteristics (singleton births, gestational age at birth, sex, birth weight) in the JECS population were similar to those in national survey data on the Japanese general population. Conclusions Our final birth data will eventually be used to evaluate the national representativeness of the JECS population. We hope the JECS will provide valuable information on the impact of the environment in which our children live on their health and development.

Toward Greater Implementation of the Exposome Research Paradigm within Environmental Epidemiology.

Investigating a single environmental exposure in isolation does not reflect the actual human exposure circumstance nor does it capture the multifactorial etiology of health and disease. The exposome, defined as the totality of environmental exposures from conception onward, may advance our understanding of environmental contributors to disease by more fully assessing the multitude of human exposures across the life course. Implementation into studies of human health has been limited, in part owing to theoretical and practical challenges including a lack of infrastructure to support comprehensive exposure assessment, difficulty in differentiating physiologic variation from environmentally induced changes, and the need for study designs and analytic methods that accommodate specific aspects of the exposome, such as high-dimensional exposure data and multiple windows of susceptibility. Recommendations for greater data sharing and coordination, methods development, and acknowledgment and minimization of multiple types of measurement error are offered to encourage researchers to embark on exposome research to promote the environmental health and well-being of all populations.

In utero and Lactational Exposure to Acetamiprid Induces Abnormalities in Socio-Sexual and Anxiety-Related Behaviors of Male Mice

Neonicotinoids, a widely used group of pesticides designed to selectively bind to insect nicotinic acetylcholine receptors, were considered relatively safe for mammalian species. However, they have been found to activate vertebrate nicotinic acetylcholine receptors and could be toxic to the mammalian brain. In the present study, we evaluated the developmental neurotoxicity of acetamiprid (ACE), one of the most widely used neonicotinoids, in C57BL/6J mice whose mothers were administered ACE via gavage at doses of either 0 mg/kg (control group), 1.0 mg/kg (low-dose group), or 10.0 mg/kg (high-dose group) from gestational day 6 to lactation day 21. The results of a battery of behavior tests for socio-sexual and anxiety-related behaviors, the numbers of vasopressin-immunoreactive cells in the paraventricular nucleus of the hypothalamus, and testosterone levels were used as endpoints. In addition, behavioral flexibility in mice was assessed in a group-housed environment using the IntelliCage, a fully automated mouse behavioral analysis system. In adult male mice exposed to ACE at both low and high doses, a significant reduction of anxiety level was found in the light-dark transition test. Males in the low-dose group also showed a significant increase in sexual and aggressive behaviors. In contrast, neither the anxiety levels nor the sexual behaviors of females were altered. No reductions in the testosterone level, the number of vasopressin-immunoreactive cells, or behavioral flexibility were detected in either sex. These results suggest the possibility that in utero and lactational ACE exposure interferes with the development of the neural circuits required for executing socio-sexual and anxiety-related behaviors in male mice specifically.

Baseline Profile of Participants in the Japan Environment and Children’s Study (JECS)

Background The Japan Environment and Children’s Study (JECS), known as Ecochil-Chosa in Japan, is a nationwide birth cohort study investigating the environmental factors that might affect children’s health and development. We report the baseline profiles of the participating mothers, fathers, and their children. Methods Fifteen Regional Centres located throughout Japan were responsible for recruiting women in early pregnancy living in their respective recruitment areas. Self-administered questionnaires and medical records were used to obtain such information as demographic factors, lifestyle, socioeconomic status, environmental exposure, medical history, and delivery information. In the period up to delivery, we collected bio-specimens, including blood, urine, hair, and umbilical cord blood. Fathers were also recruited, when accessible, and asked to fill in a questionnaire and to provide blood samples. Results The total number of pregnancies resulting in delivery was 100,778, of which 51,402 (51.0%) involved program participation by male partners. Discounting pregnancies by the same woman, the study included 95,248 unique mothers and 49,189 unique fathers. The 100,778 pregnancies involved a total of 101,779 fetuses and resulted in 100,148 live births. The coverage of children in 2013 (the number of live births registered in JECS divided by the number of all live births within the study areas) was approximately 45%. Nevertheless, the data on the characteristics of the mothers and children we studied showed marked similarity to those obtained from Japan’s 2013 Vital Statistics Survey. Conclusions Between 2011 and 2014, we established one of the largest birth cohorts in the world.

