• Title/Summary/Keyword: Fetal brain

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Mechanisms of 5-azacytidine-induced damage and repair process in the fetal brain

  • Ueno, Masaki
    • Proceedings of the Korean Society of Toxicology Conference
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    • 2006.11a
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    • pp.55-64
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    • 2006
  • The fetal central nervous system (CNS) is sensitive to diverse environmental factors, such as alcohol, heavy metals, irradiation, mycotoxins, neurotransmitters, and DNA damage, because a large number of processes occur during an extended period of development. Fetal neural damage is an important issue affecting the completion of normal CNS development. As many concepts about the brain development have been recently revealed, it is necessary to compare the mechanism of developmental abnormalities induced by extrinsic factors with the normal brain development. To clarify the mechanism of fetal CNS damage, we used one experimental model in which 5-azacytidine (5AZC), a DNA damaging and demethylating agent, was injected to the dams of rodents to damage the fetal brain. 5AzC induced cell death (apoptosis)and cell cycle arrest in the fetal brain, and it lead to microencephaly in the neonatal brain. We investigated the mechanism of apoptosis and cell cycle arrest in the neural progenitor cells in detail, and demonstrated that various cell cycle regulators were changed in response to DNA damage. p53, the guardian of genome, played a main role in these processes. Further, using DNA microarray analysis, tile signal cascades of cell cycle regulation were clearly shown. Our results indicate that neural progenitor cells have the potential to repair the DNA damages via cell cyclearrest and to exclude highly affected cells through the apoptotic process. If the stimulus and subsequent DNA damage are high, brain development proceeds abnormally and results in malformation in the neonatal brain. Although the mechanisms of fetal brain injury and features of brain malformation afterbirth have been well studied, the process between those stages is largely unknown. We hypothesized that the fetal CNS has the ability to repair itself post-injuring, and investigated the repair process after 5AZC-induced damage. Wefound that the damages were repaired by 60 h after the treatment and developmental processes continued. During the repair process, amoeboid microglial cells infiltrated in the brain tissue, some of which ingested apoptotic cells. The expressions of genes categorized to glial cells, inflammation, extracellular matrix, glycolysis, and neurogenesis were upregulated in the DNA microarray analysis. We show here that the developing brain has a capacity to repair the damage induced by the extrinsic stresses, including changing the expression of numerous genes and the induction of microglia to aid the repair process.

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Accelerated Evolution of the Regulatory Sequences of Brain Development in the Human Genome

  • Lee, Kang Seon;Bang, Hyoeun;Choi, Jung Kyoon;Kim, Kwoneel
    • Molecules and Cells
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    • v.43 no.4
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    • pp.331-339
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    • 2020
  • Genetic modifications in noncoding regulatory regions are likely critical to human evolution. Human-accelerated noncoding elements are highly conserved noncoding regions among vertebrates but have large differences across humans, which implies human-specific regulatory potential. In this study, we found that human-accelerated noncoding elements were frequently coupled with DNase I hypersensitive sites (DHSs), together with monomethylated and trimethylated histone H3 lysine 4, which are active regulatory markers. This coupling was particularly pronounced in fetal brains relative to adult brains, non-brain fetal tissues, and embryonic stem cells. However, fetal brain DHSs were also specifically enriched in deeply conserved sequences, implying coexistence of universal maintenance and human-specific fitness in human brain development. We assessed whether this coexisting pattern was a general one by quantitatively measuring evolutionary rates of DHSs. As a result, fetal brain DHSs showed a mixed but distinct signature of regional conservation and outlier point acceleration as compared to other DHSs. This finding suggests that brain developmental sequences are selectively constrained in general, whereas specific nucleotides are under positive selection or constraint relaxation simultaneously. Hence, we hypothesize that human- or primate-specific changes to universally conserved regulatory codes of brain development may drive the accelerated, and most likely adaptive, evolution of the regulatory network of the human brain.

