Serum 5-Methyltetrahydrofolate Status Is Associated with One-Carbon Metabolism-Related Metabolite Concentrations and Enzyme Activity Indicators in Young Women.

Maintaining optimal one-carbon metabolism (OCM) is essential for health and pregnancy. In this cross-sectional study, folate status was assessed based on 5-methyltetrahydrofolate (5-MTHF) levels, and the association between 5-MTHF and OCM-related metabolites was investigated in 227 female Japanese university students aged 18-25 years. The participants were divided into high and low 5-MTHF groups based on their folate status. Serum samples of the participants were collected while they were fasting, and 18 OCM-related metabolites were measured using stable-isotope dilution liquid chromatography-electrospray tandem mass spectrometry. The association between serum 5-MTHF and OCM-related metabolite concentrations was assessed using Spearman's rank correlation coefficient. Serum 5-MTHF concentrations were negatively correlated with total homocysteine (tHcy) concentrations and positively correlated with S-adenosylmethionine (SAM) and total cysteine (tCys) concentrations. Serum 5-MTHF concentrations demonstrated a stronger negative correlation with tHcy/tCys than with tHcy alone. The negative correlation between betaine and tHcy concentrations was stronger in the low 5-MTHF group than in the high 5-MTHF group. The 5-MTHF status could be linked to Hcy flux into the transsulfuration pathway via SAM. Therefore, the tHcy/tCys ratio may be a more sensitive indicator of the 5-MTHF status than tHcy alone. Furthermore, a low 5-MTHF status can enhance Hcy metabolism via betaine.

Association of Fatty Acid Desaturase 1 rs174547 Polymorphism with the Composition of Long-Chain Polyunsaturated Fatty Acids in Serum Glycerophospholipids during Pregnancy.

The increase in fetal requirements of long-chain polyunsaturated fatty acids (LCPUFAs) during pregnancy alters maternal fatty acid metabolism, and therefore, fatty acid desaturase (FADS) gene polymorphisms may change blood fatty acid composition or concentration differently during pregnancy. We investigated the relationship between a FADS1 single-nucleotide polymorphism (SNP) and maternal serum LCPUFA levels in Japanese pregnant women during the first and third trimesters and at delivery. Two hundred and fifty-three pregnant women were included, and fatty acid compositions of glycerophospholipids in serum (weight %) and the FADS1 SNP rs174547 (T/C) were analyzed. LCPUFAs, including arachidonic acid (ARA) and docosahexaenoic acid (DHA), significantly decreased from the first to the third trimester of pregnancy. Furthermore, DHA significantly decreased from the third trimester of pregnancy to delivery. At all gestational stages, linoleic acid (LA) and α-linolenic acid were significantly higher with the number of minor FADS1 SNP alleles, whereas γ-linolenic acid and ARA and the ARA/LA ratio were significantly lower. DHA was significantly lower with the number of minor FADS1 SNP alleles only in the third trimester and at delivery, suggesting that genotype effects become more obvious as pregnancy progresses.

Cervical muscle stiffness and parasympathetic nervous system improvements for treatment-resistant depression.

BACKGROUND: Although treatment-resistant depression (TRD) is a major public health problem that increases mortality due to suicides, a considerable percentage of patients do not respond adequately to variable treatments. Patients with TRD sometimes have comorbid cervical stiffness. This observational study aims to examine the association of local modulation of cervical muscles with TRD and to learn the involvement of the parasympathetic nervous system in the underlying mechanism. METHODS: A total of 1103 hospitalized patients with TRD who were resistant to outpatient care were enrolled between May 2006 and October 2021. All patients underwent local modulation of the cervical muscles by physical therapy during hospitalization. The presence or absence of TRD and whole-body disorders, such as headache, dazzling, cervical stiffness, and cardiovascular and gastrointestinal disorders, was determined by the patient's subjectivity using the self-rated medical interview sheet at admission and discharge. Pupil light reflex parameters were also measured at admission and discharge using a binocular infrared pupilometer. RESULTS: The improvement rate of TRD during hospitalization was 72.1%, and did not differ significantly by sex, age, and hospitalization period. The improvement of TRD showed a strong association with those of cervical stiffness and dazzling, a pupil light reflex disorder (p < 0.001: odds ratios = 12.76 and 6.39, respectively), but not with those of headache or cardiovascular and gastrointestinal disorders (p > 0.05). In the TRD-improved patients, the pupil light reflex parameters representative of the parasympathetic nervous system function ameliorated: pupil diameter decreased, while constriction rate and velocity increased during hospitalization. In contrast, little amelioration of the parameters was seen in the TRD-unimproved patients. CONCLUSIONS: Cervical muscle stiffness may be associated with TRD, possibly through dysfunction of the parasympathetic nervous system. TRIAL REGISTRATION: ID: UMIN000040590. First registration date: 30/05/2020.

