ABSTRACT Cyclopia, the paradigmatic “face [that] predicts the brain” in severe holoprosencephaly (HPE) (DeMyer et al., 1964), has been recognized since ancient times. Descriptive embryologists and pathologists have noted the continuum of defective separation of the forebrain and loss of central nervous system (CNS) mid-line structures for more than a century. It has been recognized more recently that inhibitors of cholesterol biosynthesis, whether consumed in native plants by range sheep, or experimentally applied to early embryos, could pheno-copy the natural malformation, as could a variety of other teratogens (maternal diabetes, alcohol). Yet it has been less than a decade that the genomic knowledge base and powerful analytic methods have brought the sciences of descriptive, molecular, and genetic embryology within range of each other. In this review, we discuss the clinical presentations and pathogenesis of HPE. We will outline various genetic and teratogenic mechanisms leading to HPE. Lastly, we will attempt to examine the pivotal role of cholesterol and the Sonic Hedgehog (Shh) pathway in this disorder and in normal embryonic forebrain development.
ABSTRACT Molecular pathogenesis of human cerebral malformations is briefly reviewed from a neuro-pathologic viewpoint, with emphasis on holoprosencephaly and neuronal migration disorders. Immunopathologic approaches are useful in elucidating the essential pathomechanism of these anomalies. In alobar holoprosencephaly, for instance, immunostaining for glial fibrillary acidic protein clarifies the pathologic significance of the leptomeningeal glioneuronal heterotopia along the ventral prosencephalic surface. In type 1 lissencephaly and subcortical laminar heterotopia, immunohistochemistry for the causative gene products revealed the temporal and spatial pattern of their localization in the normally developing cerebrum, as well as their reduction in these disorders.
ABSTRACT Infants of epileptic women treated with valproic acid (VPA) during pregnancy have a higher risk of developing spina bifid a than those of the general population. VPA induces exencephaly in experimental animal embryos. But the pathogenetic mechanism remains rather elusive. Antiepileptic drugs (AED) in general accentuate pregnancy-imposed fall in maternal folate levels. Periconceptional folic acid supplementation is reported to protect embryos from developing neural tube defects (NTD). Conflicting results have been reported by experimental studies that attempted to alleviate VPA-induced NTD by folic acid. Our objectives were to determine the critical developmental stages and an effective dose of folic acid for the prevention of VPA-induced exencephaly in mouse fetuses. A single teratogenic dose of 400 mg/kg of VPA was administered to TO mice on gestation day (GD) 7 or 8. It was followed by (1) a single dose of 12 mg/kg of FA (folinic acid) or (2) 3 doses of FA 4 mg/kg each. In experiment (3), FA (4 mg/kg) was administered thrice daily starting on GD 5 and continued through GD 10. These animals received VPA on GD 7 or 8. VPA and B12 concentrations were determined by radioimmunoassay. The single heavy dose of FA had no rescue effect on NTD. Three divided doses of FA on GD 7 and continuous dosing of FA from GD 5 through GD 10 substantially reduced the VPA-induced exencephaly in the fetuses. In the later experiments, the neural folds elevated faster than the non-supplemented group. VPA considerably reduced maternal plasma folate and B12 concentrations. The heavy dose of FA only moderately improved vitamin levels. Three divided doses of FA elevated the vitamin levels slightly better but it was the prolonged dosing of FA that was associated with sustained elevation of plasma levels higher than the control levels and acceleration of neural tube closure thus accounting for the pronounced protection against VPA-induced NTD development. These data suggest that plasma levels of FA and B12 have to be kept substantially elevated and maintained high throughout organogenesis period to protect embryos against VPA-induced NTD in this mouse model.
ABSTRACT Pregnant ICR mice were given 20% ethanol intraperitoneally twice on day 13 of gestation and allowed to give birth to offspring. The offspring were killed at 56 days of age and the motor root of their facial nerve was examined histologically and morphometrically. The cross-sectional area of the facial nerve of mice prenatally exposed to ethanol was significantly smaller than that of the control mice. There was no significant difference in the total number of myelinated axons or the mean axonal diameter between control and ethanol-exposed mice, but the mean diameter of myelinated fibers (axon + myelin sheath) and the thickness of myelin sheath were significantly decreased in the treated group. These results suggest that prenatal exposure to ethanol disturbs myelination of the motor root of the facial nerve and may cause permanent neurological effects.
