official journal of Congeital Anomalies Research Association of Japan
Online ISSN : 2433-1503
Print ISSN : 0037-2285
Volume 35 , Issue 1
Congenital Anomalies
Showing 1-12 articles out of 12 articles from the selected issue
  • 1995 Volume 35 Issue 1 Pages 1-13
    Published: 1995
    Released: July 29, 2021
    JOURNALS OPEN ACCESS
    ABSTRACT The developing mammalian brain is highly susceptible to ionizing radiation. A significant increase in small head size and mental retardation has been noted in prenatally exposed survivors of the atomic bombing, with the highest risk in those exposed during 8-15 weeks after fertilization. This stage corresponds to day 13 of pregnancy for mice and day 15 for rats in terms of brain development. The initial damage produced by radiation at this stage is cell death in the ventricular zone (VZ) of the brain mantle, the radiosensitive germinal cell population. During histogenesis of the cerebellum, on the other hand, the external granular layer (EGL) is also radiosensitive. Although extensive cell death results in microcephaly and histological abnormality, both VZ and EGL have an ability to recover from a considerable cell loss and form the normal structure of the central nervous system. The number of cell deaths to induce tissue abnormalities in adult brain rises in the range of 15-25% of the germinal cell population; and the threshold doses are about 0.3 Gy for cerebral defects and 1 Gy for cerebellar anomalies in both mice and rats. A similar threshold level is suggested in human cases in induction of mental retardation. Radiation-induced cell death in the VZ and EGL has been revealed as apoptosis, by the nuclear and cytoplasmic condensation, transglutaminase activation, required macromolecular synthesis, and internucleosomal DNA cleavage. Apoptosis of the germinal cell is assumed to eliminate acquired genetic damage. Once an abnormality in DNA has been induced and fixed in a germinal cell, it would be greatly amplified during future proliferation, bringing with it the risk of producing malformations and tumors. These cells would commit suicide when injured for replacement by healthy cells, rather than undertake DNA repair which is rarely complete. In fact they show very slow repair of cellular damage. Thus the high sensitivity of undifferentiated neural cells to the lethal effect of radiation may constitute a biological defense mechanism.
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  • 1995 Volume 35 Issue 1 Pages 15-24
    Published: 1995
    Released: July 29, 2021
    JOURNALS OPEN ACCESS
    ABSTRACT The definite etiology in most cases of congenital hydrocephalus still remains unknown. Many studies have been reported on the experimental hydrocephalus induced by viral infection other than TORCH (Toxoplasma, Other agents, Rubella virus, Cytomegalovirus and Herpes simplex type 1 and 2 viruses). Above all mumps virus induces a high frequency of hydrocephalus. Several pediatric cases of hydrocephalus after mumps virus infection have been reported. These cases are thought to be caused by ependymitis due to mumps virus infection. Clinical cases of congenital hydrocephalus possibly caused by intrauterine mumps or influenza virus infection are also accumulating. The definitive evidence of a teratogenic potential for mumps and influenza virus, however, has been obscure yet. Our experimental studies demonstrated that mumps and parainfluenza virus type 3 could induce hydrocephalus by destructive ependymal infection in suckling hamsters. However, the transplacental infection of these viruses was rare. These results show that myxoviruses such as mumps and parainfluenza virus have a strong affinity to ependy- ma1 cells, and then they cause resultant ependymal destruction. We suggest that when the placenta is impaired so severely that these viruses are able to pass through the placental barrier, maternal infection would cause the hydrocephalus to the infant.