Association of the Maternal Gut Microbiota/Metabolome with Cord Blood CCL17.

Chemokine (C-C motif) ligand 17 (CCL17) is a pro-allergic factor: high CCL17 levels in cord blood (CB) precede later allergic predisposition. Short-chain fatty acid (SCFA) treatment during pregnancy has been shown to protect mouse pups against allergic diseases. The maternal microbial metabolome during pregnancy may affect fetal allergic immune responses. We therefore examined the associations between CB CCL17 and gut SCFA levels in healthy pregnant Japanese women. CB CCL17 serum levels at birth, and maternal non-specific IgE levels in maternal sera at 32 weeks of gestation were measured. Maternal stool samples were collected at 12 (n = 59) and 32 (n = 58) weeks of gestation for gut microbiota analysis, based on barcoded 16S rRNA sequencing and metabolite levels. The CB CCL17 levels correlated negatively with butyrate concentrations and positively with isobutyrate at 12 weeks; CB CCL17 correlated positively with valerate and lactate at 32 weeks. Similarly, butyrate levels correlated negatively with maternal non-specific IgE levels, whereas the lactate concentration correlated positively with IgE levels. At 32 weeks, the Shannon diversity index (SDI) of Firmicutes and Proteobacteria correlated negatively with CB CCL17 levels, while those of the total microbiota correlated positively with the CB CCL17 levels. These metabolites may alter fetal immune responses. This study provides the first link between maternal metabolites during pregnancy and the risk of allergic diseases in human offspring.

Possible involvement of the autonomic nervous system in cervical muscles of patients with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS).

BACKGROUND: Patients with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) sometimes present with stiffness of the cervical muscles. To investigate the pathophysiology of ME/CFS, this observational study compared patients with versus without recovery from ME/CFS through local modulation of the cervical muscles. METHODS: Over a period of 11 years, a total of 1226 inpatients with ME/CFS who did not respond to outpatient care were enrolled in this study. All patients received daily cervical muscle physical therapy during hospitalization. Self-rated records documenting the presence or absence of ME/CFS, as well as the representative eight symptoms that frequently accompany it at admission and discharge, were compared. Pupil diameter was also measured to examine autonomic nervous system function involvement. RESULTS: The recovery rate of ME/CFS after local therapy was 55.5%, and did not differ significantly by sex, age strata, and hospitalization period. The recovery rates of the eight symptoms were variable (36.6-86.9%); however, those of ME/CFS in the symptom subpopulations were similar (52.3-55.8%). The recovery rates of all symptoms showed strong associations with that of ME/CFS (p < 0.001). The pupil diameter was more constricted in the ME/CFS-recovered patients than in the ME/CFS-unrecovered patients in the total population and the subpopulations stratified by sex, age, and hospitalization period. CONCLUSIONS: There was a strong association between the recovery of ME/CFS and other related whole-body symptoms. The recovery of ME/CFS may be partly linked to amelioration of the autonomic nervous system in the cervical muscles. TRIAL REGISTRATION: UMIN000036634 . Registered 1 May 2019 - Retrospectively registered.

Corrigendum to "Association of the maternal microbiome in Japanese pregnant women with the cumulative prevalence of dermatitis in early infancy: A pilot study from the Chiba study of Mother and Child Health birth cohort" [World Allergy Organ J 12/10 (2019) 100065].

[This corrects the article DOI: 10.1016/j.waojou.2019.100065.].

Effects of maternal and fetal choline concentrations on the fetal growth and placental DNA methylation of 12 target genes related to fetal growth, adipogenesis, and energy metabolism.

