There are a wide variety of causes of Chronic Kidney Disease (CKD), but all of them can be regarded as a condition in the decreasing number of nephrons, which consists of the glomerulus and tubules. CKD is risk factor for cardiovascular diseases and death, and the number of patients is increasing year by year, so that a new approach focusing on the "nephron number" is required. Nephrogenesis continues until the 36th week of gestation in utero, and no new nephrons develop following birth in full-term infants. Recent studies have reported a 13-fold difference in nephron number between individuals, and the number at birth can be a potential risk factor for CKD. The positive correlation between birth weight and total nephron number suggests that the intrauterine environment such as maternal nutritional status, micronutrients, smoking, drinking, drug use, renal dysfunction and impaired glucose tolerance has a significant influence on nephrogenesis. To prevent increasing CKD patients, based on the DOHaD, prenatal education for mothers and early intervention for low birth weight or immature kidney patients are important.

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Epidemiological studies have reported that low-birth-weight infants, especially small-for-gestational age (SGA) infants, who become obese in the future are more likely to develop coronary artery disease and type 2 diabetes mellitus (DM). Meanwhile, in Japanese children with type 2 DM, there are relatively many cases with non-obese type 2 DM that do not cause significant obesity. Indeed, we have reported that a case of non-obese type 2 DM with a history of being an extremely preterm SGA infant without early adiposity rebound. In recent years, there have been some reports that adults with a history of preterm birth showed insulin resistance compared to those with term infants. Our hypothesis for a pathogenesis is that the hyperglycemia may be related to have less lean body mass. However, adults born with SGA show a higher frequency of obesity with visceral fat than those with appropriate-for-gestational age and large-for-gestational age. Some SGA infants, especially extremely preterm infants may be developed to type 2 DM due to high visceral fat accumulation or low lean body mass, even if they do not become severely obese.

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DOHaD research has mainly focused on prenatal maternal factors, although there exist paternal origins of health and disease (POHaD) of the next generation. For example, paternal aging is a risk for autism spectrum disorder (ASD) and low birthweight. In these decades, the number of ASD patients has increased as the age of marriage has shifted. Epidemiological studies repeatedly show that paternal aging matters more on the risk of ASD than maternal aging. Spermatogenesis, in which sperm stem cells divides to make numerous sperm cells, may be more sensitive to genetic mutations and epigenomic changes owing to age than oocytes. There are clinical and basic evidence that epigenomic changes like DNA methylation may increase child risk of neurodevelopmental disorders. In addition, changes in histone modifications and in non-coding RNAs have been observed due to paternal aging. When the molecular mechanisms that cause disease risk in the male germline and how they interact are found, new ways to treat and prevent diseases are likely to be created. This review introduces the epigenomic changes that can occur in the germline, with a particular focus on paternal aging.

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The “Hokkaido Study on Environment and Children’s Health” is an ongoing study consisting of two prospective birth cohorts with different outcomes, periods of observation blood collection, and population sizes: the Sapporo and the Hokkaido cohorts. The aim of the study was to summarize the recent scientific results of the Hokkaido study, and to suggest future study directions. Maternal and cord blood were collected to assess for environmental and lifestyle-related chemical exposures. Health outcomes regarding birth size, child growth after birth, asthma, allergies, infectious diseases, neurodevelopment, and hormones were assessed. The results of our study suggest that the prenatal environmental and lifestyle-related chemical exposure affects birth outcome, hormone levels, allergy, infectious diseases, and neurodevelopmental processes. Furthermore, specific genotypes may influence the effects of the chemical exposure on health outcomes. Epigenomics may partly explain the biological mechanisms.

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Born with a thrifty phenotype due to undernutrition during the prenatal period are thought to be at increased risk of developing diseases due to a mismatch between the acquired constitution and the nutritional environment after birth. However, the details of the thrifty phenotype are not clear. Therefore, we generated low birth weight model rats (LBW) which delivered from dams fed an energy-restricted low carbohydrate diet during the gestational period. We clarified that increased miR-322 causes the decrease in the expression of growth hormone (GH) receptors in the liver of LBW-non catchup growth rats. Furthermore, we revealed that LBW maintains the higher blood corticosterone levels after restraint stress exposure. We then found that increased expression of Gas5 lncRNA in the pituitary inhibits glucocorticoid-induced expression of miR-449a. Thus, we proposed that is one of the causes of impaired negative feedback regulation of glucocorticoids in the pituitary. Furthermore, we have shown the possibility that the skeletal muscle of LBW is easy-to-lose, and adipose tissue is hard-to-burn from the fasting-refeeding experiment. Thus, the thrifty phenotype of model rats has a body composition similar to sarcopenic obesity. It was suggested that these changes in body constitution might form the noncommunicable disease onset risk of the disease.

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Less than 10% of drug-candidate compounds are associated with testicular toxicity. Therefore, developmental toxicity, such as paternally transmitted birth defects, is concerned if genetic abnormalities in the germ line persist and accumulate in the sperm during the spermatogenesis cycle. This paper will provide an overview of chemical and testicular toxicity and a forum for considering developmental toxicity from the perspective of male reproduction, which is often overlooked in the Developmental Origins of Health and Disease (DOHaD) discourse.