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  • 1995 Volume 35 Issue 1 Pages 25-42
    Published: 1995
    Released: July 29, 2021
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    ABSTRACT At the 34th Annual Meeting of the Japanese Teratology Society held in July 1994, the first author was asked by President Hiroshi HARA to report on the results of the international joint study on congenital anomalies that we were conducting in the former Soviet Union. It was only a short time ago that the study was begun and long-term observation needs to be made hereafter, but we made an interim report on the results obtained so far. In this report we describe (1) the results of a joint study made with Director Gennady Lazjuk of the Institute for Hereditary Diseases in Minsk, Republic of Belarus, mainly with regard to congenital anomalies that have increased after the Cherno- by1 nuclear power plant accident, (2) the results obtained in a study made with Dr. Anatoly Vacilez, Chief, Department of Obstetrics and Gynecology, Gomel District Hospital in Belarus, a heavily contaminated area in Belarus, and (3) the congenital anomalies that can be considered to have occurred as a result of the approximately 570 nuclear tests made over a period of 40 years from 1949 to 1989 in Semipalatinsk, Republic of Kazkh.
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  • 1995 Volume 35 Issue 1 Pages 43-53
    Published: 1995
    Released: July 29, 2021
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    ABSTRACT Zellweger's cerebro-hepato-renal syndrome is characterized by the absence of peroxisomes, severe neurologic manifestations, and neuropathological findings such as polymicrogyria and neuronal heterotopia which are based on disturbances of neuronal migration. We investigated the pathogenesis of peroxisome-deficient disorders in attempts to clarify the molecular basis of these brain dysgenesis. Complementation analysis revealed that at least 9 genes contribute to the formation of peroxisomes. One of these gene products, peroxisome assembly factor- 1 (PAF- 1 ), was isolated, using a functional cloning method and a mutant Chinese hamster ovary cell line with defective peroxisomes. PAF- 1 restored the peroxisomes and biochemical abnormalities in fibroblasts from patients with Zellweger syndrome and who belonged to complementation group F. Defects in PAF-1 would result in dysfunction of peroxisomal membrane or in the transport machinery of peroxisomal proteins, and metabolic disturbances such as accumulation of very long chain fatty acids and defects in plasmalogen may occur.
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  • 1995 Volume 35 Issue 1 Pages 55-71
    Published: 1995
    Released: July 29, 2021
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    ABSTRACT There is overwhelming evidence that vitamin A (retinol), presumably through its metabolite retinoic acid, participates in organogenesis at several stages and sites during normal development. Besides the important role of retinol and retinoic acid (RA) as micronutrients in growth and development, these retinoids and their synthetic analogs are now viewed as drugs for treatment of oncologic and dermatologic diseases. An excess of vitamin A, RA, or several other synthetic analogs are teratogenic. Mecha- nisms involved in teratogenesis remain unsolved but are under active investigation in many laboratories. The attention has recently focused on a series of endogenous proteins which serve as nuclear receptors for natural retinoids as means to discover how retinoids intervene in diverse cellular functions and which of their cellular and molecular targets are crucial to the developing embryo. There are two classes of receptors, termed retinoic acid receptors (RARs) and retinoid X receptors (RXRs) This brief review summarizes the results of our recent studies which suggest that: 1) the teratologic effects of retinoids are mediated by the nuclear receptors; 2) the heterodimer RXRRAR pathway is the major mechanism for the induction of teratogenesis; 3) RX R-selective synthetic retinoids have diminished teratogenicity; and 4) an overexpression of specific RARs in response to RA disrupt skeletal morphogenesis resulting in limb reduction defects.
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  • 1995 Volume 35 Issue 1 Pages 73-86
    Published: 1995
    Released: July 29, 2021
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    Abstract We investigated the embryolethality and teratogenicity of a new platinum complex, 254-S, and cisplatin (CDDP) by single dosing to dams on one day during the period of organogenesis. The results are summarized as follows: (1) Embryolethality was maximal after 254-S treatment on day 7 of gestation (Day 7) and after CDDP treatment on Days 6 to 9. It decreased with advancing gestational age. (2) Both 254-S and CDDP were teratogenic. The critical period for induction of malformation appeared twice for 254-S, at Days 6 to 9 and at Days 14 to 15, and once for CDDP, at Days 5 to 8. (3) The types of malformations induced by 254-S or CDDP were different, indicating different mode of teratogenesis. 254-S caused malformations mainly in the craniofacial or limb bud areas in the biphasic manner, whereas CDDP caused malformations mainly of the limb buds in the monophasic manner. (4) Malformations of the limb/digit and tail that are known to have critical periods during the late stage of organogenesis were induced by treatment with 254-S on Day 7 and with CDDP on Day 5 or 6.
