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Biomedical subjects

M J Wiley

Publications and source records attributed to M J Wiley.

36 records · Page 2Linked to original sources
PubMed1989

Phenytoin embryotoxicity: role of enzymatic bioactivation in a murine embryo culture model.

A murine embryo culture model was developed to study the potential contribution of enzymatic bioactivation to the teratogenicity of phenytoin. To assess the relative embryonic and maternal contributions to bioactivation, embryos were cultured respectively alone or in the presence of an exogenous source of cytochromes P-450 (P-450), which are thought to bioactivate phenytoin to a teratogenic reactive intermediate. Embryological development from gestational day 9 to day 10 was assessed, and bioactivation was quantified by the irreversible binding of radiolabeled phenytoin to embryonic protein. Embryos cultured with phenytoin and an exogenous P-450 bioactivating system showed a significant decrease in the incidence of turning and closure of the anterior neuropore, yolk sac diameter, and protein content as well as growth retardation. In the absence of an exogenous P-450 system, phenytoin did not decrease the incidence of turning or anterior neuropore closure but did cause growth retardation and a lesser but significant reduction in yolk sac diameter and embryonic protein content. An exogenous P-450 system enhanced the bioactivation of phenytoin, although significant activity also was detectable in embryos cultured without an exogenous bioactivating system. These results suggest that the embryo itself can enzymatically bioactivate embryotoxically significant amounts of phenytoin, and that bioactivation and embryotoxicity can be further enhanced, qualitatively and quantitatively, by an exogenous P-450 system, implicating a possible maternal contribution to phenytoin teratogenicity.

Animals↗
PubMed1989

The distribution of cell surface glycoconjugates during mouse secondary neurulation.

During secondary neurulation in the mouse, the neural tube develops from the tail bud by caudal extension of the primary neurocoele. The mesenchymal cells of the tail bud become radially arranged around the neurocoele and undergo a mesenchymal to epithelial transformation to form a neuroepithelium. In order to study the expression of glycoconjugates during the morphogenesis of the secondary neural tube, 14 lectins were applied to serial sections of tail buds at various stages of development. In general, binding was fairly homogeneous during the early stages of tail bud development. However, as development progressed, several lectins became localized to specific structures. The changes were observed to parallel the ongoing development of the secondary neuraxis. sWGA, which is N-acetylglucosamine (GlcNAc) specific, bound mainly to the luminal surface of the secondary neurocoele and to a lesser extent, the notochord. WGA, which has both GlcNAc and sialic acid specificities, showed most intense binding at the luminal and abluminal surfaces of the secondary neurocoele. Binding by the lectin PNA was restricted to the extracellular matrix around the developing secondary neural tube. A comparison of the lectin binding patterns in mouse with those previously reported in chick, demonstrates a less elaborate pattern of lectin binding in murine embryos. This may suggest a less complex expression of glycoconjugates in rodents, in keeping with their comparatively simpler mechanism of secondary neurulation.

Animals↗
PubMed1988

A comparative study of the effects of retinoic acid given during the critical period for inducing spina bifida in mice and hamsters.

Spina bifida occurred in the offspring of golden Syrian hamsters treated on day 8 of gestation, and CD-1 mice treated on day 9, with 80 mg/kg of retinoic acid. Light microscopic examination of term fetuses demonstrated that myeloschisis was the characteristic form of the defect in mice, whereas myelocystocele was the predominant type of spina bifida induced in the hamster. To investigate the pathogenesis of these defects, a comparative study was undertaken by light microscopy and scanning electron microscopy of the changes occurring in caudal embryonic tissues during the initial 48 hr following maternal treatment. Within 18 hr of exposure, similar effects were observed in both species. These included distortion of the neural folds at the level of the posterior neuropore, vascular damage and hematoma formation, malformation of the notochord, and abnormalities of secondary neurulation. No differences were observed that we thought could account for the apparent variation in the pattern of malformations seen in the term litters. Rather, the dissimilarity may reflect species differences in the position of the posterior neuropore in the neuraxis and in the extent to which secondary neurulation contributes to the development of the lumbosacral cord segments.

Animals↗
PubMed1987

Early stages of development in the caudal neural tube of the golden Syrian hamster (Mesocricetus auratus).

