Objectives: The developmental origins of health and disease paradigm (DOHaD) is a concept that fetal environmental factors affect adult phenotypes. We performed experiments to evaluate the DOHaD theory in developmental disorders using mouse models.
Methods: In vitro fertilization and embryo transfer techniques were used for mouse production. The AIN93G-control diet, which contains 20% protein (CD), 5% protein-restricted diet (PR), and PR with supplemental folic acid (FA) were provided as experimental diets to mothers. The body weights (BWs) of mothers and offspring, and the blood-clinical biochemistry results of mothers were examined. In addition, gene expression and genomic methylation in the brain of adult offspring and behavioral phenotypes of adult offspring were examined.
Results: Pregnant mothers that consumed the protein-restricted diets, namely, PR and FA, exhibited reduction in BW. The values of protein-related parameters determined by blood-clinical biochemistry decreased in the PR fed groups. The BWs of neonates and adult offspring did not change. The offspring exposed to maternal hyponutrition exhibited increased activity in the home cage and enhanced fear and anxiety-like behavior. The adult offspring of the PR-fed group and FA-fed groups exhibited different patterns of mRNA expression and genomic methylation in the brain.
Conclusions: The maternal PR diet affected the progenies’ behavioral phenotypes and epigenetic outcomes in the brain. However, the behavioral changes induced by maternal protein restriction were very slight. Hence, interactions between several genetic factors and environmental exposures such as maternal malnutrition may cause developmental and psychiatric disorders.
X-chromosome inactivation (XCI) occurs during the gestation period to compensate for the dosage of X-linked genes in female mammals. Xist RNA is a long noncoding RNA with a global epigenetic function and is indispensable for XCI from the initiation to establishment and maintenance phases. The X chromosome contains over 1,000 genes that are essential for proper development, especially that of the brain, immune system, metabolism and reproductive functions. We found that exposure to bisphenol A or folate deficiency during the fetal period changes the expressions of Xist, Tsix (the antisense repressor of Xist), and many X chromosome linked genes widely in newborn mice. This finding suggests that this X-chromosome mediated effect is considered one of the mechanisms of various problems encountered in the fetal environment. The Developmental Origins of Health and Disease (DOHaD) hypothesis states that nutrition and other environmental stimuli during critical periods affect developmental pathways with epigenetics and induce metabolism and chronic disease susceptibility. The XCI process has some similarities to this hypothesis and it may become one of the approaches to reveal the DOHaD mechanisms.
In Japan, the prevalence of low birth weight (< 2,500 g) has been increasing, probably owing to leanness, exposure to toxic chemicals and smoking. Epidemiological studies revealed that low birth weight poses risks of hypertension, coronary heart diseases and diabetes. Although the precise mechanism has not been understood, there is an urgent need for appropriate public health interventions. MicroRNA (miRNA) is a small RNA consisting of approximately 22 nucleotides and distributed in a wide variety of organs and body fluids. miRNAs are involved in the pathogenesis of various human diseases and expected to be their potential biomarkers. The interest on the study on miRNA in the research field of developmental origins of health and disease (DOHaD) has been growing, and the number of related papers has been increasing. There are several molecular epidemiological studies on the relationship between maternal miRNA and fetal development. The effects of smoking and dietary factors on miRNA expression and fetal development have been investigated in epidemiological and experimental studies. However, the role of maternal miRNA in fetal development has not been well understood so far. In this review, the current status of studies on miRNA expression in DOHaD research is described and future perspectives are discussed.
The brain and mind are not only determined genetically but are also nurtured by environmental stimuli in early life. However, the relationship between early life environment and phenotypes in adulthood remains elusive. Using the IntelliCage-based competition task for group-housed mice, we previously found that maternal exposure to a low dose of an environmental pollutant, dioxin, resulted in abnormal social behavior, that is, low competitive dominance, which is defined by decreased occupancy of limited resource sites under highly competitive circumstances. Although we were unable to identify which behavioral phenotype applies to abnormalities such as “human social nature”, we found signs of hypoactivation of the medial prefrontal cortex, as seen in patients with autism spectrum disorder. In addition, another model of environmental factors, repeated isolation during development, and that of genetic factors including mice with neuronal heterotopia, which refers to brain malformations resulting from deficits of neuronal migration, showed low competitive dominance. These results indicate that a constitutive approach to capture the neural network of the whole brain is necessary especially in cases where the temporal gap of causal relationships is large such as DOHaD.