AIM: We performed a birth cohort study involving 124 mother-infant pairs to investigate whether placental DNA methylation is associated with maternal choline status and fetal development. METHODS: Plasma choline concentration was assayed longitudinally in the 1st and 3rd trimesters and at term-pregnancy in mothers and cord blood. Placental DNA methylation was measured for 12 target candidate genes that are related to fetal growth, adipogenesis, lipid and energy metabolism, or long interspersed nuclear elements. RESULTS: Higher maternal plasma and cord blood choline levels at term tended to associate with lower birthweight (r = -0.246, P < 0.013; r = -0.290, P < 0.002) and body mass index (BMI) at birth (r = 0.344, P < 1E-3; r = -0.360, P < 1E-3). The correlation between maternal plasma choline level and cord blood choline level was relatively modest (r = 0.049, P = 0.639). There was an inverse correlation between placental DNA methylation at the retinoid X receptor alpha (RXRA) gene and maternal plasma choline level (r = -0.188 to r = -0.452, P = 0.043 to P < 1E-3 at three points). RXRA methylation level was positively associated with birthweight and BMI at birth (r = 0.306, P = 0.001; r = 0.390, P < 1E-3). Further, RXRA methylation was inversely correlated with RXRA gene expression level (r = 0.333, P < 1E-3). CONCLUSION: Our results suggest that the association between maternal choline status and placental RXRA methylation represents a potential fetal programing mechanism contributing to fetal growth.

Distribution of 5-Methyltetrahydrofolate and Folic Acid Levels in Maternal and Cord Blood Serum: Longitudinal Evaluation of Japanese Pregnant Women.

"Total" folate in blood has usually been measured to evaluate the folate status of pregnant women. However, folate is composed of many metabolites. The main substrate is 5-methyltetrahydrofolate (5-MTHF), with folic acid (FA) representing a very small component as an unmetabolized species in blood. We longitudinally evaluated 5-MTHF, FA and total homocysteine in maternal and cord blood from Japanese pregnant women. Subjects were 146 pregnant women who participated in the Chiba study of Mother and Child Health (C-MACH) prospective cohort study. Sera were obtained in early and late pregnancy, at delivery, and from cord blood. Species levels were measured by isotope-dilution mass spectrometry. Both 5-MTHF and FA levels were lower than reported levels from pregnant women in populations from countries with mandatory FA fortification. As gestational age progressed, serum 5-MTHF levels decreased, whereas serum FA levels were slightly reduced only at delivery compared to early pregnancy. A significant negative association between serum 5-MTHF and total homocysteine was shown at all examined times, but no associations with FA were evident. At delivery, cord 5-MTHF was significantly higher than maternal levels, while FA again showed no significant correlation. These results suggest that 5-MTHF is actively transported to the fetus through placental transporters and may reflect folate status during pregnancy as a physiologically important species.

Developmental origins of health and disease theory in cardiology.

Numerous epidemiological and animal studies disclosed that birth weight is inversely associated with the incidence of the lifestyle-related disorders in adult life, such as cardiovascular disease, diabetes, and /or chronic kidney disease. Lower birth weight occurs in numerous undesired intrauterine environments including malnutrition, smoking, alcohol consumption, or stress.　The Developmental Origin of Health and Disease (DOHaD) theory is based on the concept that the origins of lifestyle-related disease is formed at the time of fertilization, embryonic, fetal, and neonatal stages by the interrelation between genes and the environments (nutrition, stress, or environmental chemicals). Adult disease develops after delivery facing to abnormal environments such as over-nutrition, much stress, or lack of exercise. Disease develops through these two insults. This concept was first proposed as the "Barker Hypothesis." David Barker had discovered the relation between the lower birth weight and the higher prevalence of ischemic heart disease mortality. Previous epidemiologic studies have found the people exposed to famine during early life had higher risks of cardiovascular diseases in adulthood. Yet, the exact mechanisms that permanently change the structure, physiology, and endocrine status of an individual across their lifespan following altered growth during fetal life are not entirely clear. Epidemiological studies including prospective cohort and observational analysis of the people exposed to malnutrition during fetal or infancy have disclosed the strong relation between the lower birth weight and the higher cardiovascular risks in adults. Recent progress of epigenetic studies unveiled strong genetic association. Hormonal regulation and epigenetic modifications have an important role for proper organ development and physiological functions. The molecular mechanism of predisposition is supposed to be the epigenetics modifications.　Their dysregulation is related to the acquisition of the disease-susceptible trait. In this review, we overview the concept of DOHaD and introduce related clinical and basic research.