Secondary neurulation is the morphogenetic process whereby the caudal segments of the neural tube are derived from cells in the embryonic tail bud. Comparative studies have demonstrated similar characteristics in the mechanism of secondary neurulation among tailless species, which are thought to be due to the evolutionary reduction in tail length (Hughes and Freeman, 1974). In order to explore this hypothesis further, light and scanning electron microscopy was used to study early stages of neurulation in the tail buds of hamster embryos. The golden Syrian hamster is a relatively common laboratory rodent with a reduced tail. In this species, secondary neurulation first became apparent in embryos with approximately 17 pairs of somites. This was well before closure of the posterior neuropore which occurred at the 21-somite stage. The lumen of the neural tube appeared to extend into the tail bud in an even and progressive fashion accompanied by reorientation and rearrangement of tail-bud cells. The mechanism appeared to be similar to that reported in long-tailed rodents.

Animals↗
PubMed1985

Prenatal hamster development following maternal administration of PGE2 at midterm.

The effects of PGE2 on embryonic and fetal development were studied in the golden Syrian hamster. Pregnant hamsters were treated on day 8 of gestation with either 0.2, 0.5, 0.75, or 1.0 mg/kg PGE2 delivered I.P. and the near term litters were compared to those of untreated and vehicle treated controls. Fetuses from the treated litters showed significantly higher frequencies of mortality, lower weights, malformations, and missing ossification centres in comparison to control litters. The results demonstrate that PGE2 is teratogenic in the hamster and the developing neural tube and the fetal skeleton are particularly susceptible to the effects of this teratogen.

Abnormalities, Drug-Induced↗
PubMed1984

Revascularization of skin transplanted into the brain: source of the graft endothelium.

Transplantation of tissues into the brain is becoming a feasible therapeutic approach to some neurological diseases. The fate of the graft vasculature is not well understood. The purpose of the present study was to determine the source of the endothelium in the revascularized skin grafts transplanted into the brain. We hypothesized that if the skin endothelium were replaced by brain endothelium then we should observe in the grafts the following: degenerating endothelium soon after grafting, regenerating endothelium subsequently, a time course for reestablishment of circulation that is consistent with the time required for vessel growth and invasion, and doubling of the vascular basement membrane a few weeks later. We found only a few degenerating endothelial cells soon after transplantation and no evidence of regenerating endothelium or of double layers of basement membrane even after prolonged survival. The vessels within mature grafts had morphological characteristics typical of normal skin vessels. We concluded that when tissue fragments are transplanted to the brain, native graft vessels survive and anastomose with host vessels.

Animals↗
PubMed1984

Bladder exstrophy: penile lengthening procedure.

A review of bladder exstrophy experience at our institution was undertaken with reference to penile adequacy and intersymphyseal distance. Drift of the symphysis apart even with iliac osteotomy was noted to occur within two years of initial closure but remained stable after three years. This drift can be prevented if the sacral tuberous and sacral spinous ligaments are sectioned. Further, the adequacy of the phallus seems to depend directly on the intersymphyseal distance. Thus, we suggest a variation in the staged approach to bladder exstrophy repair with these facts in mind.

Age Factors↗
PubMed1983

The pathogenesis of retinoic acid-induced vertebral abnormalities in golden Syrian hamster fetuses.

Administration of single doses of retinoic acid to hamsters on days 7, 8, and 9 of pregnancy resulted in missing, irregular, and abnormally fused centers of ossification in the vertebrae of fetuses recovered near term. A study of early events in embryonic tissues following maternal treatment with 60 mg/kg of the teratogen on day 8 revealed a variety of changes which could be linked to the development of the bony defects. By 12 hours following treatment, the mean number of somites in teratogen-exposed embryos was significantly reduced in comparison to controls. Within 24 hours of maternal treatment, lesions were observed in the aortae of the retinoic acid-exposed embryos. The vessels were consistently damaged caudally with dissection of aortic contents into the adjacent unsegmented mesoderm. Kinking of the neural tube, notochordal irregularities, and a loss of intercellular relationships in the paraxial mesoderm accompanied the vascular lesions. By 36 hours following treatment, abnormalities were evident in the appearance of the caudal somites, and at later stages these appeared to translate into defects in the sclerotomes and subsequently, the vertebrae. The observations suggest that vascular damage plays a significant role in the induction of the vertebral defects by disrupting somitogenesis. Moreover, the results support the hypothesis that retinoic acid produces abnormalities in the vertebral skeleton by a mechanism different from that which has been suggested to operate in the induction of defects in the limb skeleton.

