ABSTRACT A few important aspects when considering the etiology and pathogenesis of congenital anomalies are reviewed and discussed using examples related to morphogenesis of the head and craniofacial structures. Namely, the network and cascade of gene functions, modification by environmental or exogenous factors, and morphogenetic characteristics (epigenetic events) of each body part as the result of a genetic program.
ABSTRACT With a large number of epileptic women being in the childbearing age group, complications of pregnancy in epileptic patients are of concern. Epileptic women are treated with antiepileptic drugs (AED) whether they are pregnant or not. Contrary to prevailing opinion, recent data suggest that epilepsy per se contributes significantly to birth defects possibly because of the same genetic susceptibility that predisposes to epilepsy. Many of these defects closely resemble those attributed to exposure to AED. The syndromes attributed to various AED also considerably overlap with each other. Valproic acid (VPA) induces several minor and major malformations. The relative risk for spina bifida in VPA exposed pregnancies is nearly 20 times higher than that for the general population and about 10 times higher than that attributed to other anticonvulsants. Fetuses of experimental animals treated with VPA during pregnancy exhibit exencephaly unlike the human offspring in whom VPA induces spina bifida. The cranial and spinal malformations observed in humans and laboratory animals indicate that VPA has a preferentially deleterious effect on the neural crest. Several AEDs including VPA tend to lower maternal plasma folate levels. In view of the beneficial effects of periconceptional folate supplementation in prevention of neural tube defects (NTD), future research should be directed at the role of folate in the possible alleviation of VPA-induced NTD. It is also necessary to continue prospective studies to monitor the old and new AED prescribed and to evaluate the role of interactions between drugs used in combinations.
ABSTRACT In detecting changes of the occurrence of birth malformation it is important to indicate the prevalence of environmental hazards. The Tottori Monitoring System for Birth Defects (TOM) is a small regional system covering 6,000 births yearly which was started in 1974. The system is made up mainly of two projects: a monitoring system for reporting congenital malformation and an epidemiological and genetic study for neuro-developmental and genetic disorders. The former system has changed its sampling procedure four times during the past 26 years because of the difficulty in getting cooperation from local administrations and from all maternity clinics in the Tottori prefecture. We have compared those four changes in the system with the following criteria: availability, reliability, durability, operationality and confidentiality. Our conclusion is that the population-based system which received positive support from the administration and almost all obstetricians in the field was the best in quality. On the other hand, the hospital-based system organized by a small group of pediatricians and obstetricians who belong to core hospitals in the field was a simpler but useful system for maintaining durability, operationality and confidentiality. It is, however, important to note that the data collected by the hospital-based system showed a relatively lower frequency in serious malformations like anencephaly and non-emergency malformations like syndactylia as compared with those collected by the population-based system. If an inter-regional collaboration among the similar local systems in Japan could be set-up, a useful network could be developed eventually acting as an ideal population-based system.
ABSTRACT Immunolocalization of proliferating cell nuclear antigen (PCNA), epidermal growth factor (EGF) and EGF receptor (EGFR) in the kidney of fetal rats from uninephrectomized mothers were examined. As the index of proliferative activity, PCNA positive cell ratios in glomeruli and proximal tubules were determined. In the fetuses from uninephrectomized mothers and sham-operated mothers, the PCNA positive cells were seen predominantly in the nephrogenic zone of the kidney. On fetal day 22, the PCNA positive cell ratio in the glomerulus of the fetus from uninephrectomized mothers (E fetus) was significantly lower than that in the glomerulus of the fetus from sham-operated ones (C fetus). The proximal tubular cells showed positive reaction to EGF and EGFR antibodies in both fetuses. On fetal day 22, the reactions of the proximal tubules to EGF and EGFR antibodies were stronger in E fetus than in C fetus.
These results indicate that maternal uninephrectomy causes decreased proliferative activity of the glomerulus and increased reactions of the proximal tubules to EGF and EGFR antibodies in fetal rat kidney, suggesting accelerated development of the kidney.
ABSTRACT Apert syndrome, one of craniosynostosis syndromes caused by allelic mutations of fibroblast growth factor receptor 2 (FGFR2), is characterized by symmetrical bony syndactyly of the hands and the feet. With the mutation analysis on FGFR2 gene from eight Japanese patients with Apert syndrome, two common mutations in the seven patients, 3 cases of Ser252Trp and 4 cases of Pro253Arg were detected. In the remaining patient with an atypical phenotype of the syndrome, however, no mutations were found in the regions of the FGFR2 gene responsible for Apert syndrome and other cranio-synostosis syndromes. In this study, the correspondence with paternal age and genotype-phenotype correlation was not clarified. Further analysis including mass screening is necessary to discuss those correspondences in the Japanese patients associated with Apert syndrome.
ABSTRACT 2,4-Dichlorophenoxyacetic acid (2,4-D) a plant growth regulator, has been used worldwide as an herbicide. The phenoxyacetic acid herbicides contain both 2,4-D and 2,4,5-Trichlorophenoxyacetic acid (2,4,5-T) along with emulsifiers, solvents and contaminants; these have been recognized as teratogen in the rat and mouse. Although the high teratogenicity of phenoxyacetic herbicides has been attributed to the 2,4,5-T and the contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the possibility that 2,4-D might play a role has not been clearly ruled out We designed this study to evaluate the effects of pure 2,4-D, and herein describe the precise fetal visceral malformations. We randomly distributed pregnant Wistar rats in to three main groups according to organogenesis during which pure 2,4-D was administered at different doses: l)-over all organogenesis (gestational days 6 to 15), 2)-early organogenesis (gestational days 6 to 10), and 3)-late organogenesis (gestational days 11 to 15). We found that the pure 2,4-D is maternally toxic and has a dose-related embryolethality. The visceral malformations induced in the fetuses included ureteric dilatations and hydronephrosis, as reported, in conjunction with the herbicide forms. In addition, we observed an association with renal and urogenital aplasia, which were observed in the early organogenesis period. We performed a histopatho-logical examination and discussed the mechanism of the pathological processes. We conclude that the pure 2,4-D itself is maternally toxic and embryolethal, and potential inducer of kidney and urogenital malformations in the rat. The types of kidney and urogenital malformations seen indicated that the 2,4-D interferes in the early developmental stage of the urogenital system.