Cervical muscle diseases are associated with indefinite and various symptoms in the whole body.

PURPOSE: Patients with various and indefinite symptoms in the whole body occasionally have coincident with stiffness or tenderness of the cervical muscles. This prospective case series examined the effect of local modulation of the cervical muscles in patients with cervical disorders reporting indefinite whole-body symptoms. METHODS: A total of 1863 hospitalized patients with cervical disorders accompanying three or more indefinite whole-body symptoms, who were resistant to outpatient care, were enrolled in this study for 12 years. All patients underwent daily physical therapies to the cervical muscles during hospitalization. Self-rated records on the medical interview sheets documenting 30 representative symptoms including cervical/shoulder pain or stiffness and 28 representative indefinite whole-body symptoms at admission and discharge were compared across the population. RESULTS: The number of symptoms decreased significantly with the local modulation of the cervical muscles during hospitalization. All of the 28 indefinite whole-body symptoms at admission showed recovery rates greater than 50% at discharge. The mean number of symptoms decreased significantly from 17.8 at admission to 7.4 at discharge (p < 0.0001). The percentages of patients reporting 10 or more symptoms were 91.1% and 29.3% at admission and discharge, respectively. Moreover, 8.2% of patients reported no residual symptoms at discharge. CONCLUSION: Cervical muscle lesions may contribute to indefinite whole-body symptoms, possibly through dysfunction of the parasympathetic nervous system in the muscles. Local modulation of cervical muscles could lead to a breakthrough in the management of patients with indefinite whole-body symptoms. TRIAL REGISTRATION ID: UMIN000035445. These slides can be retrieved under Electronic Supplementary Material.

Association of the maternal microbiome in Japanese pregnant women with the cumulative prevalence of dermatitis in early infancy: A pilot study from the Chiba study of Mother and Child Health birth cohort.

BACKGROUND: The prenatal maternal microbiome, including the gut microbiota, has been suggested to influence the incidence of allergies in offspring. Moreover, epidermal barrier dysfunction in early infancy has been attributed to the development of subsequent allergies. We hypothesized that the prenatal microbiome may affect the gut microbiota, acting as an initial trigger to alter immune development in the foetus. The maternal microbial composition may be linked to the prevalence of dermatitis in early infancy (DEI) of the offspring, leading to subsequent allergic symptoms. METHODS: This study was conducted as part of the Chiba Study of Mother and Child Health (C-MACH) birth cohort that was initiated in 2013; 434 healthy pregnant women at < 13 weeks of gestation were recruited. DEI was assessed for up to 4 months after birth, and allergic symptoms were determined in 10-month-old infants using questionnaires. Other information related to the maternal microbiome was obtained from questionnaires filled out during pregnancy. Stool samples were collected from pregnant women at 12 (n = 59) and 32 weeks (n = 58) of gestation, which were used for gut microbiota analysis using barcoded 16S rRNA gene sequencing. RESULTS: Symptoms of allergy, especially of inherited allergies, show a higher prevalence at 10 months after birth in the DEI group. DEI occurrence was negatively correlated with family size and cat ownership. The diversity of Proteobacteria at 12 weeks of gestation and the relative abundance of Actinobacteria at 32 weeks of gestation in maternal feces were lower at both time points of gestation in the DEI group. In addition, the diversity of Proteobacteria in prenatal feces was negatively correlated with family size at 12 weeks, and with dog ownership at both gestational time points. CONCLUSIONS: The composition of the maternal microbiome may influence the risk of allergies in offspring, even before birth. Furthermore, the diversity of Proteobacteria and the relative abundance of Actinobacteria in maternal feces were negatively associated with DEI, which may be associated with the risk of allergy development in infancy. This early trigger may be a good predictor of allergy development during infancy and childhood.

Effect of intensive inpatient physical therapy on whole-body indefinite symptoms in patients with whiplash-associated disorders.