Identification and Phylogenetic Analysis of SINE-R Retroposon Family in cDNA Library of Human Fetal Brain

  • Yi, Joo-Mi;Shin, Kyung-Mi;Lee, Ji-Won;Paik, In-Ho;Jang, Kyung-Lib;Kim, Heui-Soo
    • Animal cells and systems
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    • v.5 no.3
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    • pp.231-236
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    • 2001
  • SINE-R retroposons have been derived from human endogenous retrovirus HERV-K family and found to be hominoid specific. Both SINE-R retroposons and HERV-K family are potentially capable of affecting the expression of closely located genes. From cDNA library of human fetal brain, we identified seven SINE-R retroposons and compared them with sequences derived from GenBank database. The SINE-R retroposons from human feta1 brain showed 85∼97% sequence similarities with the human-specific retroposon SINE-R.C2. They also showed 88∼96% sequence similarities with the sequence of the schizo-cDNA clone that derived from postmortem frontal cortex tissue of a schizophrenic patient. Phylogenetic analysis using the neiqhbor-joining method revealed that the seven new SINE-R retroposons from cDNA library of the human feta1 brain have proliferated independently during human evolution. The data indicate that such SINE-R retroposons are expressed in human fetal brain and deserve further investigation as potential leads to understanding of neuropsychiatric diseases.

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Comparison of the Mercury Levels Between Maternal and Fetal Organs in Pregnant Fisher-344 Rats (염화메틸수은에 폭로된 임신 흰쥐에서 모체와 태자의 장기에 축적된 수은농도의 비교)

  • 이진헌
    • Journal of Environmental Health Sciences
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    • v.20 no.3
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    • pp.39-48
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    • 1994
  • The purpose of this study was to determine the mercury accumulated at maternal and fetal organs, and compare its levels between maternal and fetal organs on day 20 of gestation, in pregnant Fisher-344 rats which given orally methylmercuric chloride on day 7 of gestation. Pregnant rats were divided four groups by dose: control group, and methylmercuric chloride treatment groups of 10, 20 and 30 mg/kg, respectively. The results obtained are as follows: I The mercury concentrations in maternal organs were the highest in kidney, and followed by blood, spleen, liver and brain. 2. The slopes of regression equation among mercury dose levels in maternal organs were as follows: Kidney 3.62 (r$^2$=0.943), Blood 2.75 (r$^2$=0.941), Spleen 2.49 (r$^2$=0.990), Liver 1.13 (r$^2$= 0.949), Brain 0.33 (r$^2$=0.984). 3. The mercury concentrations in fetal organs and placenta were the highest in liver, and followed by kidney, placenta and brain. 4. The slopes of regression equation among mercury dose levels in fetal organs and placenta were as follows: Liver 1.79 (r$^2$= 0.968), Kidney 0.79 (r$^2$= 0.976), Placenta 0.68 (r$^2$= 0.920), Brain 0.52 (r$^2$= 0.978), All Body 0.58 (r$^2$= 0.941). 5. As to the mercury levels in kidney, dams were 4.8~14.9 times higher than fetus. But as to the mercury levels in liver and brain, fetus were 1.6~2.5 and 1.5~1.9 times higher than dams. In conclusion, the mercury which exposured to pregnant rats can easily pass through the placenta and accumulated in fetus, especially higher in fetal liver and brain.

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Age- and Area-Dependent Distinct Effects of Ethanol on Bax and Bcl-2 Expression in Prenatal Rat Brain

  • Lee, Hae-Young;Naha, Nibedita;Kim, Jong-Hun;Jo, Mi-Ja;Min, Kwan-Sik;Seong, Hwan-Hoo;Shin, Dong-Hoon;Kim, Myeong-Ok
    • Journal of Microbiology and Biotechnology
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    • v.18 no.9
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    • pp.1590-1598
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    • 2008
  • Cell proliferation and differentiation are critical processes in a developing fetal rat brain, during which programmed cell death (PCD) also plays an important role. One of the decisive factors for PCD is Bcl-2 family proteins, where Bax induces cell death, whereas Bcl-2 acts as an inhibitor of PCD. As maternal drinking is known to cause fetal alcohol syndrome (FAS) or malformation of the fetal brain during pregnancy, the objective of the present study was to investigate whether maternal ethanol exposure alters the PCD-related Bax and Bcl-2 protein expression during fetal brain development. Pregnant female rats were orally treated with 10% ethanol and the subsequent expressions of the Bax and Bcl-2 proteins examined in the fetal brain, including the forebrain, midbrain, and hindbrain, from gestational day (GD) 15.5 to GD 19.5, using Western blots, in situ hybridization, and immunohistochemistry. With regard to the ratio of Bcl-2 to Bax proteins (Bcl-2/Bax), the Bax protein was dominant in the forebrain and midbrain of the control GD 15.5 fetuses, except for the hindbrain, when compared with the respective ethanol-treated groups. Moreover, Bcl-2 became dominant in the midbrain of the control GD 17.5 fetuses when compared with the ethanol-treated group, representing an alternation of the natural PCD process by ethanol. Furthermore, a differential expression of the Bcl-2 and Bax proteins was found in the differentiating and migrating zones of the cortex, hippocampus, thalamus, and cerebellum. Thus, when taken together, the present results suggest that ethanol affects PCD in the cell differentiation and migration zones of the prenatal rat brain by modulating Bax and Bcl-2 expression in an age- and area-dependent manner. Therefore, this is the first evidence that ethanol may alter FAS-associated embryonic brain development through the alteration of Bax and Bc1-2 expression.

