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Congenital hydrocephalus in suckling hamsters caused by transplacental infection with parainfluenza virus type 3
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Congenital Hydrocephalus in Suckling Hamsters Caused by Transplacental Infection with Parainfluenza Virus Type 3 Tomoyuki Takano, MD, Masaki Ohno, MD, Tsunekazu Yamano, MD and Morimi Shimada, MD
The possible occu"ence of congenital hydrocephalus by viral infection of the mother was examined by inoculating pregnant hamsters intravenously with parainfluenza virus type 3 (PIV-3). We could produce congenital hydrocephalus in littermates born to a mother which had been inoculated into the left cervical vein on the 14th day of pregnancy. This result may indicate that the virus could pass through the placenta to a"ive at the fetus, and infect the central nervous system. Key words: congenital hydrocephalus, parainfluenza virus type 3, myxovirus, transplacental infection. Takano T, Ohno M, Yamano T, Shimada M Congenital hydrocephalus in suckling hamsters caused by transplacental infection with parainfluenza virus type 3. BrainDev 1991;13:371-3
We have reported that a high frequency of hydrocephalus was caused by the intracerebral or intraperitoneal inoculation of mumps virus or parainfluenza virus type 3 (PIV-3) into the suckling hamster [1-3]. These results suggest that fetal infection with these myxoviruses may cause congenital hydrocephalus. However, it remains unknown whether maternal infection with myxovirus induces fetal infection and subsequently produces congenital hydrocephalus or not. In this experiment, the possible occurrence of congenital hydrocephalus by viral infection of the mother was examined by inoculating PIV-3 intravenously in pregnant hamsters.
From the Department of Pediatrics, Shiga University of Medical Science,Ohtsu. Received for publication : May 9, 1991. Accepted for publication: August 11, 1991. Correspondence address: Dr. Tomoyuki Takano, Department of Pediatrics, Shiga University of Medical Science, Setatsukinowacho, Ohtsu 510-21, Japan.
MATERIALS AND METHODS Female Syrian hamsters of 9-12 weeks of age were mated with breeder males for 24 hours. The day after mating was counted as day 1 of gestation. Seven pregnant hamsters were inoculated with 0.5 ml of 1.0 x 108 pfu (plaque forming unit) / ml of PN -3 into the left cervical vein on either day 11, 12, 14 or 15 of gestation. The brains of offspring born to the mother hamsters thus treated were examined 13 to 17 days after birth to confum the possible occurrence and incidence of congenital hydrocephalus. RESULTS When PN-3 was inoculated on the 11 th day or 12th day of gestation, all mothers aborted. The hamsters which had been inoculated on the 14th or 15th day of gestation gave birth on the day of term, i.e. the 16th day of gestation. Sixteen offspings (57%) of 28 alive at birth could survive until 13 days of age (Table 1). Three of these survivors, which were born to mother number 5, showed a centroOCCipital prominence of the skull (Fig 1). Macroscopic examination of the brains of these hamsters showed a bulged cerebral hemisphere. The occipital and parietal cortices of these hamster brains looked paper-thin or even membranous. The cerebellar vermis, especially the uvula, was pushed downward and elongated. No enlargement of skull or other abnormal macroscopic findings were detected in the t>rains of offsprings born to the other mothers inoculated with this virus. Histological examination on the brains of these hydrocephalic hamsters revealed marked ventricular dilatation with thinning of the cerebral cortex and the aqueductal forking (Fig 2). DISCUSSION Some experiments have shown that congenital hydrocephalus is caused by maternal myxovirus infection. Kilham [4] and Margolis [5] demonstrated that congenital hydrocephalus was produced in the hamster by intra-amniotic inoculation of mumps or parainfluenza virus type 2 on the 10th to 12th days of pregnat:J.cy. However, congenital hydrocephalus was not produced when they inoculated these viruses intraperitoneally, although the viruses could be recovered from the placenta. These experiments suggested that myxoviruses may not be able to pass through the placenta under the condition of maternal infection. We examined the possible occurrence of congenital hydrocephalus after maternal infection with PIV-3 inoculated intravenously, since most intrauterine virus infections are caused in the condition of severe maternal viremia. This produced congenital hydrocephalus in littermates whose mother had been inoculated with PN-3 into left cervical vein on the 14th day of pregnancy. The physical signs and macroscopic findings of the brain in
Table I Clinical course after maternal intravenous parainj1uenza virus type 3 inoculation and confirmed occurrence of hydrocephalus in livebirth hamsters Mother no 1 2 3 4 5 6 7
Gestational days at maternal inoculation
11 11 11 12
14 14 15
Perinatal "1 Aborted Aborted Aborted Aborted 9 10 9
Postnatal"2 (days) 0-2
3-12
l3-17
No of offsprings with confirmed hydrocephalus" 3 (%)
6 9 7
4 9 3
4 9 3
o ( 0%) o ( 0%)
* 1 : Numbers of livebirth hamsters, *2: Numbers of surviving hamsters, days after birth.