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  • 1995 Volume 35 Issue 1 Pages 87-91
    Published: 1995
    Released: July 29, 2021
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    ABSTRACT Multiple pterygium syndrome (MPS) is a rare condition characterized by pterygia of the neck, finger, antecubital, popliteal, and intercrural areas. The present case study describes a male patient afflicted with this condition. This case has two unique features 1) the patient exhibited both mental and physical retardation at 2 years of age, a rare symptom of this disorder, and 2) the patient also had chronic idiopathic intestinal pseudo-obstruction syndrome (CIIPS). Although the pathogenesis of both MPS and CIIPS is unclear, some features of the present case suggest a possible pathogenic mechanism.
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  • 1995 Volume 35 Issue 1 Pages 93-100
    Published: 1995
    Released: July 29, 2021
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    ABSTRACT Palatal primordia of day-12.5 ICR mouse fetuses were cultured in a chemi- cally-defined serumless medium by a suspension culture technique, and the developmental toxicity of aspirin and its metabolites on in vitro palatogenesis was studied. Explanted fetal palates were exposed in vitro for 72 hr to 0.5-2 mM aspirin (ASP), 0.25-2 mM salicylic acid (SA), 0.5-2 mM salicyluric acid (SUA), 1-2 mM 2.3-dihydroxybenzoic acid (3DHB), or 1-2 mM 2,5-dihydroxybenzoic acid (5DHB). After 72 hr culture, ASP at 2 mM and SA at 0.25 mM inhibited the growth and fusion of palatal shelves, and SUA at 1 mM prevented palatal fusion. On the other hand, 3DHB and 5DHB did not exert any significant toxic effects on cultured palates at concentrations up to 2 mM. Judging from the 50% inhibitory concentration (IC~O), SA (IC50 = 0.9 mM) was the most toxic of the 5 compounds tested, with a decreasing order of ASP (IC50 = 1.5 mM), SUA (IC50 = 1.6 mM), and DHBs (IC50 = over 2 mM for both 3DHB and SDHB). With respect to develop- mental toxicity, cultured fetal mouse palates showed the susceptibility to aspirin and its metabolites which is intermediate between the susceptibility of rat embryos in vivo and that of postimplantation rat embryos cultured in vitro. The significance of fetal organ culture for evaluating developmental toxicity of chemicals is also discussed.
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  • 1995 Volume 35 Issue 1 Pages 101-111
    Published: 1995
    Released: July 29, 2021
    JOURNALS FREE ACCESS
    Abstract Forelimb buds of mouse embryos were cultured in a serum-free BGJb medium by a roller system. At the beginning of culture, acetazolamide was added to the final concentration of 10−5 M or 10−4 M. After 6 days of culture, no morphological abnormalities of the developing forelimb buds could be detected. In morphometrical analyses, the morphological scores of antebrachium and hand in the right forelimb of female embryos were 1.8 and 2.2 in the 10−5 M and 10−4 M acetazolamide-treated groups, respectively, and 1.6 in controls. There was no difference in the size of the forelimb among these groups. Concerning cartilage skeleton, the incidence of bending of the ulnoradius was increased to 64–90% in 10−4 M acetazolamide-treated group, which was different from the control (0.22%). In addition, there was a significant difference in the protein and DNA contents in only right forelimb buds between the acetazolamide-treated and control groups. However, there were no differences in sex or laterality in the development of forelimbs and cartilage skeleton. No pathological changes in the cartilage skeleton and mesenchyme were observed in the acetazolamide-treated forelimbs. From these findings, there is the possibility that acetazolamide per se may primarily interfere with the development of the forelimb in mouse embryos at the molecular level in vitro.