Recently, we have published a book containing evidence-based public health guidelines and a practical manual for the prevention of sick house syndrome. The manual is available through the homepage of the Ministry of Health, Labour and Welfare (http://www.mhlw.go.jp/file/06-Seisakujouhou-11130500-Shokuhinanzenbu/0000155147.pdf). It is an almost completely revised version of the 2009 version. The coauthors are 13 specialists in environmental epidemiology, exposure sciences, architecture, and risk communication. Since the 1970s, health problems caused by indoor chemicals, biological pollution, poor temperature control, humidity, and others in office buildings have been recognized as sick building syndrome (SBS) in Western countries, but in Japan it was not until the 1990s that people living in new or renovated homes started to describe a variety of nonspecific subjective symptoms such as eye, nose, and throat irritation, headache, and general fatigue. These symptoms resembled SBS and were designated “sick house syndrome (SHS).” To determine the strategy for prevention of SHS, we conducted a nationwide epidemiological study in six cities from 2003–2013 by randomly sampling 5,709 newly built houses. As a result 1,479 residents in 425 households agreed to environmental monitoring for indoor aldehydes and volatile organic compounds (VOCs). After adjustment for possible risk factors, some VOCs and formaldehyde were dose-dependently shown to be significant risk factors. We also studied the dampness of the houses, fungi, allergies, and others. This book is fully based on the scientific evidence collected through these studies and other newly obtained information, especially from the aspect of architectural engineering. In addition to SHS, we included chapters on recent information about “multi-chemical sensitivity.”
In this review, we examine house dust and its effect on inhabitants’ health. Residential house dust includes components from plants, pollens, microorganisms, insects, skin flakes, hairs and fibers. It also includes materials contaminated with chemicals from combustion, furniture, interior materials, electronics, cleaning agents, personal care products. Nowadays, most people spend their time indoors. Thus, dust is an important medium of exposure to pollutions. According to United States Environmental Protection Agency Exposure Factors Handbook, the estimated amount of dust ingestion is 30 mg/day for adults, and 60 mg/day for children over 1 year of age. Since 2003, we have been conducting epidemiological studies to find the association between the indoor environment and the inhabitants’ health. The levels of mite allergens, endotoxins, and β-1,3-d-glucan in house dust were measured as biological factors. Semi volatile organic compounds (SVOC) such as phthalates and phosphate flame retardants (PFRs) in dust were also analyzed. As a result, we found that the ORs (95%CI) of nasal and optical symptoms of sick building syndrome (SBS) were 1.45 (1.01–2.10) and 1.47 (1.14–1.88), respectively, when there was a 10-fold increase in the levels of mite allergens. There was no association of mite allergens with allergies. Endotoxins and β-1,3-d-glucan did not show any association with SBS. Regarding SVOC, increased levels of phthalates and PFR increased the risk of allergies. The association between phthalates and increased risk of allergies was clearer among children than adults. There were no gold standards of dust sampling and pretreatment methods. Thus, caution is needed when comparing findings of various studies. Methods should accurately reflect exposure levels.
The purpose of this short review is to describe the influence of housing environment temperature and lighting on circadian blood pressure (BP) variability using data from the HEIJO-KYO cohort, a community-based cohort study launched in 2010. Increased excess mortality from cardiovascular disease in winter is a worldwide problem. Previous studies showed higher conventional BP and higher daytime ambulatory BP in winter; however, the relationship between indoor cold exposure and circadian BP variability remained unknown. In our cohort, we found a significant inverse relationship between indoor temperature and morning BP surge, independent of potential confounding factors. In addition, we found the tertile group with the lowest daytime indoor temperatures showed significantly higher urinary sodium excretion than the tertile group with the highest daytime indoor temperatures. Higher sodium intake caused by indoor cold exposure may partly explain the higher BP in winter. Physiologically, light exposure is the most important environmental cue for the circadian timing system and melatonin secretion. In our cohort, we observed that an increase in nighttime short-wave length light exposure and a decrease in daytime light exposure were significantly associated with lower melatonin secretion. Furthermore, lower melatonin levels were significantly related to higher nighttime BPs and parameters of atherosclerosis, which are predictors of cardiovascular disease incidence. Further longitudinal studies of the influence of housing environment temperature and lighting on cardiovascular disease incidence are required.