Localization and Developmental Changes of Dopamine $D_1$ and $D_2$ Receptor mRNAs in the Rat Brain

  • Kim, Myeong-Ok;Choi, Wan-Sung;Lee, Bong-Hee;Cho, Kyung-Jae;Seo, Sook-Jae;Kang, Sung-Goo;Kim, Kyung-Jin;Baik, Sang-Ho
    • Animal cells and systems
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    • v.1 no.3
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    • pp.497-505
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    • 1997
  • Dopamine plays diverse roles in the fetal brain development and differentiation. However, the development of the dopaminergic neurons and its receptors has not been fully understood. In our studies, in situ hybridization and immunohistochemical methods were used to investigate the ontogeny of dopaminergic neurons and its receptor subtypes during the fetal development of the rat. In situ hybridization data showed that dopamine $D_1$ and $D_2$ receptor mRNAs were expressed in the ventricular and subventricular zones of ganglionic eminence, thalamus, hypothalamus, and cortical neuroepithelium on gestational day 13. Expression of dopamine $D_1$ and $D_2$ receptors during gestational days 17 and 19 reached the same or similar level of that in the adult brain. Expression of $D_1$ receptor mRNA preceded that of $D_2$ receptor mRNA in the early developmental stage, although this pattern was reversed with the sharp increase of $D_2$ receptor mRNA soon after. $D_2$ receptor mRNA was expressed in substantia nigra of mesencephalon of the fetal rat brain. However, $D_1$ receptor mRNA was not detected in substantia nigra. Our results indicate that dopamine might function in the fetal brain during the early gestational period.

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Decreasing Effects of Korean Garlic against the Accumulation of Mercury Levels in Maternal and Fetal Organs in Pregnant Fischer-344 Rats (임신흰쥐에서 모체와 태자의 장기에 축적되는 수은에 대한 마늘의 저감효과에 대한 연구)

  • 이진헌;정문호
    • Journal of Environmental Health Sciences
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    • v.22 no.3
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    • pp.17-27
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    • 1996
  • The purpose of this study was to evaluate the decreasing effects of Korean garlic against the accumulation of mercury levels in maternal and fetal organs in pregnant Fischer 344 rats, based on the theory and information that neutral amino acids have protective effects against mercury poisoning and garlic contains a large of neutral amino acids. The results obtained are as follows: 1. On the 20th day of gestation, the maternal body weight in 20 mg/wt$\cdot$kg methyl mercuric chloride groups was 76.1% of those in control group, but those recovered to be 81.2% and 93.6% by treating with garlic (0.5 g/wt$\cdot$kg and 1.0 g/wt$\cdot$kg). 2. The mercury levels in maternal organs were reduced 6.2% and 47.2% (p<0.05) in kidney, 8.2% and 42.1% (p<0.05) in spleen, 9.7% and 40.9% (p<0.05) in blood, 35.6% (p<0.05) and 67.2% (p<0.05) in liver, 38.0% (p<0.05) and 57.6% (p<0.05) in brain, by treating with garlic (0.5 g/wt$\cdot$kg and 1.0 g/wt$\cdot$kg). 3. The mercury levels were reduced 22.4% and 44.3% (p<0.05) in placenta, and 34.7% (p<0.05) and 54.9% (p<0.05) in fetal body, by treating with garlic (0.5 g/wt$\cdot$kg and 1.0 g/wt$\cdot$kg). 4. The mercury levels in fetal organs were reduced 17.5% and 46.7% (p<0.05) in kidney, 15.1% and 37.0% (p<0.05) in brain, 30.2% (p<0.05) and 46.7% (p<0.05) in liver, by treating with garlic (0.5 g/wt$\cdot$kg and 1.0 g/wt$\cdot$kg). 5. Mercury levels in maternal kidney were 6.73~7.71 times higher than those in fetal kidney, but those in fetal liver and brain were 1.67~2.25 times and 1.98~2.93 times higher than those in maternal liver and brain, respectively. In conclusion, Korean garlic decrease the accumulation of mercury levels in maternal and fetal organs in pregnant Fischer 344 rats as increasing the dose.

