摘要:

AbstractPregnant C57B1/6J mice were treated with single oral doses of 400 mg/kg 13‐cis retinoic acid (RA, isotretinoin, Accutane) in sesame oil at 9 days, 12 hours postfertilization. Among the live 16‐day fetuses from ten treated mothers, 46% (26/56) had limb malformations including small fifth digits, preaxial and/or postaxial oligodactyly, and preaxial or postaxial polydactyly. Fetuses with preaxial digit deficiencies also had absent or malformed radii. Scanning electron microscopic and light microscopic analyses of the sequence of developmental alterations leading to these malformations demonstrated abnormalities in the apical ectodermal ridge (AER). Excessive cell death in the AER of 27–30 somite enbryos (12 hours after treatment) appears to play a major role in the pathogenesis of the limb malformations observed. Previous investigations of retinoid‐induced limb malformations have concentrated on later exposure times. Evidence from this study in addition to that from previous teratologic and clinical investigations has led to the hypothesis that 13‐cis RA results in excessive cell death in regions of programmed cell death and subsequent malformations of affecte

ISSN:0040-3709    

DOI:10.1002/tera.1420370602

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

年代:1988

数据来源: WILEY

摘要:

AbstractBendectin, composed of doxylamine succinate and pyridoxine HCl (1:1), is an antinauseant previously prescribed for nausea and vomiting during pregnancy. The present study examined the maternal and developmental effects of Bendectin (0, 200, 500, or 800 mg/kg/day, po) administered to timed‐pregnant CD rats (36–41/group) during organogenesis (gestational days [gd] 6–15). At death (gd 20), all live fetuses were examined for external, visceral, and skeletal abnormalities. At 500 and 800 mg/kg/day, maternal toxicity included reduced food consumption during treatment and for the gestation period, increased water consumption in the posttreatment period, reduced weight gain during treatment, and sedation; water consumption was reduced during treatment and for the gestation period, and maternal mortality (17.1%) was observed only at the high dose. Developmental toxicity included reduced prenatal viability (800 mg/kg/day) and reduced fetal body weight/litter (500 and 800 mg/kg/day). In addition, reduced ossification of metacarpals (800 mg/kg/day), phalanges of the forelimbs (500 and 800 mg/kg/day), and of caudal vertebral centra (all doses) was observed. No increase in percent malformed live fetuses/litter was observed. The proportion of litters with one or more malformed fetuses was higher than vehicle controls only at 800 mg/kg/day, with short 13th rib (to which the test species is predisposed) as the predominant observation. By contrast, a positive control agent (nitrofen, 50 mg/kg/day, po, 14 dams) produced 85% malformed fetuses/litter with the predominant malformation being diaphragmatic hernia. In conclusion, the incidence of litters with one or more malformed fetuses was increased only at a dose of Bendectin which produced maternal mortality (17.1%) and other indices of maternal and developmental toxicity (see Discus

ISSN:0040-3709    

DOI:10.1002/tera.1420370603

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

年代:1988

数据来源: WILEY

摘要:

AbstractThe fungicide dinocap is currently used in the control of powdery mildew. We have reported that dinocap is teratogenic in the CD‐1 mouse, causing cleft palate, otolith defects, and fetal weight deficits well below maternotoxic dose levels. In this study the maternal and fetal toxicity of dinocap was determined in the Sprague‐Dawley rat and Syrian golden hamster, and adult‐to‐developmental (A/D) toxicity ratios were calculated and compared with the previously established A/D ratio of dinocap in the mouse. Dinocap in corn oil was admisnistered by gavage to pregnant rats on gestation days 7–20 (0, 100, 150, 200 mg/kg/day) and to hamsters on gestation days 7–14 (0, 12.5, 25, 50, 75, 100, 200 mg/kg/day). Dams were killed on day 21 (rat) or day 15 (hamster), and litters were removed, counted, and weighed; half of each litter was necropsied for soft tissue defects, and the remaining half was processed for skeletal examination. In the rat, maternal extrauterine weight gain was significantly affected at 150 and 200 mg/kg/ day, relative liver weight was elevated at 100 mg/kg/day and above, and fetal weight was lower at 150 and 200 mg/kg/day. In the hamster, maternal extrauterine weight was lower at 12.5 mg/kg/day and above; fetal weight was reduced, and the incidence of dilated renal pelvis was higher, at 25 mg/kg/day and above. Thus the A/D ratios for dinocap in the rat and hamster are similar, approximately 1. Our previous studies have demonstrated that dinocap is teratogenic in the mouse, with an A/D ratio in the range of 8–16 in this species. The basis for the species‐specific teratogenicity and inconsistent A/D ratio of din

