摘要:

AbstractThe mechanism responsible for prenatal bowing of long bones was investigated based on the results of morphological observation and biochemical analysis of glycosaminoglycans of the autopsied bone from a newborn patient with classic campomelic dysplasia and the result of an experiment which produced a similar deformity in rat fetuses. An excised bone with postnatal bowing from a patient with osteogenesis imperfecta was also examined for comparison. In the case of campomelic dysplasia, marked hypertrophic change of the cambium layer of the periosteum at the concave side of the bone was noted. Parallel rays of the periosteal bone extended from the concave (posterior) side toward the apex of the bowing at the anterior side. Increased amounts and differences in composition of glycosaminoglycans were found in the diaphyseal bone on the concave side, suggesting the existence of bone with maturity retardation. In contrast, there were no such differences in the case with postnatal bowing and in the control. Congenital bowing of long bone in the patients with multiple malformations such as campomelic dysplasia is probably manifested as early as the cartilaginous model as the experimental result suggested.

ISSN:0040-3709    

DOI:10.1002/tera.1420330102

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1986

数据来源: WILEY

摘要:

AbstractMitochondria prepared from the first growth of cells (fibroblasts) from skin biopsies from homozygous (but not heterozygous) achondroplastic human subjects were unable to carry out oxidative phosphorylation. However, successive crops of cells gained the ability to phosphorylate with normal P:O ratios with pyruvate‐malate and succinate as substrates. Concentrations of cytochromes a + a3were markedly and significantly lower in homogenates of homozygous achondroplastic tissue culture cells than in homogenates of normal cells. Levels of cytochromes a + a3in the heterozygous achondroplastic cells were intermediate between the levels in normal cells and the homozygous achondroplastic cells. Activities of the mitochondrial oxidative systems (NADH, succinic and cytochrome oxidases) were not significantly lower in the achondroplastic cell preparations than in normal cell preparations under standard assay conditions (saturation levels of oxygen

ISSN:0040-3709    

DOI:10.1002/tera.1420330103

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1986

数据来源: WILEY

摘要:

AbstractPregnant CD‐1 mice were administered the n‐butylester of 2,4‐dichlorophenoxyacetic acid (2,4‐D) by gastric intubation on day 11 of gestation at dosages ranging from 0 to 200 mg/kg (2,4‐D content). The immune response in the female offspring was elevated at 6 weeks of age. The humoral immune response, antibody production against sheep red blood cells, was not altered by 2,4‐D ester exposure during gestation. The mitogen responses of lymphocytes induced by concanavalin A, a T‐lymphocyte mitogen, or byEscherichia colilipopolysaccharide, a B‐lymphocyte mitogen, were reduced in the highest exposure group (200 mg/kg), although the T‐lymphocyte suppression was not statistically significant. A similar response pattern was observed in the background nonstimulated lymphocyte cultures, suggesting that the suppression was a generalized lymphocyte abnormality. Evaluation of the mitogen responses using stimulation indices to correct for the variable background responses demonstrated that 2,4‐D produced no net suppressive effect in any of the treatment groups. Since in utero 2,4‐D ester exposure produced no alterations in humoral immunity and only subtle effects on lymphocyte blastogenesis, it is unlikely to be of any immunotoxicological or immunoteratological significance. Further studies investigating commercial‐grade 2,4‐D formulations are necessary since these formulations contain other components that may potentially induce alterat

ISSN:0040-3709    

DOI:10.1002/tera.1420330104

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1986

数据来源: WILEY

摘要:

AbstractThe pharmacokinetics of the antiepileptic drug valproic acid (2‐proply‐pentanoic acid; VPA) and its main active metabolite 2‐en‐VPA (2‐propyl‐2‐pentenoic acid) in mouse serum and gestational material were studied and correlated with the drastic differences between the two compounds in their embryotoxicity. The peak levels of VPA reached after 0.5 hours were only slightly higher than that of 2‐en‐VPA (both in mother and gestational material). The free concentrations of VPA and 2‐en‐VPA in maternal serum also peaked at 0.5 hours. After that time the free maternal serum levels of 2‐en‐VPA decreased much more rapidly than the concentrations in the gestational materials. The area under the concentration/time curves (AUC) values of 2‐en‐VPA in mother and embryo were lower than corresponding values of VPA; the higher clearance of 2‐en‐VPA was predominantly due to an increased volume of distribution. Since we have previously shown that the peak concentrations and not the AUC values of VPA correlated with the teratogenicity of this compound, our present data indicate that the low teratogenic and embryotoxic potential of 2‐en‐VPA is a result of the intrinsic activity of this compound and not of lower peak concen

ISSN:0040-3709    

DOI:10.1002/tera.1420330105

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1986

数据来源: WILEY

摘要:

AbstractGlucocorticoids cause cleft palate in sensitive mouse strains by interfering with the proliferation of mesenchymal cells in the palatal shelves; 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) also causes cleft palate, but its effects involve the epithelial cells. The purpose of this study was to examine the interaction of TCDD and the glucocorticoid hydrocortisone in the induction of malformations. Pregnant C57BL/6N mice were treated on gestation days 10–13 with TCDD (0 or 3 μg/kg, p.o.), hydrocortisone (0, 25, 50, or 100 mg/kg, s.c.) or a combination of TCDD and hydrocortisone. The dams were killed on gestation day 18 and the mice were analyzed for maternal and fetal toxicity and soft tissue malformations. TCDD alone had no effect on litter size, fetal weight or viability, or maternal weight gain. This dose of TCDD is essentially a threshold dose and it did not produce cleft palate in this study, but all the TCDD‐treated fetuses had hydronephrosis, the most sensitive indicator of TCDD teratogenicity. Hydrocortisone alone caused dose‐related decreases in fetal weight and maternal liver/body weight ratios, and dose‐related increases in cleft palate (0, 5, 10, and 30%). No effects of hydrocortisone were detected on litter size or fetal viability, but maternal weights were affected. Combination of all doses of hydrocortisone with TCDD resulted in a 100% incidence of cleft palate, accompanied by a decrease in litter size and fetal weight and an increase in fetal mortality related to the dose of hydrocortisone. TCDD tended to reverse the decrease in liver/body weight ratio seen with hydrocortisone alone. Morphological assessment of the palatal shelves late on gestation day 14 revealed that the embryos exposed to both TCDD and hydrocortisone resembled hydrocortisone alone. The synergism observed between these two teratogens may be due to changes in the receptors which mediate sensitivity to the induction o

ISSN:0040-3709    

DOI:10.1002/tera.1420330106

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1986

数据来源: WILEY

摘要:

AbstractHydrocortisone (30–40 μg on day 10) and triamcinolone (10–20 ng on day 7–8) both inhibit or alter morphogenesis of scales and feathers. However, there are marked temporal and region‐specific differences in the effects induced by these two glucocorticoids. Triamcinolone (TAC) is most teratogenic on day 7 or 8, inhibiting formation of spurs and feathers and inducing club feather formation. Hydrocortisone is most teratogenic later in development, on day 10. Unique hydrocortisone‐induced responses are complete inhibition of scutellate scale formation, bent feathers, and apteria around the external auditory meatus. Altered synthesis of keratin polypeptides follows inhibition of scale morphogenesis by hydrocortisone and TAC. These in vivo data suggest that heterogeneity of glucocorticoid binding occurs in embryonic chick metatarsal skin. Survival data indicate that TAC is 2,000 times more embryotoxic than hydr

ISSN:0040-3709    

DOI:10.1002/tera.1420330107

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1986

数据来源: WILEY

摘要:

AbstractNigericin (Na+salt) was given intraperitoneally at doses of 5.0 or 7.0 mg/kg on one of gestation days 7–12 to pregnant CD‐1 mice. Additional mice were injected ip with 2.5 mg/kg on day 11 or 12 only. Injections on single gestation days reduced fetal growth and increased prenatal deaths. Additional signs of toxicity to the conceptus included treatment‐related extra ribs and delayed ossification. Treatment was also associated with gross and skeletal malformations, such as median facial cleft, exencephaly, encephalocele, fused ribs, and anomalous vertebrae and exoccipitals. With the possible exception of the 5.0 mg/kg dose given on gestation day 8, nigericin doses associated with gross or skeletal malformations also resulted in observable maternal tox

ISSN:0040-3709    

DOI:10.1002/tera.1420330108

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1986

数据来源: WILEY

摘要:

AbstractAn in vivo murine model was developed to measure maternal phenytoin biotransformation along with the covalent binding of phenytoin to fetal tissues in the same fetuses which were assessed for fetal anomalies. Acetaminophen was administered to pregnant CD‐1 mice 1 hour prior to phenytoin, both given i.p. at varying doses and gestational times between days 11 and 13. Dams were killed between days 12 and 19. Metabolites reflecting the enzymatic bioactivation of phenytoin were quantified in maternal plasma and urine with high‐performance liquid chromatography (HPLC). Acetaminophen pretreatment caused a threefold increase in phenytoin‐induced fetal cleft palates without increasing resorptions. The covalent binding of radiolabeled phenytoin to fetal and placental tissues measured on day 13 was increased twofold and threefold, respectively, by acetaminophen pretreatment. Phenytoin covalent binding measured on day 16 was significantly increased in the livers of fetuses with cleft palates, but not in the livers of dams with fetuses having cleft palates. Binding to fetal brain on day 16 was over fourfold higher than that in maternal brain. Acetaminophen pretreatment differentiated dams into poor and extensive metabolisers of phenytoin, with only the latter group carrying fetuses with cleft palates. The incidence of fetal cleft palates correlated positively with maternal urinary levels of phenytoin (r = + .81,P<.01) and its dihydrodiol metabolite (r = + .61, 0.05

ISSN:0040-3709    

DOI:10.1002/tera.1420330109

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1986

数据来源: WILEY

摘要:

AbstractDiabetes mellitus in pregnancy is associated with an increased incidence of various congenital anomalies that occur during organogenesis. Because a well functioning yolk sac is crucial to embryonic growth and development during this period, we performed an ultrastructural study of the effects of excess glucose (total glucose 750 mg/dl, osmolality 305 mOsm/kg) on pregnancy day 10 (Witschi stage 13) rat conceptuses cultured for 48 hr in heat‐inactivated male rat serum with and without added d‐ or l‐glucose. Embryos exposed to excess d‐glucose demonstrated decreased conceptus size (P<0.001), and gross malformations in a dose‐related fashion. The visceral yolk sac capillaries and vitelline vessels of conceptuses in excess d‐glucose were sparse, patchy, and nonuniformly located. Ultrastructurally, the visceral yolk sac endodermal cells had reduced numbers of rough endoplasmic reticulum, ribosomes, and mitochondria. These obvious defects in yolk sac structure suggest that hyperglycemia during organogenesis has a primary deleterious effect on yolk sac function with resultant

ISSN:0040-3709    

DOI:10.1002/tera.1420330110

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1986

数据来源: WILEY

摘要:

AbstractAcetazolamide, a potent and highly specific inhibitor of carbonic anhydrase, is teratogenic in mammalian embryos and when administered during early limb development causes unique limb defects in a time‐ and dose‐dependent manner. The regenerating urodele limb is often considered to be a good experimental analog of limb development and, if it employs the same mechanisms of tissue interactions during pattern formation, should be susceptible to teratogens which selectively disrupt developmental limb patterning. This study demonstrates that while carbonic anhydrase inhibition is toxic to the red‐backed salamander,Plethodon cinereus, it does not have the same teratogenic effect on limb regeneration as seen in mammalian limb development. Several points are considered as to why the regenerating limb, at least in this salamander species, may not be suitable for studying this class of tera

ISSN:0040-3709    

DOI:10.1002/tera.1420330111

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1986

数据来源: WILEY