After the 1990s, many effective measures were taken to improve indoor air pollution in Japan. However, as a result of major changes in building materials, consumer products, and lifestyle, and new scientific findings on health effects associated with indoor environmental pollution, new issues have been indicated, such as chemical pollutants in indoor dusts or indoor pollutants caused by new chemicals that were substituted from chemicals that Indoor Air Quality Guideline was set. On the other hand, scientific evidence for the links between housing environment and health has accumulated substantially in recent decades. Therefore, the World Health Organization (WHO) is developing Housing and Health Guidelines to provide policymakers with recommendations on healthy housing conditions such as thermal comfort, indoor air pollution, crowding, and home injuries. In this paper, the basic principles of healthy housing, the current status of Japanese dwellings, and the recent approaches of WHO are summarized.
This article presents not only a brief overview of birth cohort studies focusing on environmental health in which the associations between health and environment were examined, but also a tentative plan to apply epidemiological data to benchmark dose calculation. According to the preceding studies, the checkpoints to be scrutinized when a result is not consistent with those of other researchers are as follows: (1) whether the study included all crucial confounders, (2) whether it included any exposure marker or confounder with a U-shaped dose-response curve, (3) whether the outcome measure was conducted by two or more examiners that might lead to measurement bias, (4) whether such examiners picked up information about exposure levels of the subjects before measuring the endpoints, and (5) whether subjects with different genetic factors were included in the analysis. In addition, (6) researchers conducting a children’s study on developmental effects due to toxic substances must keep in mind that the impact of prenatal methylmercury exposure, independent of postnatal exposure, may continue for at least seven years. (7) When an environmental health research emphasizes to be population-based study, the levels of exposure to environmental chemical substances in developed countries with strict environmental regulations may be too low to examine a dose-response relationship for critical dose estimation. Such risk assessment should be carried out among the subjects with a wide range of exposure levels.
In this review, we present an initial plan for exposure assessment in the Japan Environment and Children’s Study (JECS) by focusing on a biomonitoring technique and discuss the challenges encountered when using the biomonitoring technique for exposure measurements. JECS registered 103,099 pregnant mothers and has been following children born to them. Various biological samples were collected from mothers during pregnancy (blood and urine), at birth (blood and hair) and at check-up one month after birth (breast milk). Samples were also collected from children at birth (cord blood) and at check-up one month after birth (hair and blood spot). Those samples will be used to assess maternal and foetal exposures to chemical substances. Measurement reliability, i.e., intraclass correlation coefficient (ICC), and attenuation bias related to low ICCs should be taken into consideration when using the biomonitoring results. Along with the biomonitoring technique, simulation models, pharmacokinetic (PK) models and exposomics techniques are under development in JECS. New analytical techniques include deciduous teeth measurements and -omics analyses. In particular, PK models and sensor technologies are one of the most important methodologies for future JECS exposure analyses. Statistical methods for examining the effects of intercorrelated multiple exposures as well as nondetection data should also be explored.
Since “Our Stolen Future” by Theo Colborn was published in 1996, global interest on the impact of chemical substances, such as the endocrine-disrupting action of chemicals, has increased. In Japan, “The Hokkaido Study on Environment and Children’s Health: Malformation, Development and Allergy” was launched in 2001. It was a model of Japan Environment and Children’s Study of the Ministry of the Environment. In a large-scale, Hokkaido cohort, we obtained the consent of 20,926 mothers at the organogenesis stage with the cooperation of 37 obstetrics clinics in Hokkaido. We tracked the effects of endocrine disruptors on developmental disorders. In a small-scale Sapporo cohort, we observed in detail the neuropsychiatric development of children with the consent of 514 mothers in their late pregnancy. We examined how prenatal exposure to low concentrations of environmental chemicals affect the development of organs and the postnatal development of children. Maternal exposure to POPs, such as PCB/dioxins and perfluorinated alkyl substances, has affected not only children’s birth size, thyroid functions, and sex hormone levels, but also postnatal neurodevelopment, infection, and allergy among others. The associations of short-half-life substances, such as DEHP and BPA, with obesity, ASD, and ADHD have been investigated. Gene-environment interactions have been found for smoking, caffeine, folic acid, and PCB/dioxin. In 2015, our center was officially designated as the WHO Collaborating Centre for Environmental Health and Prevention of Chemical Hazards, and we continue to the contribute to the global perspectives of child health.