BACKGROUND: A considerable number of patients with whiplash-associated disorders (WAD) report variable and indefinite symptoms involving the whole body, despite there being no evidence of direct injuries to organs other than the neck. However, little is known about their management or underlying mechanism. This study examined the effect of intensive physical therapy at the cervical muscles in patients with WAD reporting whole-body indefinite symptoms. METHODS: A total of 194 hospitalized patients with WAD who were resistant to outpatient care by reporting whole-body indefinite symptoms between May 2006 and May 2017 were enrolled in this observational study. All patients underwent daily physical therapies by low-frequency electric stimulation therapy and far-infrared irradiation to the cervical muscles during hospitalization. Self-rated records in the medical interview sheets on 22 representative whole-body symptoms at admission and discharge were compared. RESULTS: The number of symptoms was markedly decreased by the physical therapies during hospitalization. Almost all symptoms showed recovery rates of more than 80% at discharge as compared to those at admission. Although the percentage of patients reporting at least four of the 22 representative indefinite symptoms was 99.0% at admission, it decreased to 7.7% at discharge. Sixteen percent of patients recovered completely without any residual symptoms. The mean number of symptoms significantly decreased from 13.1 at admission to 2.0 at discharge. Notably, symptoms other than those in the neck or shoulder recovered to a greater extent than those in the neck or shoulder. CONCLUSIONS: This study, for the first time, examined the management of whole-body indefinite symptoms in patients with WAD. The intensive physical therapy markedly improved the symptoms, suggesting the involvement of cervical muscles in the pathogenesis. TRIAL REGISTRATION: UMIN000035435 (Retrospectively registered on Jan 3, 2019).

One-Carbon Metabolism and Lipid Metabolism in DOHaD.

The predisposing factors to lifestyle-associated diseases are established in the early period of life with underlying gene-environment interaction. Epigenetics is a chemical modification-based genetic mechanism that is affected by various nutritional factors. One-carbon metabolism is a metabolic system associated with methyl residue that is supplied from folic acid. Therefore, from the epigenetic point of view, proper intake of folic acid is important for pregnant women not only to prevent congenital abnormalities such as neural tube defect but also to prevent various adult disorders of the offspring. Dyslipidemia is an important risk factor of coronary heart disease, and epidemiological studies on Dutch winter famine, Jewish holocaust survivors, and Chinese famine suggested that prenatal malnutrition was associated with the dyslipidemia. Recent animal studies revealed that malnutrition in utero causes an epigenetic change in the Pparα gene, which accelerates the activity of delta-6 desaturase and delta-5 desaturase, that potentially induces dyslipidemia in adulthood. It has been known that overnutrition also increased the risk of cardiovascular diseases. Recent animal studies revealed that high-fat diet increased DNA methylation in the promoter region of delta-6 desaturase gene (Fads 2) that downregulates the gene expression in the arterial smooth muscle, which potentially contributes to cardiovascular diseases. Taken together, either insufficient or excessive nutrition alters epigenetic modification of genes that encodes enzymes associated with lipid metabolism. This altered epigenetic state persists during one's lifetime, which is potentially involved in noncommunicable diseases in adulthood.

The methylation levels of the H19 differentially methylated region in human umbilical cords reflect newborn parameters and changes by maternal environmental factors during early pregnancy.