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  • 1995 Volume 35 Issue 1 Pages 113-122
    Published: 1995
    Released: July 29, 2021
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    ABSTRACT Developmental alteration of the dendritic arborization and axonal boutons of vasoactive intestinal polypeptide (VIP) neurons in the CAI hippocampus was immuno- histochemically examined in both control and microcephalic rats at postnatal days 15 and 60. Microcephaly was induced by prenatal exposure to methylazoxymethanol acetate (MAM; 20 mgkg) on day 15 of gestation (MAM rats). In the control at postnatal day 15, VIP-immunoreactive axonal boutons were densely aggregated specifically in the stratum pyramidale. At postnatal day 60, these axonal boutons in the stratum pyramidale of the controls were somewhat less dense. Another aggregation of axonal boutons was also observed along the upper part of the stratum oriens near the alveus border (area A). In the MAM rats at postnatal day 15, on the other hand, VIP-immunoreactive neurons in the CAI hippocampus were decreased in number and the dendritic arborization of these neurons was very poor compared with the controls. The density of VIP-immunoreactive axonal boutons was remarkably lower than the controls. In the MAM-rats at postnatal day 60, density of the axonal boutons was almost similar with that of MAM-rats at postnatal day 15 in the stratum pyramidale, whereas a drastic increase was observed in area A, which made the bouton aggregation more dense than in the controls at postnatal day 60. These observations suggest that there is an area-dependent difference in the development of VIP neurons in the CAI hippocampus which may be related to the area-dependent heterogeneous vulnerability of VIP neurons to MAM exposure.
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  • 1995 Volume 35 Issue 1 Pages 123-132
    Published: 1995
    Released: July 29, 2021
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    ABSTRACT An N-phenylimide herbicide, S-53482, exhibited developmental toxicity in rats in the absence of maternal toxicity at a dose of 30 mgkg. The developmental toxicities noted were embryolethality, teratogenicity (mainly ventricular septal defect [VSD] and wavy ribs) and growth retardation. In contrast to rats, the herbicide showed no develop- mental toxicity in rabbits even at a maternal toxic dose of 3,000 mag. There was a remarkable species difference between rats and rabbits. A single dose of S-53482 was administered to pregnant rats on one of gestation days 11 through 15 (detection of plug = day 0). Day 12 of gestation was the most sensitive day for embryonic death, VSD, and decreased fetal body weight. It is likely that there is a common mechanism for the three types of developmental toxicity and that S-53482 does not produce VSD by its direct damage to embryonic heart tissue.
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  • 1995 Volume 35 Issue 1 Pages 133-140
    Published: 1995
    Released: July 29, 2021
    JOURNALS OPEN ACCESS
    ABSTRACT The induction of abnormal palatal development by three glucocorticoids; prednisolone, triamcinolone acetonide and hydrocortisone was evaluated in rat fetuses. Pregnant rats were injected subcutaneously with either prednisolone (12.5-100 mgkgl day), triamcinolone acetonide (0.25-2 mg/kg/day) or hydrocortisone (1 00 mg/kg/day) on days 14 and 15 of gestation. These females were humanely killed on day 20 of gestation and viable fetuses were inspected for their palatal abnormalities. The frequencies of cleft palate were significantly higher in the group treated with 100 mg/kg/day prednisolone (10.6%), and in the groups treated with 0.5, 1 and 2 mg/kg/day triamcinolone acetonide (8.6%, 26.1% and 58.3%, respectively) than the control frequency of 0%. Triamcinolone acetonide was 70 times as potent as prednisolone in inducing palatal slit, with ED50 value of 1 .O mgkg/day and 70 mgkg/day, respectively. Hydrocortisone showed no potentiality for the induction of cleft palate and palatal slit. Other developmental abnormalities including omphalocele and general edema, late resorption, and growth retardation were induced by triamcinolone acetonide and prednisolone. These findings indicate that triamcinolone acetonide has a significantly higher potentiality for the induction of palatal slit in rats, as well as in mice, compared to prednisolone and hydrocortisone.
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