摘要:

AbstractThe purpose of this study was to examine the toxicokinetics of embryo uptake following exposure to a variety of chemically related phenols in rat embryo culture. The uptake of nine radiolabeled para‐substituted phenols by day 10(9–13 somite stage) rat embryos in vitro was determined from 1 to 42 hrs after being placed in culture media containing various phenols. Uptake was rapid, having a half‐life of 3 hr or less, with 7 of the nine compounds having uptake half‐times of less than one hour. The equilibrium concentration in the embryo ranged from 53 to 136% of the media concentration, indicating only a factor of 2 in maximum discrimination against the compound for any of the phenols studied. The fraction of radioactivity remaining unbound in the media decreased with increasing logP(octanol/water partition coefficient). The binding was calculated to be 50% for logP= 1.77 from the fitted regression equation and decreased by a factor of 5.9 for every decade increase inP.When hepatocytes were also present in the media the equilibrium concentration in the embryos was less than when hepatocytes were absent. With the limited data, four of the phenols appeared to have no (i.e., zero) equilibrium level when hepatocytes were present. Thus the metabolites produced by the hepatocytes appeared to have less affinity for the embryo than the parent phenol. Toxicodynamic information as given by the effective concentration of the phenol in the embryo to cause somite or tail teratological effects was best predicted by the measured unbound fraction. © 1993 Wiley‐Liss, Inc.This article is a US Government work and, as such, is in the public domain in the United States

ISSN:0040-3709    

DOI:10.1002/tera.1420480402

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

年代:1993

数据来源: WILEY

摘要:

AbstractWe have tested the potential of a single dose of ethanol (0.20ml 50% ethanol in chick Ringer's saline (CRS) administered into the air sac) to produce ventricular septal defect (VSD) in three distinct commercially available strains of White Leghorn chick embryo: stress‐resistant Dekalb Delta strain, Hy‐Vac SPF type V, and Hy‐Vac SPF type L. Eggs were controlled for both size and developmental stage (Hamburger‐Hamilton stage 18–19) at time of injection. The frequency of VSD in Dekalb Delta embryos was 4.0% (1/25), in Hy‐Vac SPF type L embryos 9.1% (3/33), and in Hy‐Vac SPF type V embryos 38.9% (14/36). Statistical analysis with the two‐tailed Fisher Exact Test indicated that frequencies were not significantly different (P= 0.3215) when Dekalb Delta and Hy‐Vac type L embryos were compared. However, the frequency of VSD for Hy‐Vac type V embryos was significantly greater than that for either the Dekalb Delta or the Hy‐Vac type L embryos (P<0.005). All VSDs observed were located within the crista supraventricularis. When Hy‐Vac SPF type V embryos were exposed to either 0.20 ml 50% ethanol in CRS or to 0.20 ml CRS (controls), ethanol‐treated embryos showed a VSD incidence of 34.1% compared with a 3.6% incidence in the controls (P= 0.0017). These data suggest that ethanol is the cause of VSD in this strain. From the results of this study, we are led to conclude that different commercial strains of White Leghorn chick embryo show different susceptibilities to the induction of VSD by ethano

ISSN:0040-3709    

DOI:10.1002/tera.1420480403

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

年代:1993

数据来源: WILEY

摘要:

AbstractVisual impairment is one of the most common ophthalmic abnormalities in fetal alcohol syndrome. Pathologic changes in optic nerve development related to alcohol consumption could be involved in this dysfunction. In order to assess the consequences of pre‐ and postnatal exposure to alcohol on the developing optic nerve, we administered an ethanol‐containing liquid diet (5% w/v) before and during gestation and throughout lactation to rats and their offspring. A group of control animals were kept on a pair‐fed isocaloric diet. The optic nerves were obtained at key stages from fetuses (21 days of gestation) and pups (4, 7, 14, 21 and 28 postnatal days). Samples of the optic nerve cross‐section, behind the eyeball, were processed for analysis of gliogenesis, myelinogenesis, axonal growth, and remodelling events, using light and electron microscopy. Qualitative, morphometric, and immunocytochemical analyses, alternatively using anti‐GFAP and anti‐MBP antibodies, were carried out. Optic nerve cross‐sections from prenatal and postnatal alcohol‐exposed rats showed a decrease in size. Ultrastructural alterations and retarded development in macroglial cells, optic axons, and myelin sheath were also observed. The most prominent abnormalities were: damage of cytoplasmic organelles and disorganization of cytoskeleton in astrocytes; a decrease in free ribosome density and nuclear membrane inclusions in oligodendrocytes; and fragmentation of lamellae, aberrant myelin sheaths and intralamellar inclusions in myelin. These findings suggest that alcohol abuse during pregnancy is teratogenic to the optic nerve and closely related to the altered visual function. © 1993