Evaluating an Alternative Method for Rapid Urinary Creatinine Determination

Creatinine (CR) is an endogenously produced chemical that is routinely assayed in urine specimens to assess kidney function and sample dilution. The industry-standard method for CR determination, known as the kinetic Jaffé (KJ) method, relies on an exponential rate of a colorimetric change, and can therefore require automated processing equipment for moderate- to high-throughput analysis (hundreds to thousands of samples per day). This study evaluates an alternative colorimetric method, the “plateau Jaffé” (PJ) method, which utilizes the chemistry of the KJ method, a commercially available kit, and a multipoint calibration curve. This method is amenable to moderate-throughput sample analysis and does not require automated processing equipment. Thirty-two spot urine samples from healthy adult volunteers were analyzed for creatinine concentration (CRc) using the KJ and PJ methods. Samples were also analyzed using a liquid chromatography time-of-flight mass spectrometry (LC-TOF/MS) method, which acted as an analytical control. Replicate measurements of spot samples (natural log-transformed values) were used to estimate method precision, and linear regression models were used to evaluate method accuracy (LC-TOF/MS measurements were considered the analytical benchmark). Measurement precision was comparable across all three methods, with coefficent of variation estimates ranging from 3 to 6%. Regression models generally showed good agreement across methods with R2 estimates ranging from .996 to .998, slope estimates ranging from .944 to .986, and y-intercept estimates ranging from 0.111 to 0.303. Minor bias (between 2 and 16%) was observed across methods at the tails of the measurement distributions. The provided regression equations can be used to adjust for this bias and to improve CR measurement comparisons across studies employing different methods. Considering these results, the PJ method is a suitable alternative to the industry standard KJ method for urinary CRc determination. It can be implemented for moderate-throughput sample analysis using modest and commonly available lab instrumentation and manual sample preparation techniques.

Harmonizing Biomarker Measurementsin Longitudinal Studies of Children’s Healthand the Environment

Abstract Large scale studies of environmental influences on children’s health and development are being planned or conducted in many places, including Japan, France, Shanghai (China), the United States, and Germany. The objective of these “next generation” studies is to better understand a broad range of environmental and social factors that influence the health and well-being of children. Some of these studies are designed to enroll tens of thousands of children and follow them for many years to investigate the influence of the environment on child growth, development and health. Environment is broadly defined in these studies and includes investigation of chemical, biological, physical and socioeconomic factors. An international group composed of study teams from Japan, France, Shanghai (China), the United States, and Germany has been meeting since 2011 to exchange information and work towards harmonization of processes that would provide the opportunity to compare methods and develop procedures to conduct combined analyses of results and data pooling procedures. Harmonization of infant health outcomes, biomarkers, environmental measurements, socioeconomic and migration status has been initiated. This manuscript provides an overview of the Environment and Child Health International Birth Cohort Group and its history, describes the progress of work, and discusses the advantages of this international collaborative effort.

A relationship in adrenal androgen levels between mothers and their children from a dioxin-exposed region in Vietnam

Over the past decades, southern Vietnam has been burdened by dioxins from contaminated herbicides sprayed during the Vietnam War. In a previous study, we found that dioxin exposure decreased levels of salivary dehydroepiandrosterone (DHEA), an adrenal androgen, in 3-year-old children. In present study, to assess the relationship between adrenal hormones disruption in lactating mothers and in children, we compared mother-child pairs from dioxin- and nondioxin-contaminated regions. In 2010 and 2011, mother-child pairs from a dioxin hotspot region (n=37) and a non-contaminated region (n=47) were recruited and donated breast milk and serum samples for dioxin and steroid hormones determination. Mothers were 20-30years old and had given birth to their first child between 4 and 16weeks previously. One year later, saliva samples were collected from the children. Dioxin levels in breast milk were determined by gas chromatography/high-resolution mass spectrometry. Salivary DHEA, cortisol in children and androstenedione (A-dione), estradiol, cortisol, and DHEA in maternal serum were analyzed by liquid chromatography/tandem mass spectrometry. Concentrations of dioxin congeners in the hotspot region were 2- to 5-fold higher than in samples from the non-contaminated region. Salivary DHEA levels in children and serum A-dione levels in mothers were significantly higher in the hotspot region; no difference was found in the levels of other hormones. Moreover, there was a significant positive correlation between the elevated hormone levels in mothers and children (r=0.62, p<0.001). Several dioxin congeners exhibited strong significant dose-response relationships with salivary DHEA and serum A-dione levels. Our findings suggest that dioxin disrupts adrenal androgens in mothers and breastfeeding children through the same mechanism.