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DNA methylation is presumably one of the molecular mechanisms underlying the Developmental Origins of Health and Disease (DOHaD) because of the properties that the modification is actively made during the fetal stage and the methylation patterns are stably maintained afterward. In addition, it is known that aberrant regulation of DNA methylation cause growth and obesity symptoms and phenotypes. Mutations in DNMT3A, a de novo DNA methyltransferase, cause Tatton-Brown-Rahman syndrome, which is related to overgrowth and obesity. Dnmt3a heterozygous knockout mice and paraventricular hypothalamus-specific Dnmt3a knockout mice show obesity phenotypes. In this review, associations between DNA methylation and DOHaD are introduced, and the possibility that DNA methylation works as a molecular mechanism of DOHaD is discussed.

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In Japan, the childbearing age is increasing in line with changes in the social system, and as such, the incidence of diabetic-complicated pregnancies and gestational diabetes are also increasing. In the intrauterine environment of diabetic mothers, a high concentration of blood glucose passing through the placenta causes the production of advanced glycation end-products (AGEs) through excessive protein glycation reactions. AGEs induce oxidative stress and inflammation through their receptors, resulting in insulin resistance and other related disorders. This is thought to result in signaling disorders, such as insulin resistance, in various organs of the fetus. Signaling disorders at the fetal stage have been shown to be closely associated with the development of future diseases in the child. Our studies using experimental animal and cell models and the latest findings on the molecular mechanisms of the effects of AGEs in the intrauterine hyperglycemic environment on the fetus will be presented. We will also introduce the importance of exploratory research on the development of functional foods for primary prevention, as the use of oral hypoglycemic drugs other than insulin is not permitted for the treatment of insulin resistance in pregnant women in Japan.

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Immune responses play important roles in the pathogenesis of neuropsychiatric disorders. Recent studies showed that an increase in circulating interleukin (IL)-17A causes cognitive dysfunction, although it is unknown how increased systemic IL-17A affects brain function. Using transgenic mice overexpressing RORγt, a transcription factor essential for differentiation of Th17 cells, we examined changes in the brain caused by chronically increased IL-17A resulting from excessive activation of Th17 cells. We found that the immunoreactivity of Iba1 and density of Iba1+ microglia were lower in the dentate gyrus of RORγt Tg mice compared with wild-type mice. The immune response by Th17 cells not only directly affects the brain of the individual concerned, but has also been shown to affect the next generation. It is unclear how IL-17A acts on fetal brain cells to cause ASD pathologies. To assess the effect of IL-17A on cortical development, we performed direct administration of IL-17A into the lateral ventricles of fetal mouse brain. We found that IL-17A activated microglia and altered their localization in the cerebral cortex. Our data suggest that IL-17A activates cortical microglia, which could lead to a series of ASD-related brain pathology, including excessive phagocytosis of neural progenitor cells in the ventricular zone.

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The prenatal (in utero) environment is now recognized as a key driver of non-communicable diseases (NCDs) risk later in life, namely called as developmental origins of health and disease (DOHaD). The current studies are increasingly links between diverse stressors during pregnancy and the risk to offspring of a milieu of NCDs, including cardiovascular disease, metabolic disorders. On the other hand, our intestinal microbiota are extremely important for the preservation of human health and the changes in these bacterial communities (dysbiosis) are linked to disease states such as NCDs. This review paper describes methods of the microbiota manipulations in pregnancy, infant and children with dysbiosis, using probiotics and nutrition.

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For several decades in Japan, in contrast to continuously declining birth rates, the rate of low-birth-weight infants has been increased and remaining high. Studies on birth statistics of Japan and those of author’s hospital found that growth restriction started prenatally and lasted through early infancy followed by a catch-up phase in late infancy, which was never to be completed. Interestingly, prenatal growth level tended to be reversed postnatally till 3 years but kept similar stature afterwards till 6 years, always remained skinny (low BMI), and showed no sign of early ‘adiposity rebound’. What level of postnatal growth should we aim for preterm infants? We have no clear answer to this question yet. What we can do at the moment is to aim for a smooth and well-balanced growth with repeated careful and individualized assessment and adjustments, and not to chase for a certain fixed goal for everyone.

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Background: During the novel coronavirus disease 2019 (COVID-19) pandemic, perinatal outcomes, including maternal death, intrauterine fetal demise, and maternal depression, have worsened, from a global perspective. We aimed to examine the changes in perinatal complications between 2020 and 2021, during the COVID-19 pandemic. Methods: This study included pregnant women admitted to our hospital for perinatal complications, including morning sickness, preterm labor, preterm premature rupture of membranes, and hypertensive disorder of pregnancy (HDP), and preterm or term deliveries between April 1st and June 30th, 2019 (n= 151), 2020 (n= 128), and 2021 (n= 143). COVID-19-positive patients and expectant mothers with multi-fetal pregnancies were excluded; inbound patient transfers for emergency obstetric management from other hospitals were also excluded. Results: The proportion of preterm delivery and HDP in the 2020 group was significantly lower than that in the 2019 or 2021 group (p= 0.02 and p= 0.02); however, there was no difference in the proportion of preterm delivery and HDP between the 2021 and 2019 groups (p= 0.70 and p= 0.77, respectively). Conclusion: In 2021, the incidence of preterm delivery and HDP might have eventually returned to baseline levels as before the spread of COVID-19.

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