ISSN:0040-3709    

DOI:10.1002/tera.1420370604

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

年代:1988

数据来源: WILEY

摘要:

AbstractEthanol was orally administered once per week to 54 gravid pigtailed macaques (Macaca nemestrina) in doses of 0.0, 0.3, 0.6, 1.2, 1.8, 2.5 or 4.1 gm/kg from the 1st week in gestation or in doses of 2.5, 3.3, or 4.1 gm/kg from the 5th week. Mean maternal mean peak plasma ethanol concentrations (MPPEC) ranged from 24 ± 6 mg/dl at the 0.3 gm/kg dose to 549 ± 71 mg/dl at the 4.1 gm/kg dose. Thirty‐three viable infants were followed from birth to 6 months of age and assessed for growth, health, congenital anomalies and developmental rate. Facial anomalies, growth deficiency, or central nervous system dysfunction were found in 57% of the alcohol‐exposed animals. No animal showed all the features of the human fetal alcohol syndrome. Ten of the twelve animals (83%) with mean MPPEC above 140 mg/dl had evidence of a teratogenic impact. The animals with full gestational exposure to ethanol and mean MPPEC between 140 and 249 mg/dl had much more severe and consistent cognitive abnormalities than the animals with delayed gestational exposures, even though the latter were exposed to mean MPPEC between 260 and 540 mg/dl. Conclusions from this study included: 1) ethanol‐related behavioral teratogenesis occurred without accompanying physical anomalies, 2) measurable teratogenic effects fromweeklyexposures occurred only at intoxicating doses of ethanol, and 3) early gestational exposure to ethanol appeared to be more damaging to cognitive function than later and considerably greater alcohol e

ISSN:0040-3709    

DOI:10.1002/tera.1420370605

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

年代:1988

数据来源: WILEY

摘要:

AbstractThe nature and frequency of a developmental variation of the diaphragm and liver in Fischer 344 rats are described. Totals of 20, 98 and 55 (25 for caesarean‐sectioning and 30 for natural delivery) mated female rats were used for Experiments 1, 2, and 3, respectively. Each rat was intubated (gavage) with either an aqueous suspension of 0.2% METHOCEL®, 0.25% methyl cellulose, or distilled water as a single daily dose from days 6 through 15 (inclusive) of gestation. On the 20th day of gestation, a caesarean‐section was performed, and the uterine contents of each rat were examined. A gross necropsy was performed on the pups of 30 mated female rats on day 21 postpartum. The visceral examinations conducted on these fetuses and pups included an evaluation of a developmental variation in the diaphragm and liver. The variation consisted of a thin fibrous central tendon of the diaphragm with an area of liver (0.5–3 mm diameter) that protruded within the thin central tendon of the diaphragm. The incidence (mean % of fetuses affected per litter) of the diaphragm/liver developmental variation was 9% and 11% for METHOCEL®‐ and water‐treated groups, respectively. A thin central tendon was present in the diaphragm of all fetuses of methyl cellulose‐treated dams; these fetuses did not have a raised area of the liver present within the diaphragm's central tendon. However, in a few weaned pups of the Fischer 344 rats in this study, liver protruded within the central tendon of the diaphragm. The incidence of the diaphragm/liver developmental variation differed with the vehicles used, and it has never been observed in the Sprague‐Dawley or Wistar rat fetuses

ISSN:0040-3709    

DOI:10.1002/tera.1420370606

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

年代:1988

数据来源: WILEY

摘要:

AbstractValproic acid (VPA), cytochalasin D (CD) and 7–hydroxy–2–acetylaminofluorene (7–OH–AAF) each caused abnormal closure of the anterior neuropore in rat embryos cultured in vitro in the absence of an exogenous bioactivation system. Morphological comparisons showed that although all three compounds prevented normal neural tube closure, each did so in a distinctive manner. Modulation of GSH in cultured rat conceptuses was evaluated to determine whether common responses occurred relative to the ability of different chemicals to elicit neural tube defects. Malformation incidence in embryos (10–14 somites) varied widely following exposure to CD (44%), 7–OH–AAF (29%) or VPA (17%). The incidence of CD‐elicited malformations was increased by 50% following GSH depletion by L‐buthionine‐S, R‐sulfoximine (BSO) and was decreased by nearly 60% when the cysteine pro‐drug 2–oxothiazolidine–4–carboxylate (OTC) was added to the culture medium. GSH modulation also exerted significant effects on the incidence of abnormal neurulation caused by VPA or 7–OH–AAF. A relatively low incidence of open neural tubes produced by VPA or 7–OH–AAF alone was shown to be a function of the state of maturation in the embryos. Conceptuses cultured in the presence of VPA or 7–OH–AAF from an earlier gestational age (6–10 somites) showed 2–3 fold increases in the number of embryos with open neural tubes. Differential alterations in protein and DNA content were observed among embryos and yolk sacs after various treatments indicating possible differences in the site of embryotoxicity. These results demonstrate the role of GSH status on the capacity of three chemically diverse compounds to elicit abnormal neurulation in cultured rat embryos and suggest some possible mechanisms

ISSN:0040-3709    

DOI:10.1002/tera.1420370607

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

年代:1988

数据来源: WILEY

摘要:

AbstractCellular aspects of vertical development of the secondary palate were examined in control and 6‐mercaptopurine (6MP)‐treated hamster embryos. Cross‐sectional area of the palatal shelf was measured and the numbers of both epithelial and mesenchymal cells counted. Also, in 6MP‐treated palates the damaged mesenchymal cells, characterized by the presence of dense bodies, were counted. DNA synthesis in both control and treated fetuses was measured by3H‐thymidine incorporation. The results indicated that both the shelf area and cell numbers increased with age in control and 6MP‐treated palates. However, in controls the mesenchymal cell density and DNA synthesis showed two peaks that were absent following 6MP treatment. Unlike controls, in treated embryos the damage to mesenchymal cells became increasingly pronounced between days 10:00 and 10:12 but subsided by day 11:00 of gestation. It is suggested that a major force in the development of the initial primordia and early vertical development of the palatal shelf may be provided by a spurt of DNA synthesis in the mesenchymal cells resulting in their increased number. After 6MP treatment, depression of DNA synthesis and consequent reduction in the mesenchymal cell number and density followed by cell damage lead to retardation in the vertical development of the pala

ISSN:0040-3709    

DOI:10.1002/tera.1420370608

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

年代:1988

数据来源: WILEY

摘要:

AbstractFemale mice (strain: “Heiligenberger Stamm”) were irradiated with neutrons (7 Me V) or X‐rays when embryos were at the early zygote stage; uterine contents were examined on gestation day 19 for prenatal mortality and malformed fetuses. For both radiation qualities, the dose dependent survival curve fitted well to a simple exponential equation; the neutron relative biological efficiency (RBE) value was 2.3. The major fraction of deaths induced by exposure to neutrons or X‐rays occurred before implantation. Aside from dead embryos, malformed fetuses were observed 19 days p.c. (postconception). The number of malformed fetuses increased with a linear‐quadratic function of neutron or X‐ray dose. Malformations were mainly gastroschisis, although omphaloceles and anencephalies were also observed. The neutron RBE value for the induction of malformations varied from 2.0 to 2.8 in the dose range tested. Except after 75‐cGy neutrons, no significant increase in the proportion of stunted or skeletally malformed fetuses was noted. Our results indicated that the reaction of preimplantation embryos to irradiation could be more complex than the simple “all‐or‐none” respo

ISSN:0040-3709    

DOI:10.1002/tera.1420370609

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

年代:1988

数据来源: WILEY

ISSN:0040-3709    

DOI:10.1002/tera.1420370610

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

年代:1988

数据来源: WILEY

ISSN:0040-3709    

DOI:10.1002/tera.1420370611

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

年代:1988

数据来源: WILEY