H19 is a tumor-suppressor gene, and changes in the methylation of the H19-differential methylation region (H19-DMR) are related to human health. However, little is known about the factors that regulate the methylation levels of H19-DMR. Several recent studies have shown that maternal environmental factors during pregnancy, such as smoking, drinking, chemical exposure, and nutrient intake, can alter the methylation levels of several genes in fetal tissues. In this study, we examined the effects of maternal factors on changes in the methylation levels of H19-DMR in the human umbilical cord (UC), an extra-embryonic tissue. Participants from the Chiba study of Mother and Children's Health (C-MACH) were enrolled in this study. Genomic DNA was extracted from UC samples, and the methylation level of H19-DMR was evaluated by methylation-sensitive high resolution melting analysis. Individual maternal and paternal factors and clinical information for newborns at birth were examined using questionnaires prepared in the C-MACH study, a brief-type self-administered diet history questionnaire (BDHQ) during early pregnancy (gestational age of 12 weeks), and medical records. Univariate and multivariate logistic regression analyses indicated that reduced H19-DMR methylation (<50% methylation) in UC tissues was positively related to decreased head circumference in newborns [odds ratio (OR) =2.82; 95% confidence intervals (CI): 1.21-6.87; p=0.0183 and OR =2.51; 95% CI: 1.02-6.46; p=0.0499, respectively]. Moreover, multiple comparison test showed that H19-DMR methylation in UC tissues was significantly reduced in the low calorie group (intake of less than 1,000kcal/day; methylation level: 40.98%; 95% CI: 33.86-48.11) compared with that in the middle (1,000-1,999kcal/day; methylation level: 51.28%; 95% CI: 48.28-54.27) and high (≥2,000kcal/day; methylation level: 52.16%; 95% CI: 44.81-59.51) calorie groups (p=0.0054 and 0.047, respectively). In the subpopulations with low to moderate calorie intake (<2,000kcal/day), reduced H19-DMR methylation in UC tissues was significantly related to serum homocysteine concentration (OR =0.520; 95% CI: 0.285-0.875; p=0.019), maternal age (OR =1.22; 95% CI: 1.01-1.52; p=0.049), and serum folate levels (OR =0.917; 95% CI: 0.838-0.990; p=0.040). These data indicated that H19-DMR methylation levels in human UC tissues could be modulated by maternal factors during early pregnancy and may affect fetal and newborn growth.

Prevention of Lifestyle-related Diseases by Utilization of Newly Developed Health Record Booklet "My Karte" in Mitoyo and Kanonji Areas.

In the Mitoyo and Kanonji areas, Kagawa Prefecture, Japan, we have newly developed a simple health record booklet for parents with children called "My Karte", which is an enlarged edition of the maternal and child health handbook. Our municipality borough gives this booklet together with the maternal and child handbook to all pregnant women without exception. In this booklet, care personnel or child by themselves write down the health condition and body development of the child, including medical examination records and vaccinations. From an overview of this simple record, healthcare practitioners, caretakers or school nurses can immediately grasp the child's body condition, for example, whether the child is overweight or underweight, and various health problems early and precisely. In addition, the child and care personnel can evaluate the health condition of the child through self-assessment. We hope that the self-assessment will promote health during the child's life. Moreover we are planning to collect and analyze the data from the distributed My Karte. The analyzed results will be released to the public, which will promote health consciousness in this area and give healthcare professionals basic and important data useful for daily medical practice.

Overview of Longitudinal Survey of Newborns in the 21st Century: Factors Affecting Infant Growth.

There are two major nationwide birth cohort studies in Japan, namely, the Longitudinal Survey of Newborns in the 21st Century conducted by the Ministry of Health, Labor and Welfare (MHLW) and the Japan Environment and Children's Study (JECS) conducted by the Ministry of Environment. The former was a longitudinal questionnaire survey focusing on environmental and socioeconomic factors for descriptive epidemiology conducted every year since 2001 by mail. The latter was based on 15 unit centers nationwide with environmental measurements and collection of biological samples for environmental risk evaluation. Both are prospective birth cohort studies whose findings will be expected as the basis for establishing health policies. The data obtained in the former study can be used for research with permission from MHLW. To date, there have been more than ten published studies using those data. We have reviewed these studies and introduced our preliminary findings on factors affecting infant growth. Employment before delivery, educational background of parents, household income, and smoking habit of both parents have been suggested to affect infant growth. We will analyze the associations between socioeconomic factors and infant growth trajectory to elucidate the most adequate intervention for children.

Molecular Mechanism of Developmental Origins of Health and Disease (DOHaD).