Abnormalities, Drug-Induced↗
PubMed1983

Effects of retinoic acid on the development of the facial skeleton in hamsters: early changes involving cranial neural crest cells.

Treatment of gravid hamsters with 60/mg of retinoic acid on the 8th day of pregnancy resulted in facial skeleton defects in 100% of the survivors examined by alizarin staining at term. An investigation of the early stages in the development of these malformations indicated that the teratogen induced delayed and disorganized patterns of cranial neural crest cell migration as well as extensive death and damage of crest cells. The results demonstrate that retinoic acid provides a useful tool for studies in the pathogenesis of facial skeletal abnormalities in vivo. Moreover, the extensive defects seen in the teratogen-treated litters at term, together with the results of the microscopical analyses, support the hypothesis that cranial neural crest cells make an important contribution to the development of the mammalian facial skeleton.

Animals↗
PubMed1982

Inhibition of beta-aminopropionitrile (beta APN)-induced skeletal teratogenesis by the flavonoid beta-hydroxyethylrutosides (HR) in hamster fetuses.

Since biochemical studies have shown that flavonoids such as beta-hydroxyethylrutosides (HR) protect against the damage to collagen induced by lathyrogens in adult rats, this compound was given to pregnant hamsters in order to determine its effects on the teratogenicity induced by beta-aminopropionitrile (beta APN). A dose of 2,500 mg/kg of beta APN alone given by gavage on day 11 produced a high frequency (69.5%) of skeletal anomalies in the offspring of hamsters. Administration of HR immediately following beta APN to pregnant animals resulted in a significantly decreased teratogenic response (P less than 0.05). These data provide evidence to support the view that the primary mechanism for the beta APN-induced skeletal dysmorphogenesis is the inhibition of cross linking during the maturation of collagen fibers.

Abnormalities, Drug-Induced↗
PubMed1981

Structural and histochemical features of the avian blood-brain barrier.

We have investigated the structural and histochemical features of the blood-brain barrier (b-bb) in both adults and embryos of chicken (Gallus domesticus, White Leghorn) and quail (Corturnix coturnix japonica). We found that brain endothelial cells of both species are characterized structurally by tight junctions, a low density of pinocytotic vesicles, and a moderately elevated density of mitochondria. Both alkaline phosphatase and butyryl cholinesterase were found in adult quail brain capillaries, but only alkaline phosphatase was found in adult chick brain capillaries. Aromatic amino acid decarboxylase was not found in brain capillaries of either species. In the chick embryo alkaline phosphatase appeared during the time when b-bb matures functionally; i.e., during the third week of development. However, an elevation in mitochondrial density was not apparent until after hatching. In the quail, alkaline phosphatase and butyryl cholinesterase appeared during the last week of embryonic development. By 2 days posthatching the structural characteristics of the brain capillaries were similar to those in the adult.

Alkaline Phosphatase↗
PubMed1980

Retinoic acid-induced heart malformations in the hamster.

In order to determine the effect of retinoic acid on the developing mammalian heart, pregnant golden Syrian hamsters were given single doses of 80 mg/kg of the teratogen by gavage, at various times in gestation. Examination of the surface features of hearts from near-term fetuses was followed by microdissection to reveal internal cardiac structures. This has proven to give more reliable results than other methods of determining congenital heart malformation. The results of the study demonstrate that retinoic acid is a potent cardiac teratogen capable of inducing high frequencies of heart abnormalities in a reproducible fashion. The highest rates of malformation resulted from maternal treatment on day 7 (69%), 8 (74%), and 9 (30%) of gestation. Ventriculo-bulbar malformations including double outlet right ventricle, complete transposition, and an overriding aorta complex were the most commonly seen abnormalities. The findings support the hypothesis that these abnormalities are not entirely discrete entities but are instead part of a single spectrum of malformation.

Animals↗
PubMed1980

The effects of cytochalasins on the ultrastructure of neurulating hamster embryos in vivo.