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Molecular Cloning and Phylogeny of the Human Endogenous Retrovirus HERV-W LTR Family in cDNA Library of Human Fetal Brain (인간 태아의 뇌로부터 만들어진 cDNA library에서 내생 레트로바이러스 HERV-W LTR의 클로닝 및 분자계통분류)

  • 이주민;허재원;신경미;이지원;이영춘;백인호;장경립;김희수
    • Journal of Life Science
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    • v.11 no.4
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    • pp.379-384
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    • 2001
  • Long terminal repeats(LTRs) of the human endogenous retrovirus(HERV) heve been found to be coexpresed with genes located nearby. It has been suggested that the LTR elements have contributed to the genetic variation of human genome connected to various diseases. Recently, HERV-W family was identified in the cerebrospinal fluids and brains of individuals with schizophrenia. Using cHNA library derived from human fetal brain, we performed PCR amplification and identified seven new HERV-W LTR elements. Those LTR elements showed a high degree of sequence similarity(98∼99%) with HERV-W (AF072500). A phylogentic tree obtained by the neighbor-joining method revealed that seven new HERV-W LTR elements(FB-1, 2, 4, 8, 9, 10, 12) were closely related to the AX000960, AF072504, and AF072506 from Gen Bank database. Our data suggest that several copy numbers of the HERV-W LTR elements are expressed in human feta brain and may contribute to an understanding of biological function connected to neuropsychiatric diseases.

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Effect of Prenatal Dexamethasone on Sex-specific Changes in Embryonic and Placental Growth

  • Yun, Hyo Jung;Lee, Ji-Yeon;Kim, Jongsoo;Kim, Myoung Hee
    • Biomedical Science Letters
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    • v.20 no.1
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    • pp.43-47
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    • 2014
  • To understand the effect of prenatal stress on sex-specific changes in embryonic and placental growth, a synthetic glucocorticoid (dexamethasone) was administered intraperitoneally at a dosage of 1 mg/kg body weight (BW) (Dex1) or 10 mg/kg BW (Dex10) to pregnant ICR mice at the gestational days 7.5, 8.5 and 9.5 post coitum (p.c.). Embryos and placentas were then harvested at days 11.5 and 18.5 p.c., and their body weight and size were measured following the determination of sex through PCR using Sry specific primers in tail tissues. As a result, female embryos presented reduced fetal body weight and size in Dex1- and Dex10-treated groups than those of control group at the embryonic day 11.5 p.c. Interestingly, the growth seems to be recovered at day 18.5 as there was no difference in growth between control and dexamethasone treated groups. In the case of males, Dex1 induced a decrease in fetal weight in day 11.5 and this pattern was maintained until day 18.5, whereas their growth was not affected by Dex10 treatment. Placental growth showed similar patterns to fetal growth in both sexes but the extent of reduction was not statistically significant in most cases. Placental weights in Dex1- and Dex10-treated group were decreased significantly in male only. The results imply that the effect of prenatal stress is largely sex dependent due to different strategies for growth and survival in a stressful environment.

Evidence for adverse effect of perinatal glucocorticoid use on the developing brain

  • Chang, Young Pyo
    • Clinical and Experimental Pediatrics
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    • v.57 no.3
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    • pp.101-109
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    • 2014
  • The use of glucocorticoids (GCs) in the perinatal period is suspected of being associated with adverse effects on long-term neurodevelopmental outcomes for preterm infants. Repeated administration of antenatal GCs to mothers at risk of preterm birth may adversely affect fetal growth and head circumference. Fetal exposure to excess GCs during critical periods of brain development may profoundly modify the limbic system (primarily the hippocampus), resulting in long-term effects on cognition, behavior, memory, co-ordination of the autonomic nervous system, and regulation of the endocrine system later in adult life. Postnatal GC treatment for chronic lung disease in premature infants, particularly involving the use of dexamethasone, has been shown to induce neurodevelopmental impairment and increases the risk of cerebral palsy. In contrast to studies involving postnatal dexamethasone, long-term follow-up studies for hydrocortisone therapy have not revealed adverse effects on neurodevelopmental outcomes. In experimental studies on animals, GCs has been shown to impair neurogenesis, and induce neuronal apoptosis in the immature brains of newborn animals. A recent study has demonstrated that dexamethasone-induced hypomyelination may result from the apoptotic degeneration of oligodendrocyte progenitors in the immature brain. Thus, based on clinical and experimental studies, there is enough evidence to advice caution regarding the use of GCs in the perinatal period; and moreover, the potential long-term effects of GCs on brain development need to be determined.