CYTOTOXIC EFFECTS OF ETHYLNITROSOUREA ON CENTRAL NERVOUS SYSTEM OF RAT EMBRYOS Special References to Carcinogenesis and Teratogenesis

Fujiwara, Hisao

doi:10.1111/j.1440-1827.1980.tb01332.x

Cited by 10 publications

(8 citation statements)

References 20 publications

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“…The degree of tissue injury to the NE at the neurogenesis stage is proportional to the dose of ENU administered (Fujiwara, 1980; Yoshida et al, 1984). In the present study, a single intravenous injection of ENU (60 mg/kg body weight) was administered to maintain the glia on the brain surface and the tight junctions of the NE cells of the neocortex (Yoshida et al, 1984; Oyanagi et al, 1986, 1987, 1998, 2001).…”

Section: Methodsmentioning

confidence: 99%

“…We examined immunohistologically and by immunoelectron microscopy the time course of alterations of MK expression in fetal rat brains at the neurogenesis stage after injury by transplacental administration of ethylnitrosourea (ENU). One main effect of ENU is to block DNA synthesis (Swann and Magee, 1971), resulting in microcephalus or cortical and spinal cord dysgenesis in rats (Hallas and Das, 1978, 1979; Fujiwara, 1980; Houle and Das, 1984; Yoshida et al, 1984; Oyanagi et al, 1986, 1987, 1988, 1998, 2001) up to 48 hr after the administration, when repair of the injured NE is completed (Fujiwara, 1980; Yoshida et al, 1984; Oyanagi et al, 1986, 1987, 1988). A single intravenous injection of ENU (60 mg/kg body weight) does not disrupt the glial limitans over the cerebrum or tight junctions of NE cells, and does not induce hemorrhage, tissue laceration, or heterotopic mass (Yoshida et al, 1984; Oyanagi et al, 1986, 2001).…”

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confidence: 99%

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Distinctive expression of midkine in the repair period of rat brain during neurogenesis: Immunohistochemical and immunoelectron microscopic observations

Kikuchi-Horie

Kawakami

Kamata³

et al. 2004

J of Neuroscience Research

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Distinctive expression of midkine (MK) was observed during the repair period of fetal brain neuroepithelium. MK is a heparin-binding growth factor that occurs as a product of a retinoic acid-inducible gene, and has a molecular mass of 13 kDa. MK expression was examined immunohistochemically and by immunoelectron microscopy during a period of repair in developing rat brain at the neurogenesis stage. Injury was induced in rat fetuses by transplacental administration of ethylnitrosourea (ENU) on embryonic Day (E) 16, and histological changes were examined up to 48 hr thereafter (i.e., up to E 18). In normal rat fetuses, MK immunostaining was observed in the cytoplasm and radial and horizontal processes of all cells in the neuroepithelium (NE), subventricular zone (SV), and intermediate zone (IMZ). In ENU-administered brains, cells in the NE, SV, and IMZ were damaged severely, especially 16-24 hr after ENU administration. The remaining neuroepithelial cells, with the exception of those in M-phase and the tips of processes at the ventricular surface, were negative for MK immunohistochemistry 16-24 hr after the administration of ENU. Forty-eight hours after the administration, the cytoplasm and processes of cells in the NE, SV, and IMZ were MK immunopositive. Our previous data reported that the cell cycle of most NE cells is synchronized to the S-phase 16 hr after ENU administration and to the M-phase at 24 hr, and many NE cells were recovered 48 hr after ENU administration. The previous results taken together with the present results indicate that: (1) MK expression does not increase during the repair period of the NE, being different from adults; (2) MK expression is likely to be suppressed at S-phase according to the condition of the NE; and (3) MK expression is not essential for every cell cycle phase of NE cells; but (4) is necessary to maintain the M-phase of NE cells.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Distinctive expression of midkine in the repair period of rat brain during neurogenesis: Immunohistochemical and immunoelectron microscopic observations

Kikuchi-Horie

Kawakami

Kamata³

et al. 2004

J of Neuroscience Research

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“…Weights of some other organs were also reduced to some degree. It is reported that ENU causes not only apoptotic cell death [10] but also cell growth arrest [3,6,14], so it is suspected that the organs which did not have an increase in apoptosis might be affected by cell growth arrest caused by ENU.…”

Section: Discussionmentioning

confidence: 99%

Teratologic Studies on Rat Perinates and Offspring from Dams Treated with Ethylnitrosourea(ENU).