Fig 1 Three 14·day·old suckling hamsters born to mother number 5, and their removed brains in non·hydrocephalic (a) and hydro· cephalic (b and c) hamsters. Note remarkable thinning of the cerebral cortex (arrowheads in c).
these hydrocephalic hamsters bore close similarity to those noticed on the hydrocephalus in the suckling hamster produced by intraperitoneal inoculation of PN-3 [I, 3]. The result thus obtained in this experiment may indicate that a virus inoculated into the cervical vein can arrive in the fetuses after passing through the placenta, and infect the central nervous system. Recently a case of congenital hydrocephalus, which was confIrmed to be caused by a maternal influenza virus infection, was reported [6] . It is not the matter of controversy that most common virus infections usually terminate without clinical manifestations even during
372 Brain & Development, Vol 13, No 5, 1991
3 (33%)
*3: Hydrocephalus was determined by gross evaluation 13-17
Fig 2 Coronal sections at the midthalamus and cerebral aqueduct of non·hydrocephalic (A and a) and hydrocephalic (B and b) brain. Fourteen days after birth. Note the marked ventricular dilatation (B) and the aqueductal forking (b) in hydrocephalic brain. HE stain. A and B: x 7; a and b: x 150.
pregnancy . However, with cases of congenital hydrocephalus of unknown origin, we should make efforts to fInd their microbial pathogens.
ACKNOWLEDGMENTS We are deeply indebted to Dr. M. Matsumoto (National Institute of Health) for providing PIV-3 and anti-PIV-3 hyperimmune serum. This work was supported by the Japanese Ministry for Health and Welfare grant-in-aid for scientific research into "Intractable Hydrocephalus," and by a grant-in-aid for scientific research C. No. 02670435, Ministry of Education, Japan.
REFERENCES 1. Takano T, Ohno M, Yamano T, Shimada M. Experimental hydrocephalus in suckling hamsters induced by parainfluenza virus inoculation (in Japanese). Igaku No Ayumi (Tokyo) 1990;155:525-6. 2. Takano T, Ohno M, Yamano T, Shimada M. Experimental hydrocephalus in suckling hamster induced by parainfluenza infection : I. Pathogenesis of hydrocephalus caused by mumps virus. Cong Anom (Hiroshima). 1991 ;submitted. 3. Takano T, Ohno M, Yamano T, Shimada M. Experimental hydrocephalus in suckling hamster induced by myxovirus infection: H. Pathogenesis of hydrocephalus caused by
parainfluenza virus type 3. Cong Anom (Hiroshima). 1991; submitted. 4. Kilham L, Margolis G. Induction of congenital hydrocephalus in hamsters with attenuated and natural strains of mumps virus. J Infect Dis 1975 ; 132:462-6. 5. Margolis G, Kilham L. Induction of congenital hydrocephalus in hamsters with parainfluenza type 2 virus. Exp Mol Pathol 1977;27 :235-48. 6. Conover P, Roessmann U. Malformational complex in an infant with intrauterine influenza viral infection. Arch Pathol LabMed 1990;114:535-8 .