Single intraperitoneal injections of cytochalasin B (CB) in dimethylsulfoxide were given to gravid Syrian hamsters on the eighth day of pregnancy at various dose levels. Exencephaly and encephalocele, the only defects which were seen in the term litters, occurred in dose-response patterns reaching peak frequencies of 14.9% and 53.2%, respectively, at the highest dose level, while accompanied by a mortality of 27.7% of implantations. Although these abnormalities were the same as those resulting from cytochalasin D (CD) treatment at this time, the frequencies were lower and the distribution of defects somewhat different. Morphological comparison of embryos fixed at various times after maternal treatment with 7.0 mg/kg CB or 1.5 mg/kg CD demonstrated qualitatively similar changes in response to either teratogen, leading to failure of the cranial neural folds to approximate and close. The principal ultrastructural changes involved alterations in the topography of the apical membranes of neuroectoderm cells. At doses which produced high frequencies of gross defects in the term litters, no changes were seen in the apical bundles of microfilaments in these cells, although much higher dose levels did disrupt these structures. The results support the hypothesis that the cell membrane is the primary target of these teratogens in vivo.

Abnormalities, Drug-Induced↗
PubMed1978

The morphogenesis of beta-aminopropionitrile-induced rib malformation in fetal golden Syrian hamsters.

In order to provide information on the mechanism of beta-aminopropionitrile (betaapn) induced teratogenesis, the pathogenesis of a fetal rib abnormality was studied at relatively short time intervals following maternal treatment with 2,500 mg/kg aqueous betaapn on day 11 of gestation. Histochemical tests of ribs from betaapn-exposed fetuses indicated a slight decrease in the level of glycosaminoglycans but at a time when the defect was already morphologically established. Ultrastructural observations on the chondrocytes of ribs from betaapn-exposed fetuses revealed alterations in mitochondrial structure indicative of a slight cytotoxic effect for the teratogen. The mitochondrial changes were transient, occurring initially at three hours after treatment and lasting for nine hours. Alterations in the size of collagen fibres in the cartilage of the fetal rib were also observed in the offspring of betaapn treated females. The mean diameter of collagen fibres in the ribs of control fetuses increased throughout the course of the study. The mean diameter of fibres in the fetuses of betaapn-exposed females failed to show any increase and was found to be significantly less than controls as early as three hours following maternal administration. The results suggested that the principal factor in the production of the fetal rib deformity was fundamentally the same as that known to affect the adult; namely a defect in the extracellular maturation of collagen.

Abnormalities, Drug-Induced↗
PubMed1978

Neural tube lesions in the offspring of hamsters given single oral doses of lathyrogens early in gestation.

The lathyrogens aminoacetonitrile, D-penicillamine and semicarbazide were tested for their teratogenicity in hamster on day 7 of gestation at three different dose levels. The results showed that aminoacetonitrile and penicillamine were typical teratogens in hamsters, capable of causing significant embryotoxic effects consisting of increased fetal mortality, growth retardation and malformation. Semicarbazide at a dose of 100 mg/kg had only minor teratogenic effects, while slightly higher doses were lethal to the dams. The most severe fetal malformations following maternal exposure to aminoacetonitrile or penicillamine were exencephaly and encephalocele. Since lathyrogens inhibit the process of collagen cross-linking, the results of this study indicate that there may be an important relationship between collagen fiber formation in the embryo and neural tube closure.

Abnormalities, Drug-Induced↗
PubMed1976

The teratogenic effects of beta-aminopropionitrile in hamsters.

The teratogenicity of beta-aminopropionitrile (beta APN) was evaluated in golden Syrian hamsters; single doses of 1250, 2500, and 3750 mg/kg given on days 7-13 produced fetal mortality, growth retardation and malformations. All time-dose combinations produced gross external abnormalities with the highest rate (92.5%) occurring following day-12 treatment. High frequencies of skeletal abnormalities including deformities of the ribs, fibula, and scapula occurred after days-10-12 treatment. Deformed ribs occurred in 100% of fetuses exposed on day 11 to any of the dosages. The types of abnormality generally resembled those produced by lathyrogens in other species except for exencephaly and encephalocele, which occurred after treatment on day 7. These results indicate that betaAPN is a typical teratogen, capable of producing abnormalities of the central nervous system early in gestation, and may reflect a broader mechanism for its activity than previously suggested.

Abnormalities, Drug-Induced↗