et al. 2000

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Ethylnitrosourea (ENU), a well known DNA alkylating agent, induces anomalies in the central nervous system (CNS), craniofacial tissues, limbs and male reproductive organs. Recently we clarified that excess cell death caused by apoptosis occurred in these organs and tissues of rat fetuses from dams treated with ENU at day 13 of gestation (GD13). In this study, we examined fetuses at GD21 and offspring at 10 weeks of age after ENU administration to pregnant rats at GD13 in order to clarify the relationship between ENU-induced apoptosis in the fetal tissues and teratogenicity of ENU. Severe intrauterine growth retardation was observed in the ENU group, and the body weight of the offspring in the ENU group was significantly lower than that of the control group throughout the experiment. In addition, a high incidence of microencephaly, ectrodactyly and curved caudal vertebrae was observed in the offspring from dams treated with ENU at GD13. Judging from the results of our previous and present studies, it was strongly suggested that ENU-induced apoptosis in rat fetal tissues may play an important role in the induction of anomalies in the corresponding tissues.

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“…The degree of tissue injury to the NE at the neurogenesis stage has been reported to be proportional to the dose of ENU administered [10,23,56]. The dose of ENU used was 60 mg/kg body weight administered once by intravenous injection; this dose maintains intact the glia limitance of the brain surface and the tight junctions of neuroepithelial cells of the neocortex [23,38,56].…”

Section: Induction Of Neuroepithelium Injurymentioning

confidence: 99%

“…This may indicate that the expression of these Ca-binding proteins had been destined in particular neuroblasts at the neurogenesis stage. To analyze the mechanism of the expression of CaBP and PV in the cerebrum, we inflicted an injury to rat fetuses at the neurogenesis stage, while preserving the glia limitance of the brain surface and tight junctions of the neuroepithelium (NE) of the ventricle wall, which are the basis of neuroblast migration and brain formation [23,56]. In fact, rapid increases of gene expression and immunoreactivity of CaBP [32,35,44,53] and PV [14,34,44,46] occur in the cerebral cortex at the stage of robust synaptogenesis after birth [31,54].…”

Section: Introductionmentioning

confidence: 99%

Expression of calbindin D-28k and parvalbumin in cerebral cortical dysgenesis induced by administration of ethylnitrosourea to rats at the stage of neurogenesis

et al. 2001

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It has been reported that transplacental administration of ethylnitrosourea (ENU), which is cytotoxic immediately after administration, to rat fetuses at the neurogenesis stage induces dysgenesis of the cerebral cortex, characterized by neuronal sparseness and architectural irregularity. In the present study, we examined the topographic distribution of neurons containing 5-bromo-2-deoxyuridine (BrdU), and those containing calbindin D-28k (CaBP) and parvalbumin (PV), most of latter two are considered to be interneurons located in particular layers of the normal cerebral cortex in rats with experimentally induced cerebral cortical dysgenesis. Pregnant Wistar albino rats were given a single transplacental administration of ENU on embryonic day 16, followed 4, 8, 16, 24, 36, or 48 h later by a single intraperitoneal injection of BrdU. The pups were killed 10 weeks after birth. In the normal cerebral cortex, BrdU-immunopositive neurons showed an inside-out pattern according to the time of BrdU injection, whereas in ENU-treated rats the topographic localization of the BrdU-immunopositive neurons was irregular and the inside-out pattern was disrupted. Although the number of CaBP-and PV-immunopositive neurons was lower in ENUtreated animals, no topographic difference was evident between the normal and the dysgenetic cerebral cortices. These findings indicate that the expression of CaBP and PV in the neurons of the rat cerebral cortex is extrinsic, and depends on the position of the neurons rather than on the time of their formation or on genetic control. This suggests the existence of re-regulation of the expression of CaBP and PV in the developing brain, which may be one of the effective mechanisms by which the cerebral cortex can maintain its normal function in spite of cytoarchitectural abnormality.

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CYTOTOXIC EFFECTS OF ETHYLNITROSOUREA ON CENTRAL NERVOUS SYSTEM OF RAT EMBRYOS Special References to Carcinogenesis and Teratogenesis

Cited by 10 publications

References 20 publications

Distinctive expression of midkine in the repair period of rat brain during neurogenesis: Immunohistochemical and immunoelectron microscopic observations

Distinctive expression of midkine in the repair period of rat brain during neurogenesis: Immunohistochemical and immunoelectron microscopic observations

Teratologic Studies on Rat Perinates and Offspring from Dams Treated with Ethylnitrosourea(ENU).

Expression of calbindin D-28k and parvalbumin in cerebral cortical dysgenesis induced by administration of ethylnitrosourea to rats at the stage of neurogenesis

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