Research Themes

• Elucidation of the onset mechanism of osteoporosis and osteoarthritis caused by stress on mesenchymal stem cells
  Grant-in-Aid for Scientific Research (C)
  01 Apr. 2017 - 31 Mar. 2020
  Surgery to remove the ovaries was performed on female offspring undernutrition in the rat dams during early pregnancy. Osteoporosis and osteoarthritis could not be confirmed in the undernutrition menopausal model rat. However, it led to clear that they fell into severe obesity. In addition, it was suggested that early embryonic undernutrition stress causes non-alcoholic fatty liver disease.
• Multi-omics approach unraveling neonatal mouse brain for DOHaD
  Grant-in-Aid for Scientific Research (C)
  University of Tsukuba
  01 Apr. 2017 - 31 Mar. 2020
  The DOHaD theory that the nutritional environment in the fetal and neonatal period is behind the risk of developing adult diseases has been advocated. Recently, it has been pointed out that it is also associated with mental disorders such as depression. Data of the neonatal brain and fetal brain of undernourished mice was performed in order to elucidate the predisposition mechanism of psychiatric disorders based on the DOHaD theory (Project C: Elucidation of the molecular basis of adult disease development focusing on fetal tissues as a result of a comparative examination in 2011-2013), and an increase in haptoglobin gene expression was confirmed. Haptoglobin is also a marker for inflammatory diseases, and many other factors involved in the acute phase reaction proteins and myelin regeneration were detected. It was suggested that the malnutrition environment may increase the risk of neurological diseases by causing inflammation in the fetal/neonatal brain.
• Mechanism of vulnerability formation by nutritional environment change at developmental stage.
  Grant-in-Aid for Scientific Research (C)
  Showa University
  01 Apr. 2015 - 31 Mar. 2019
  We have investigated candidate genes which are associated with increased risk of adult diseases by analyzing developing tissues from the C57BL/6J mouse model of developmental origins of health and disease (DOHaD). We focused on experimental evidence that the effect of undernutrition on adult offspring is opposite between the fetal and neonatal periods. We selected 21 candidate genes which were expressed opposite between prenatal and neonatal undernutrition. After 7-days neonatal 50% food restriction in dam, offspring kept until 11-weeks of age. At 11-weeks of age, LPS (TLR4 inducer) was administered to offspring and expression of 21 candidate genes were examined. One of 21 genes such as OATP family transporter (Slco2b1) were affected, and development of spleen and thymus altered after neonatal undernutrition. Adult LPS treatment changed 4 genes such as Lrtm1, Mrap, Il1b, and Slco2b1 between neonatal FR offspring and control offspring. These four genes may be candidate genes for DOHaD.
• 発生毒性試験における胎児形態異常に関するデータ収集と骨格変異の毒性学的意義に関する研究：フルシトシン誘発性過剰肋骨の発現機序からの考察
  Nov. 2016 - Mar. 2019
• later
  Grant-in-Aid for Scientific Research (C)
  Showa University
  01 Apr. 2012 - 31 Mar. 2015
  Although undernutrition during gestation is harmful for fetuses, calorie restriction is a strategy proven to extend healthy and maximum life span after birth. By focusing our attention on genes whose expression oppositely regulated between under- or high-nutrition during neonatal period, we selected candidate genes responsible for DOHaD. The results of microarray in C57BL mouse pup’s liver exposed to neonatal under- (50% food restriction) and high-nutrition (60% high fat food) demonstrated that innate immune system (Fos、Il1b、Rgs1、Ppp1r3g、Hamp、Igll1) was activated shortly after exposure. At weaning, expression of Aldhla 7 was decreased resulting of low resolution of acetaldehyde regardless of the nutritional conditions. By histopathological examination, abnormal development of immune tissues such as thymus and spleen was detected.
• Histone modification in a rat fetal brain an neuronal network formation in a rat neonate after prenatal valproic acid treatment.
  Grant-in-Aid for Scientific Research (C)
  Showa University
  2009 - 2011
  Clinical reports revealed that VPA exposure during early pregnancy increases the risk of a child having an autistic disorder. In this study, focusing on VPA pharmacological action, inhibition of histone deacetylase, the relationship between histone modification and morphological changes in the rat fetal brain after VPA treatment was examined. Disruption of neuronal migration in the cortex was detected in SD, F344 as well as Wistar Kyoto(WK) rat fetus at the gestational day(GD) 16 after VPA treatment at GD11. However, abnormal neural running tract in the midbrain was observed in SD rat fetal brain, but not in F344 or WK rat fetal brain, indicating that "some" morphological changes in the fetal brain are partly due to genetic factors. In the functional observation of neonates on postnatal day 11, an abnormal brain function, such as an increase in fear response, was identified on analyzing the distribution of c-Fos immunoreactive cells after maternal derivation in neonate treated prenatally with VPA. The study could not go to schedule in order to different sensitivity for VPA among rat strains. Therefore, effects of histone modification by VPA on morphological changes in a rat fetal brain have not revealed in this study period.
• A new approach for the detection of developmental neurotoxicity induced by prenatal chemical exposure and an analysis of the critical period for the induction of neurodevelopmental disorders.
  Grant-in-Aid for Scientific Research (C)
  Showa University
  2005 - 2006
  In this research, using two animal models for neurodevelopmental disorders (ND) such as hyperactivity (an easy model to detect some behavioral changes in a behavioral test) and autism (difficult model), the usefulness of histopathological observation of the fetal rodent brain after chemical exposure, and the analysis of the critical period for induction of ND were evaluated. The relationship between findings obtained from fetal brain and postnatal behavioral abnormality was also investigated.
  We already reported that 5-bromo-2'-deoxyuridine (BrdU) induced hyperactivity in offspring when BrdU was administered to rats on gestational days (GD) 9 to 15. In this study, a treatment period was divided before (GD9-10) and after the closure of neural tube (GD11-13, GD14-15). The critical period of hyperactivity induced by prenatal BrdU exposure was estimated to begin after closure of the neural tube and continued for a relatively long period. On observation of GD16 fetal brain, dysgenesis of the cortical plate (CP) was observed in the GD11-13, GD14-15 and GD9-15 (positive control)-treated groups. The findings in GD16 fetal brain (abnormal CP) reflected the grade of hyperactivity in the offspring.
  As a proposed rat model of autism, valproic acid (VPA, 800mg/kg) was administered to rats on GD9 or GD11 (before and after closure of the neural tube). GD9 treatment increased fetal mortality. Dysgenesis of CP was observed in both GD9 and GD11 treatments. Retardation of development of pons was detected in GD11-treated group.
  In conclusions, examination of fetal brains shortly after chemical exposure is a good new endpoint to support postnatal observation in developmental neurotoxicity (DNT) tests. The concept of critical period of ND should be important to improve the sensitivity and reproducibility of a DNT test.