In this paper, we describe the historical transition of sexuality education in Japan and the direction of sexuality education taken by the Ministry of Education, Culture, Sports, Science and Technology (MEXT). Reproductive health/rights, a key concept in sex education, is also discussed. In Japanese society, discussion on sexuality has long been considered taboo. After the Second World War, sexuality education in Japan began as “purity education.” From 1960 until the early 1970s, physical aspects such as genital organs, function, secondary sexual characteristics, and gender differences were emphasized. Comprehensive education as a human being, including physiological, psychological, and social aspects, began to be adopted in the late 1970s. In 2002, it was criticized that teaching genital terms at primary schools and teaching about sexual intercourse and contraceptive methods at junior high schools were “overdue guidance” and “extreme contents.” Sexuality education in schools has become a problem and has stagnated for about 10 years. Currently, schools teach sexuality education that does not deviate from the MEXT course guidelines. The direction of MEXT regarding sexuality education should be examined from the basic position that sexual activity by children is inappropriate. Reproductive health/rights apply the concept of human rights to sexuality and reproduction. Reproductive health/rights are key concepts that support sex education and women’s health.
In this paper, we describe the trends in research on adolescent sexuality education in Japan and other countries and on fertility awareness, as well as the possibility of life planning based on sex and reproductive health education. Mason-Jones AJ et al. reviewed the results of school-based intervention studies on the prevention of human immunodeficiency virus infection, sexually transmitted diseases, and pregnancy. There is little evidence supporting the idea that educational curriculum-based programs alone are effective in improving sex and reproductive health outcomes in adolescents. In another study, the effectiveness of school-based sexuality education for adolescents in Japan was evaluated. The Japan Medical Abstract Society was searched for articles published in the last 10 years. In many studies, the effects were compared before and after a single sexuality education lecture by professionals, such as doctors, midwives, and public health nurses. In Japan, effort has been directed toward sexuality education, but no systematic program based on behavior theory has been adopted. Therefore, sex education is insufficient. A third study clarified research on fertility awareness in adults and issues regarding improvements in related education and research. The Japan Medical Abstract Society and PubMed were searched for articles published in the last 10 years. The review suggested that awareness of female fertility is insufficient. Delaying childbearing based on inaccurate knowledge of the decline in female fertility could lead to unintended infertility. For males and females, sexual health education in schools and communities should include information on the age-related decline in female fertility. Although the determinants of the timing of childbearing are multifactorial, education on fertility issues is necessary to help adults make informed reproductive decisions based on accurate information. Finally, in this paper, we introduce examples of the pioneering efforts in sexual health education through collaboration between the governments of Oita and Okayama Prefectures and Oita and Okayama Universities.
Japan is currently facing serious social problems related to low birth rates and aging. We propose two possible solutions from the perspective of occupational health. First, companies should establish support systems to help working women with pregnancy and childbirth. Such systems would require the cooperation and understanding of coworkers, including men, and the introduction of flexible work schedules that are also designed to allow workers to care for family members with disabilities. Additionally, with regard to the protection and promotion of the fertility of working women, occupational health staff members should provide education to working women regarding appropriate lifestyle choices in areas such as diet, prevention of work-related health problems, and mental health before and after childbirth. Moreover, workers undergoing assisted reproductive technology procedures should be supported as they experience physical, mental, and economic burdens associated with this process. Second, companies should guarantee the right of workers to take a sick leave and then return to work so they can balance work and the need to treat chronic conditions. Occupational staff members should follow up employees who return to work, by offering, for example, mental health care to cancer survivors. They should also play important roles in preventing the exacerbation of disease and empowering workers to continue their visits to medical institutions. Collaborative study bridges between companies and medical institutions are necessary for the promotion of these harmonization schemes.
