Presented here is the outline of a workshop that was held during the Japanese DOHaD meeting in 2022, with the objective of developing a strategy to popularize the concept of DOHaD.

View full abstract

The Tohoku Medical Megabank (TMM) project advances DOHaD research, studying how prenatal and early postnatal environmental factors influence health via DNA methylation in adulthood. A correction method for cellular composition bias in DNA methylation analysis of newborn umbilical cord blood was established based on whole epigenome analysis of nucleated red blood cells from 15 newborns. The methylation status of 92 umbilical cord blood samples, excluding perinatal disease cases, has been analyzed, supporting predictions of fetal epigenetic alterations. The analyzed cord blood epigenomic information is available in the iMETHYL database. Furthermore, ongoing research on DNA methylation in 158 three-generation families and 60 sets of identical twins within the TMM cohort could elucidate DOHaD's molecular mechanisms and environmental transgenerational impacts on health.

View full abstract

The Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study) included pregnant women, fetuses, and their families and relatives from 2013 to 2017. Currently, we are conducting follow-up surveys through questionnaires, blood and urine tests, disease onset surveys, and the collection of school health check-up information. Based on medical records from pregnancy to a month after delivery, the prevalence of hypertensive disorders of pregnancy, gestational diabetes, premature birth, low birth weight, and small for gestational age were described and characterized according to parity, pre-pregnancy body mass index, and multiple pregnancies. The TMM BirThree Cohort Study promotes collaborative research and expands the use of valuable information for researchers. We aim to continue generating useful findings that would benefit the participants and local people.

View full abstract

Oxytocin (OT) is a well-known peptide hormone that is responsible for uterine contractions during labor and milk ejection during lactation in humans. The OT receptor (OTR) is expressed in several regions of the brain, including the hippocampus, amygdala, nucleus accumbens, and prefrontal cortex. OT plays a crucial role in regulating emotional behaviors such as anxiety and fear as well as social behaviors such as nurturing behavior and trust formation. Distribution patterns of OTR in the brain differ between animal species or sexes, and these differences are associated with diverse social behaviors. Moreover, OT is secreted within the brain during breastfeeding; it promotes maternal behavior and strengthens the mother–infant relationship. OT and OTR are also expressed in males, where they play a role in promoting paternal behavior as well as marital and partner relationships. Further, it contributes to social interactions by fostering trust among humans. In this review, we describe the significance of OT in emotional and social behaviors and explored its potential as a drug for treating mental disorders.

View full abstract

Umbilical venous blood transports nutrient substrate from the maternal to the fetal compartment, and the fetal liver is the primary organ where nutrient inter-conversion occurs. We aimed to determine whether fetal liver blood flow (fLBF) influences newborn adiposity. Placental corticotrophin-releasing hormone (CRH) has been implicated as a key mediator of placental-fetal perfusion. Hence, we also aimed to determine whether circulating levels of placental CRH across gestation are associated with variations in fLBF. fLBF was quantified at 30 weeks in 62 uncomplicated pregnancies. Multiple regression analysis was used to determine the association between fLBF and newborn adiposity. Placental CRH was also measured in maternal circulation at 12, 20, and 30 weeks in 79 uncomplicated pregnancies. fLBF at 30 weeks was significantly and positively associated with newborn total fat mass and percent body fat, but not with lean mass. Placental CRH at 30 weeks, but not at 12 and 20 weeks, was significantly and positively associated with fLBF at 30 weeks. In conclusion, fetal fat mass is affected by fetal liver blood perfusion. Placental CRH in late gestation is a possible modulator of fetal liver blood flow and may constitute a biochemical marker in clinical investigations of fetal growth and body composition.

View full abstract

Early life stress (ELS) is the extreme mental or physical stresses in early life stages. Recently, we have focused on ELS as environmental factor involved in a health hazard for male reproductive system in children. Neonatal maternal separation model and corticosterone administration model are used to evaluate the effects of ELS on male reproductive system. As a result, it is showed that the exposure to ELS and following excessive secretion of corticosterone are related to decreased number of Sertoli cells through upregulation of p27, the cyclin-dependent kinase inhibitor. Moreover, the decrease of Sertoli cell number was not recovered in postpuberty and it may be involved in long-lasting damages on male reproductive system, including the decrease of spermatozoa count.

View full abstract

Atherosclerosis is one of the major causes of mortality in Japan. Risk factors for atherosclerosis include lifestyle factors and other noncommunicable diseases, such as dyslipidemia and diabetes mellitus. In addition, environmental factors during the fetal period, such as undernutrition, increase the risk of atherosclerosis. Therefore, in addition to during adulthood, preventative measures also need to be taken from the fetal period to adulthood, as the life course approach. Furthermore, research is required that assesses the entire life course from the perspective of the developmental origins of health and disease (DOHaD). Birth cohort studies are suggested to be important in DOHaD research. The Japan Environment and Children's Study (JECS) is a large-scale birth cohort study; the follow-up period was extended to the age of approximately 40 years. This long follow-up period allows us to obtain data regarding atherosclerosis research, which usually occurs after the age of 30 years. In terms of DOHaD mechanisms, birth cohort studies can be used to assess atherosclerosis in relation to epigenetic mechanisms. Here, we discuss the potential of birth cohorts in arteriosclerosis research.

View full abstract

Glucocorticoid exposure during pregnancy have multigenerational effects on neuroendocrine function and behaviours in offspring. Importantly, effects are transmitted through the paternal lineage. Altered phenotypes are associated with profound differences in transcription and DNA methylation in the brain. In the present study, we hypothesized that maternal prenatal synthetic glucocorticoid (sGC) exposure in the F0 pregnancy will result in differences in miRNA levels in testicular germ cells and sperm across multiple generations, and that these changes will associate with modified miRNA profiles and gene expression in the prefrontal cortex of subsequent generations. Pregnant female guinea pigs (F0) were treated multiple courses of sGC in late gestation. miRNA levels were assessed in testes germ cells using the miRNA Array, and candidate miRNA measured in epididymal sperm by qRT-PCR. Maternal sGC exposure did not alter miRNA levels in germ cells derived from the testes of adult male offspring. However, there were significant differences in the levels four candidate miRNAs in the sperm of F1 and F2 adult males. This study has identified that maternal sGC exposure leads to altered miRNA levels in sperm that are apparent for at least two generations.

View full abstract