ABSTRACT Effects of stimulation of the maternal immune system on abnormal pregnancy induced with 5-azacytidine (5ACDR) administration at embryonic day 7.5 (E7.5) were examined in mice treated with recombi-nant interleukin 1β (IL-1β) at E6.5 (5ACDR + IL-1 at E6.5) or E9.5 (5ACDR+IL-1 at E9.5), OK432 (5ACDR + OK432) at E7.5 or PSK (5ACDR+PSK) at E7.5. Embryos from these dams were examined at E13.5. The frequency of dead and malformed embryos and number of malformations on each embryo increased in the 5ACDR + IL-1 at E6.5 groups compared with the 5ACDR-alone group. Adverse pregnancy outcomes in the 5ACDR + OK432 and 5ACDR + PSK groups were less frequent than in the 5ACDR-alone group. The frequency of exencephaly, facial cleft, eye anomalies (micro- or anophthalmos), and micrognathia significantly increased in the 5ACDR + IL-1 groups, in contrast, that of exencephaly decreased in the 5ACDR + OK432 and 5ACDR + PSK groups compared with the 5ACDR-alone group. The phagocytes on the exencephalic surface drastically increased in the 5ACDR + IL-1 groups, and they often appeared to ingest the migrating neuroepithelial cells. Such findings, however, were rarely observed in the 5ACDR-alone, 5ACDR + OK432 and 5ACDR + PSK groups. Thus, administration of IL-1β to the abnormal pregnant dams increased the mortality and severity of the malformations in the embryos caused by 5ACDR, whereas PSK or OK432 decreased them. These results suggest that the different modes of activation of the maternal immune system may exert alternative or opposite effects on teratogenic pregnancy.
ABSTRACT To evaluate the role of vitamin B12 on spermatogenesis, the effects of dietary vitamin B12 deficiency on sperm maturation in developing rat fetuses and young growing rats were examined. The vitamin B12-defi-cient diet was given to all the animals for three different periods: whole period (gestation to mature), gestation period (gestation to weaning), or immature period (3–12 weeks postnatal). Sperm examination revealed that the sperm count was markedly lower in male progeny (F1) that were vitamin B12-deficient during the whole period. In addition, a significantly higher number of abnormal sperm, such as tailless and amorphous sperm, was observed. In male rats that were vitamin B12-deficient during the immature period, the incidence of abnormal sperms was 14.4% and 4.8% for tailless and short tail, respectively. The motion rates, such as path velocity and straight line velocity, were decreased to 20–40% of the control value in rats that were vitamin B12-deficient both during the whole and gestation periods. However, no effects of vitamin B12 deficiency on sperm motility were observed during the immature and mature periods. From these findings, we suggest that dietary vitamin B12 deficiency during pregnancy may induce irreversible damage in the germ cells of embryos and affect the maturation of spermatozoa.
ABSTRACT A new mutation was identified in the PD (Preaxial Duplication) strain of rats, the main manifestations of which were curly and sparse vibrissae with retarded outer hair growth. As the main characteristic of this mutant rat is abnormally curled appearance of the vibrissae, “curly vibrissae” is proposed as the name of this mutant gene, and “cv” as its symbol. Genetic analyses reveal that the mutant characteristics are inherited as autosomal recessive traits and the cv gene is independent from the pd gene that carried by the original PD colony. The cv/cv homozygous rats have a small number of short and/or curly vibrissae around the nose. The vibrissae on the cheek and/or above the eyes are also short and curled; however, no vibrissa appears on the lower mandible. Although hair growth seems to be retarded, the outer hairs showed nearly normal length by 10 weeks of age. The outer hairs of matured cv/cv rats appear silky and translucent. The adult mutant rats often exhibit loss of hair on the head and/or back. Lactating females usually lose their abdominal hair. Both sexes of cv/cv homozygotes have normal reproductive ability. No internal malformations accompany vibrissa and hair abnormalities.
ABSTRACT We experienced five pregnancy cases with type I congenital cystic adenomatoid malformation (CCAM) of fetuses and summarized here their clinical characteristics, pregnancy outcomes, and fetal therapies. Four of five cases were prenatally diagnosed using magnetic resonance imaging (MRI) as having lung abnormality, and the remaining case was prenatally diagnosed as having congenital diaphragmatic herniation (CDH). One fetus underwent the puncture of cysts in the lung, and two fetuses received in utero thoracoshunts between cysts and the amniotic fluid cavity (thoracoamniotic shunt). One pregnancy ended in artificial termination at 17 gestational weeks, and 4 pregnancies succeeded in live births. All these 4 infants underwent surgical operations for CCAM, and 1 infant underwent an additional operation for CDH. The MRI examinations were useful to prenatally identify CCAM, and the in utero thoracoamniotic shunt appears to be beneficial in preventing lung hypoplasia in the affected fetuses.
ABSTRACT Renal agenesis (RA) appears to be a multifactorial condition with combined genetic and environmental influences. We performed a retrospective case-control study of reproductive history of 26 isolated RA live births cases referred to Sicilian Registry of Congenital Malformations. A statistical significant association for birth weight if we considered all RA together and for bilateral RA alone, an increasing risk for maternal age only in the bilateral RA subgroup and a male predominance both for unilateral and bilateral RA was found. Our results show that some reproductive risk factors may be associated with RA, moreover differences found between subgroups indicate that some risk factors may be different in unilateral and bilateral RA. The association between reproductive risk factors and RA may reflect pathogenetic interaction between genetic and environmental factors. Nevertheless further studies are needed to clarify these associations and to explore the role of perinatal factors in the etiology of renal agenesis. In fact if prenatal or perinatal risk factors are in a causal chain influencing the risk for developing RA, then these data could have important implications in the prevention or treatment of this condition.