Epigenetic modification takes place in many types of environment. Undesirable epigenetic changes for the postnatal life at the developmental stage are induced in utero by exposure to harsh environment such as endocrine disruptors, severe psychological stress and insufficient or excessive nutrition. Some of these changes continues even for a long time after birth from womb to tomb. Under these circumstances with an unhealthy life style, such as higher caloric intake, insufficient exercise, or stress, there is a higher risk of developing various illnesses including lifestyle-related diseases, such as essential hypertension, type 2 diabetes mellitus, dyslipidemia, psychological disorders and cancers. An illness goes through these two steps, first having origins in the early stage of life and secondary exposure of unhealthy life. In addition, some of these modifications have a tendency to be transmitted to the next generations, (transgenerational effect). This is the concept of Developmental Origins of Health and Disease theory (DOHaD). The incidence of noncommunicable diseases (NCDs) have been markedly increasing, especially in developing countries, and the prevention of these diseases is a high-profile objective for world economic growth. In addition to birth weight, specific epigenetic modifications are expected to be good marks for developing illness in later life. With analysis of these makers, even for the individuals with a higher risk, the illness development will be expected to be effectively controlled through intervention in the early stage. Research on predicting markers, and intervention supplements, and pharmacological materials for higher risk individuals has been progressing considerably. This DOHaD theory is expected to be highly beneficial for the prevention of many illnesses.

[Environmental Effect In Utero for Adult Disease].

Worldwide, lifestyle-related diseases such as type 2 diabetes and cardiovascular diseases are presently the leading causes of death and disability, and their incidences tend to increase. A lifestyle-related disease has been considered mainly to be induced by specific disease susceptibility genes and lifestyle after birth. However, the steep increase in the incidences of lifestyle-related diseases is difficult to be explained only by specific genes. Presently, a new theory has been proposed. Epidemiological and animal studies have disclosed the intimate links between malnutrition in the developmental stage and lifestyle-related chronic diseases. Such studies provide the foundation and framework for a new life science, that is, the theory of developmental origins of health and diseases (DOHaD). Although much research has been carried out to elucidate the putative concepts and mechanisms that relate specific exposures in early life to the risk of chronic diseases, a complete picture still remains obscure. Historically, the world has experienced severe famines, for example, the Dutch Winter Famine, the Chinese Great Leap Forward Famine, the Leningrad Siege and the Biafran Famine. These famines showed that malnutrition in utero poses higher risks of lifestyle-related diseases. The main research point has been focused on periconceptional and perinatal undernutrition and specific nutrient deficiencies. However, presently, the number of people who are overweight and obese has been increasing. Therefore, perinatal overnutrition and specific nutrient excesses should also be examined. In addition, psychological stress, environmental chemicals and artificial reproductive techniques are other important research fields in DOHaD.

Chiba study of Mother and Children's Health (C-MACH): cohort study with omics analyses.

PURPOSE: Recent epidemiological studies have shown that environmental factors during the fetal period to early childhood might affect the risk of non-communicable diseases in adulthood. This is referred to as the developmental origins of health and disease (DOHaD) concept. The Chiba study of Mother and Children's Health (C-MACH) is a birth cohort study based on the DOHaD hypothesis and involves multiomics analysis. This study aims to explore the effects of genetic and environmental factors--particularly the fetal environment and postbirth living environment--on children's health, and to identify potential biomarkers for these effects. PARTICIPANTS: The C-MACH consists of three hospital-based cohorts. The study participants are pregnant women at <13 weeks gestation. Women who underwent an examination in one of the three hospitals received an explanation of the study. The participants consented to completing questionnaire surveys and the collection and storage of biological and house/environmental samples. Participants were provided unique study numbers. All of the data and biological specimens will be stored in the Chiba University Center for Preventive Medical Sciences and Chiba University Center for Preventive Medical Sciences BioBank, respectively. FINDINGS TO DATE: Consent to participate was obtained from 433 women. Of these women, 376 women completed questionnaires in the early gestational period. The mean age was 32.5 (4.4) years. The mean body mass index (BMI) was 21.1 (3.0) kg/m(2). Before pregnancy, 72.3% of the women had a BMI of 18.5-24.9 kg/m(2). During early pregnancy, 5.0% of the participants smoked. FUTURE PLANS: Primary outcomes are allergy, obesity, endocrine and metabolic disorders, and developmental disorders. Genome-level, metabolome-level, umbilical cord DNA methylation (epigenome), gut microbiota and environmental chemical exposure variables will be evaluated. We will analyse the relationships between the outcomes and analytical variables.

DOHaD (Developmental Origins of Health and Disease) and Birth Cohort Research.

Epidemiological and animal experimental studies are disclosing that the malnutrition or overnutrition in utero would induce epigenetic changes of fetus, what is the origin of lifestyle-related disease in adult. Representative birth cohorts studies in DOHaD are explained.