Japan Environment and Children’s Study: backgrounds, activities, and future directions in global perspectives

There is worldwide concern about the effects of environmental factors on children’s health and development. The Miami Declaration was signed at the G8 Environment Ministers Meeting in 1997 to promote children’s environmental health research. The following ministerial meetings continued to emphasize the need to foster children’s research. In response to such a worldwide movement, the Ministry of the Environment, Japan (MOE), launched a nationwide birth cohort study with 100,000 pairs of mothers and children, namely, the Japan Environment and Children’s Study (JECS), in 2010. Other countries have also started or planned large-scale studies focusing on children’s environmental health issues. The MOE initiated dialogue among those countries and groups to discuss and share the various processes, protocols, knowledge, and techniques for future harmonization and data pooling among such studies. The MOE formed the JECS International Liaison Committee in 2011, which plays a primary role in promoting the international collaboration between JECS and the other children’s environmental health research projects and partnership with other countries. This review article aims to present activities that JECS has developed. As one of the committee’s activities, a workshop and four international symposia were held between 2011 and 2015 in Japan. In these conferences, international researchers and government officials, including those from the World Health Organization, have made presentations on their own birth cohort studies and health policies. In 2015, the MOE hosted the International Advisory Board meeting and received constructive comments and recommendations from the board. JECS is a founding member of the Environment and Child Health International Birth Cohort Group, and has discussed harmonization of exposure and outcome measurements with member parties, which will make it possible to compare and further combine data from different studies, considering the diversity in the measurements of variables between the studies. JECS is expected to contribute to the international environmental health research community and policy-making. More international collaboration would enhance our understanding of the possible environmental causes of diseases and disabilities.

Androgen disruption by dioxin exposure in 5-year-old Vietnamese children: Decrease in serum testosterone level

Dioxins have been suspected to be potential substances causing endocrine disruptions in humans. We are conducting the research in one of three dioxin exposure areas (hotspots) in Vietnam. We previously reported that the salivary dehydroepiandrosterone (DHEA) level decreased in 3-year-old Vietnamese children and that it was significantly inversely correlated with polychlorinated dibenzodioxin/dibenzofuran levels in their mothers breast milk. In this study, we investigated the influence of exposure to dioxin on steroid hormone biosynthesis in the same children when they reached 5 years of age, focusing on androgens. Thirty-five and 50 mother-child pairs from dioxin hotspot and non-sprayed areas, respectively, participated in this study. Maternal breast milk was donated at 4 to 16 weeks postpartum in 2008 to measure dioxin levels by gas chromatography/high-resolution mass spectrometry. Serum was collected from 5-year-old children in 2013. Seven steroid hormones were measured by liquid chromatography/mass spectrometry. Most dioxin congeners in breast milk were 2- to 10-fold higher in the hotspot than in the non-sprayed area. DHEA and testosterone (T) were significantly lower in the hotspot and showed negative correlations with most dioxin congeners. Similar results were observed for the activities of cytochrome P450-17, 20 lyase (CYP17 lyase), and 17β-hydroxysteroid dehydrogenase (HSD). Conversely, the elevated androstenedione (A-dione) level and 3β-HSD activity in children from the hotspot were positively correlated with dioxin levels. Moreover, a positive correlation was shown between T and 17β-HSD. It is possible that dioxin inhibits 17β-HSD activity, leading to a decrease in the T level. Multiple regression analysis indicated that dioxin had a strong association with the DHEA, A-dione, and T levels. In conclusion, the present study suggests that dioxin is associated with low levels of DHEA and T and inhibition of the activity of steroidogenic enzymes such as CYP17 lyase and 17β-HSD in 5-year-old children.