The low birthrate and aging population of Japan are entering a serious phase. As measures against the declining birthrate, improvement of the environment is promoted to support childbirth and child-rearing, but even if the birthrate increases in the future, it will take time before the effect is observed as an increase in the population. As the number of children and young people is decreasing, in order to maintain a wealthy and sustainable society, we should create an environment wherein each child can grow healthily and demonstrate sufficient abilities in participating in society. The authors have been studying the influence of exposure to environmental chemical substances on the development of children. Lead is especially considered to impair neurological development even at low concentrations of exposure. In this paper, using lead as an example, we discuss risk assessment and countermeasures for the health effects of trace chemical substances on a society with a declining birthrate. Substances that show neurotoxicity increase social costs even at low concentrations of exposure. To preserve and promote social vitality in Japan despite the declining birthrate and aging population, it is essential that measures are taken on the basis of scientifically reasonable cost/benefit assessment. For this purpose, we think that it is necessary to analyze costs and benefits in addition to the risk assessment of low concentrations of chemical substances.
In this paper, we examine the trend in Japan towards nonregular employment and its effects on marriage, childbirth, and childcare from the viewpoint of a decreasing societal birthrate. Although the decision to marry includes personal values and preferences, socioeconomic status factors such as income and employment type are also associated with the determinants of marriage. Nonregular employment workers have a lower rate and motivation for marriage than regular workers. Thus, socioeconomic disparity caused by employment needs to be minimized through governmental measures and policies. Nonregular employment is increasing among younger generations, and for them, maternity and childcare leave are especially vital. Employee insurance coverage should be expanded to function as a form of income security during these leaves of absence, such that nonregular workers are also covered. During the childcare period, which lasts more than 10 years, it is necessary to cover childrearing costs and also the time required to spend with children. If a single working parent is involved in childcare alone, there is the burden of both work and childcare. Additionally, long work hours can also impact workers that are not involved in childcare. This is a dilemma: a stable and regular employment is often necessary to achieve a higher education; however, it is difficult for nonregular employees to take care of and prepare children for higher education owing to limited financial means. Properly designed measures and policies are necessary to break this chain. Importantly, considerations about life and work are important for all workers, including nonregular workers, who are especially affected in terms of marriage, childbirth, and childcare.
Objectives: Nowadays, attention deficit hyperactivity (ADH) problems are observed commonly among school-age children. However, questionnaires specific to ADH behaviors among preschool children are very few. The aim of this study was to investigate the reliability and validity of the 25-item Behavioral Check List (BCL), which was developed from interviews of parents with children who were diagnosed as having Attention-deficit/hyperactivity disorder (ADHD) and measures ADH behaviors in preschool age.
Methods: We recruited 22 teachers from 10 nurseries/kindergartens in Miyagi Prefecture, Japan. A total of 138 preschool children were assessed using the BCL. To investigate inter-rater reliability, two teachers from each facility assess seven to twenty children in their class, and intraclass correlation coefficients (ICCs) were calculated. The teachers additionally answered questions in the 1/5-5 Caregiver-Teacher Report Form (C-TRF) to investigate the criterion validity of the BCL. To investigate structural validity, exploratory factor analysis with promax rotation and confirmatory factor analysis were performed.
Results: The internal consistency reliability of the BCL was good (α = 0.92) and correlation analyses also confirmed its excellent criterion validity. Although exploratory factor analysis for the BCL yielded a five-factor model that consisted of a factor structure different from that of the original one, the results were similar to the original six factors. The ICCs of the BCL were 0.38–0.99 and it was not high enough for inter-rater reliability in some facilities. However, there is a possibility to improve it by giving raters adequate explanations when using BCL.
Conclusions: The present study showed acceptable levels of reliability and validity of the BCL among Japanese preschool children.
Objectives: The stress check program has been part of annual employees’ health screening since 2015. Employees are recommended, but not obliged, to undergo the stress check offered. This study was designed to examine the factors associated with stress check attendance.
Methods: A total of 31,156 Japanese employees who underwent an annual health examination and a stress check service at an Occupational Health Service Center in 2016 participated in this study. Data from the annual health examination and stress check service included stress check attendance, date of attendance (if implemented), gender, age, workplace industry, number of employees at the workplace, and tobacco and alcohol consumption. Data were analyzed using multiple logistic regression.
Results: The mean rate of stress check attendance was 90.8%. A higher rate of stress check attendance was associated with a lower duration from the annual health examination, age ≥30 years, construction and transport industry, and 50–999 employees at the workplace. A lower rate of stress check attendance was associated with medical and welfare industry and ≥1,000 employees at the workplace.
Conclusions: These findings provide insights into developing strategies for improving the rate of stress check attendance. In particular, stress check attendance may improve if the stress check service and annual health examination are conducted simultaneously.