ISSN:0040-3709    

DOI:10.1002/tera.1420480404

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

年代:1993

数据来源: WILEY

摘要:

AbstractA population‐based and validated data set of 195 cases with isolated terminal transverse‐type congenital limb deficiency was evaluated in Hungary, 1975–1984. Terminal transverse types of congenital limb deficiency are not usually associated with non‐limb defects, and typically only one limb is affected. Upper limb is more frequently affected than lower (9:1) in monomelic cases. The left side and females are affected more often in upper limbs while lower limb defects are evenly distributed between right and left sides and both sexes. Familial occurrence was not found. © 1993 Wiley

ISSN:0040-3709    

DOI:10.1002/tera.1420480405

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

年代:1993

数据来源: WILEY

ISSN:0040-3709    

DOI:10.1002/tera.1420480406

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

年代:1993

数据来源: WILEY

摘要:

AbstractMurine embryonal carcinoma cells have been used in in vitro models to study the effects of cadmium chloride on proliferation and differentiation of early embryonic cells. This approach allows the various cell types within the early embryo as well as several developmental mechanisms to be dissected and studied in isolation using larger numbers of cells than would be readily available from the embryo itself. The present study shows that both embryonal carcinoma cell proliferation and differentiation into parietal endoderm are inhibited by cadmium chloride. The effects are counteracted by the additional presence of zinc chloride. The uptake of cadmium into the cells is inhibited in the presence of zinc chloride, suggesting that competition between these metals for passage into the cells contributes to the mechanism underlying the protective effect of zinc. In addition, metallothionein gene expression is enhanced more rapidly after simultaneous incubation with zinc chloride, indicating that the attenuating effect of zinc on cadmium toxicity is also partly attributable to detoxification by metallothioneins. © 1993 Wiley‐Liss, I

ISSN:0040-3709    

DOI:10.1002/tera.1420480407

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

年代:1993

数据来源: WILEY

摘要:

AbstractA micro‐fiberoptic methodology has been developed for noninvasive, real time measurement of endogenous pyridine nucleotide fluorescence from the surface of the visceral yolk sac (VYS) in intact, viable rat conceptuses. Gestational day (GD) 10–12 conceptuses are maintained in a customized perifusion system, which allows for control of oxygenation, as well as the continuous measurement of pH and oxygen concentration in the effluent perifusate. Miniaturized light guides were constructed by drawing 250 μm ESKA acrylic optical fibers through a stainless steel sheath with a high strength epoxy polymer. A single fiber supplied the excitation signal from a mercury arc lamp at a wavelength of 366 nm. The emission signal was returned via three additional fibers, electronically amplified, processed, and recorded, using a dual channel lamp‐compensated fluorometer, optimized for detection of reduced pyridine nucleotides at 455 nm. Endogenous fluorescence in the conceptus was monitored by placing the polished tip of the sensor directly on the surface of the VYS. Oxygen‐equilibrated conceptuses, exposed to 100% nitrogen, produced a reproducible biphasic surface fluorescence peak, which returned to baseline levels upon reoxygenation of the perifusate. This biphasic response consisted of an initial rapid rise in fluorescence (phase I), followed by an attenuated rate in fluorescence signal increase (phase II). The hypoxia produced age‐dependent rates of fluorescence change during phase I, while phase II remained relatively unchanged throughout GD 10–12. These results demonstrate the ability to monitor endogenous fluorescence, non‐invasively and in real time, during the period of organogenesis in the intact rat conceptus and will provide valuable information in studies of embryonic metabolism and response to chemical embryotoxicants. © 1993

ISSN:0040-3709    

DOI:10.1002/tera.1420480408

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

年代:1993

数据来源: WILEY

摘要:

AbstractCell‐cycle analysis of nuclei obtained from the circulating erythroblasts (gestational day [GD] 11–16), livers (GD 14–19), and whole embryos (GD 10–13) or remaining (extrahepatic) tissues (GD 14–16) of rat embryos/fetuses revealed age‐ and tissue‐dependent variations in the relative percentages of cells in the G0/G1, S, and G2/M phases of the cell cycle. With development, the rate of cell proliferation declined resulting in decreases in the relative percentage of S‐phase cells and increases in the G0/G1percentage, while the percentage of G2/M‐phase cells remained relatively constant. Comparing tissue cell‐cycle profiles during development, erythroblasts exhibited the most rapid age‐dependent decline in S‐phase percentage (from 75% at GD 11 to 8% by GD 14), embryos/extrahepatic tissues exhibited a more gradual reduction (from 55% at GD 10 to 14% by GD 15), while the hepatic isolates exhibited a relatively constant S‐phase percentage of approximately 40% from GD 14 to GD 18 before decreasing to 23% at GD 19. These age‐dependent variations suggest that cellcycle distribution may be useful in staging embryogenesis and in detecting abnormal development.To determine how these developmental and organ‐specific cell‐cycle variations affect toxic response, we sampled GD 11–13 embryos 6 hr after maternal administration of a teratogenic dose of 5‐fluorouracil (5‐FU), a thymidylate synthetase inhibitor that induces S‐phase accumulation. The results indicate that, on a relative basis, the amount of induced S‐phase accumulation in erythroblasts and whole embryos 6 hr postdosing increased with development. In contrast, a time course of hepatic cell‐cycle distributions from GD 14 embryos after maternal dosing revealed that S‐phase accumulations occurred at an earlier time, possibly as a consequence of a higher proliferative rate. These findings suggest that the extent of observed toxicant‐induced cell‐cycle perturbations depends on gestational age, tissue type, and the time of sampling. © 1993 Wiley‐Liss, Inc.This article is a US Government work and, as such, is

ISSN:0040-3709    

DOI:10.1002/tera.1420480409

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

年代:1993

数据来源: WILEY

摘要:

AbstractGemcitabine was given intravenously to female mice on gestation days (GD) 6–15 at doses of 0, 0.05, 0.25, or 1.5 mg/kg/day (0, 0.15, 0.75, or 4.5 mg/m2/day, respectively). Animals assigned to the teratology segment (25/group) were killed on GD 18 for examination of maternal hematologic parameters and organ weights, as well as fetal viability, weights, and morphology. The postnatal segment females (20/group) were allowed to deliver, and offspring physical, behavioral, and reproductive parameters were monitored. After offspring weaning, these dams were killed for hematologic and organ weight evaluations. At necropsy, 3 days after the final dose, the teratology segment dams showed dose‐related increases in spleen and thymus weights. These changes were accompanied by a dose‐related decrease in leukocytes and modest increases in mean corpuscular volume (MCV) and hemoglobin (MCH) at the two higher doses. On postpartum day (PPD) 21, the dams in the postnatal segment showed no treatment‐related effects on these organ weights or hematologic parameters, indicating recovery of these maternal parameters within 3.5 weeks following termination of treatment. The decreases in maternal body weight and food consumption observed during gestation, and in liver and uterine weights at term in the 1.5 mg/kg/day group, were considered to be secondary to a high rate of prenatal mortality, evidenced by increased resorptions in the teratology segment and decreased live litter size in both segments of the study. Additional indications of developmental toxicity in this dose group were an increased incidence of malformations, primarily cleft palate, decreased fetal weights in the teratology segment, and decreased neonatal survival in the postnatal segment. Other indications of offspring toxicity were decreased startle amplitude in the 0.05 and 1.5 mg/kg/day treatment‐derived males, and decreased ovarian weights in all F1females compared to controls. However, offspring growth, appearance of physical landmarks, F1activity levels, active and passive avoidance, and reproductive performance were not affected adversely in the surviving offspring of the 1.5 mg/kg/day treatment‐derived group or in mice from either of the two lower dose groups. These results indicate that maternal effects related to the antiproliferative actions of gemcitabine may be detected at doses below those which result in overt developmental toxicity, i.e., malformations, weight changes, and decreased prenatal and neonatal survival. © 1993 Wil

ISSN:0040-3709    

DOI:10.1002/tera.1420480410

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

年代:1993

数据来源: WILEY

摘要:

AbstractA new mouse mutant, tail short variable (Tsv) produces a reduction deformity of the tail, growth retardation, and, in adults, a mild anemia. Genetic and embryological studies show that on all genetic backgrounds there is variable viability ofTsv/TsvandTsv/+ and phenotypic overlap within these and with +/+. A modifier is located to a short segment of chromosome 7, which alters the tail length ofTsv/+ mice up to 15%. The modifier,Tsv, and a coat texture mutant come from the same wild Peru mouse. The tail deformity is associated with, and may be caused by, a vascular disruption of the caudal aorta starting on day 11 of gestation. ThusTsvappears to be different from each of the thirty known mouse mutants involving the tail. It is suggested thatTsvcould be a mouse model for human conditions involving transverse terminal limb defects such as Moebius and de Lange syndromes. © 1993 Wiley‐Liss, I

ISSN:0040-3709    

DOI:10.1002/tera.1420480411

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

年代:1993

数据来源: WILEY