Takano et al: Congenital hydrocephalus 373
Congenital Hydrocephalus in Suckling Hamsters Caused by Transplacental Infection with Parainfluenza Virus Type 3 Tomoyuki Takano, MD, Masaki Ohno, MD, Tsunekazu Yamano, MD and Morimi Shimada, MD
The possible occu"ence of congenital hydrocephalus by viral infection of the mother was examined by inoculating pregnant hamsters intravenously with parainfluenza virus type 3 (PIV-3). We could produce congenital hydrocephalus in littermates born to a mother which had been inoculated into the left cervical vein on the 14th day of pregnancy. This result may indicate that the virus could pass through the placenta to a"ive at the fetus, and infect the central nervous system. Key words: congenital hydrocephalus, parainfluenza virus type 3, myxovirus, transplacental infection. Takano T, Ohno M, Yamano T, Shimada M Congenital hydrocephalus in suckling hamsters caused by transplacental infection with parainfluenza virus type 3. BrainDev 1991;13:371-3
We have reported that a high frequency of hydrocephalus was caused by the intracerebral or intraperitoneal inoculation of mumps virus or parainfluenza virus type 3 (PIV-3) into the suckling hamster [1-3]. These results suggest that fetal infection with these myxoviruses may cause congenital hydrocephalus. However, it remains unknown whether maternal infection with myxovirus induces fetal infection and subsequently produces congenital hydrocephalus or not. In this experiment, the possible occurrence of congenital hydrocephalus by viral infection of the mother was examined by inoculating PIV-3 intravenously in pregnant hamsters.
From the Department of Pediatrics, Shiga University of Medical Science,Ohtsu. Received for publication : May 9, 1991. Accepted for publication: August 11, 1991. Correspondence address: Dr. Tomoyuki Takano, Department of Pediatrics, Shiga University of Medical Science, Setatsukinowacho, Ohtsu 510-21, Japan.
MATERIALS AND METHODS Female Syrian hamsters of 9-12 weeks of age were mated with breeder males for 24 hours. The day after mating was counted as day 1 of gestation. Seven pregnant hamsters were inoculated with 0.5 ml of 1.0 x 108 pfu (plaque forming unit) / ml of PN -3 into the left cervical vein on either day 11, 12, 14 or 15 of gestation. The brains of offspring born to the mother hamsters thus treated were examined 13 to 17 days after birth to confum the possible occurrence and incidence of congenital hydrocephalus. RESULTS When PN-3 was inoculated on the 11 th day or 12th day of gestation, all mothers aborted. The hamsters which had been inoculated on the 14th or 15th day of gestation gave birth on the day of term, i.e. the 16th day of gestation. Sixteen offspings (57%) of 28 alive at birth could survive until 13 days of age (Table 1). Three of these survivors, which were born to mother number 5, showed a centroOCCipital prominence of the skull (Fig 1). Macroscopic examination of the brains of these hamsters showed a bulged cerebral hemisphere. The occipital and parietal cortices of these hamster brains looked paper-thin or even membranous. The cerebellar vermis, especially the uvula, was pushed downward and elongated. No enlargement of skull or other abnormal macroscopic findings were detected in the t>rains of offsprings born to the other mothers inoculated with this virus. Histological examination on the brains of these hydrocephalic hamsters revealed marked ventricular dilatation with thinning of the cerebral cortex and the aqueductal forking (Fig 2). DISCUSSION Some experiments have shown that congenital hydrocephalus is caused by maternal myxovirus infection. Kilham [4] and Margolis [5] demonstrated that congenital hydrocephalus was produced in the hamster by intra-amniotic inoculation of mumps or parainfluenza virus type 2 on the 10th to 12th days of pregnat:J.cy. However, congenital hydrocephalus was not produced when they inoculated these viruses intraperitoneally, although the viruses could be recovered from the placenta. These experiments suggested that myxoviruses may not be able to pass through the placenta under the condition of maternal infection. We examined the possible occurrence of congenital hydrocephalus after maternal infection with PIV-3 inoculated intravenously, since most intrauterine virus infections are caused in the condition of severe maternal viremia. This produced congenital hydrocephalus in littermates whose mother had been inoculated with PN-3 into left cervical vein on the 14th day of pregnancy. The physical signs and macroscopic findings of the brain in
Table I Clinical course after maternal intravenous parainj1uenza virus type 3 inoculation and confirmed occurrence of hydrocephalus in livebirth hamsters Mother no 1 2 3 4 5 6 7
Gestational days at maternal inoculation
11 11 11 12
14 14 15
Perinatal "1 Aborted Aborted Aborted Aborted 9 10 9
Postnatal"2 (days) 0-2
3-12
l3-17
No of offsprings with confirmed hydrocephalus" 3 (%)
6 9 7
4 9 3
4 9 3
o ( 0%) o ( 0%)
* 1 : Numbers of livebirth hamsters, *2: Numbers of surviving hamsters, days after birth.
Fig 1 Three 14·day·old suckling hamsters born to mother number 5, and their removed brains in non·hydrocephalic (a) and hydro· cephalic (b and c) hamsters. Note remarkable thinning of the cerebral cortex (arrowheads in c).
these hydrocephalic hamsters bore close similarity to those noticed on the hydrocephalus in the suckling hamster produced by intraperitoneal inoculation of PN-3 [I, 3]. The result thus obtained in this experiment may indicate that a virus inoculated into the cervical vein can arrive in the fetuses after passing through the placenta, and infect the central nervous system. Recently a case of congenital hydrocephalus, which was confIrmed to be caused by a maternal influenza virus infection, was reported [6] . It is not the matter of controversy that most common virus infections usually terminate without clinical manifestations even during
372 Brain & Development, Vol 13, No 5, 1991
3 (33%)
*3: Hydrocephalus was determined by gross evaluation 13-17
Fig 2 Coronal sections at the midthalamus and cerebral aqueduct of non·hydrocephalic (A and a) and hydrocephalic (B and b) brain. Fourteen days after birth. Note the marked ventricular dilatation (B) and the aqueductal forking (b) in hydrocephalic brain. HE stain. A and B: x 7; a and b: x 150.
pregnancy . However, with cases of congenital hydrocephalus of unknown origin, we should make efforts to fInd their microbial pathogens.
ACKNOWLEDGMENTS We are deeply indebted to Dr. M. Matsumoto (National Institute of Health) for providing PIV-3 and anti-PIV-3 hyperimmune serum. This work was supported by the Japanese Ministry for Health and Welfare grant-in-aid for scientific research into "Intractable Hydrocephalus," and by a grant-in-aid for scientific research C. No. 02670435, Ministry of Education, Japan.
REFERENCES 1. Takano T, Ohno M, Yamano T, Shimada M. Experimental hydrocephalus in suckling hamsters induced by parainfluenza virus inoculation (in Japanese). Igaku No Ayumi (Tokyo) 1990;155:525-6. 2. Takano T, Ohno M, Yamano T, Shimada M. Experimental hydrocephalus in suckling hamster induced by parainfluenza infection : I. Pathogenesis of hydrocephalus caused by mumps virus. Cong Anom (Hiroshima). 1991 ;submitted. 3. Takano T, Ohno M, Yamano T, Shimada M. Experimental hydrocephalus in suckling hamster induced by myxovirus infection: H. Pathogenesis of hydrocephalus caused by
parainfluenza virus type 3. Cong Anom (Hiroshima). 1991; submitted. 4. Kilham L, Margolis G. Induction of congenital hydrocephalus in hamsters with attenuated and natural strains of mumps virus. J Infect Dis 1975 ; 132:462-6. 5. Margolis G, Kilham L. Induction of congenital hydrocephalus in hamsters with parainfluenza type 2 virus. Exp Mol Pathol 1977;27 :235-48. 6. Conover P, Roessmann U. Malformational complex in an infant with intrauterine influenza viral infection. Arch Pathol LabMed 1990;114:535-8 .
Takano et al: Congenital hydrocephalus 373