ISSN:0040-3709    

DOI:10.1002/tera.1420510611

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

年代:1995

数据来源: WILEY

摘要:

AbstractPath (Ph)mice, whose platelet‐derived growth factor receptor alpha subunit (αPDGFR) gene has been deleted, have been used to elucidate requirements for αPDGFR for normal murine development. In this report we evaluate the role of αPDGFR in cardiovascular development by using in situ hybridization to follow the changing pattern of αPDGFR expression in cardiovascular tissues after embryonic day 13, and comparing this pattern with the pattern of cardiovascular defects observed in homozygousPhmutants. Both mesodermally derived and neural crest‐derived components of the cardiovascular system are severely dysmorphic inPh/Phembryos and those structures most severely affected are those that normally express αPDGFR mRNA at the highest levels and for the longest duration.Ph/Phvessels appear to be lined with a normal endothelium, but contain a reduced number of smooth muscle cells and are fragile during processing for histology. The myocardium is thin, the heart is small and dysmorphic, the valves are malformed, and the interventricular and interatrial septa of the heart are defective. In the outflow tract, the spectrum of defects includes both persistent truncus arteriosus and double outlet right ventricle. This pattern of abnormalities is consistent with the hypothesis that deletion of αPDGFR results in a functional ablation of cranial neural crest cells, and that mesodermally derived components of the vascular system also require αPDGFR. © 1995 Wile

ISSN:0040-3709    

DOI:10.1002/tera.1420510602

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

年代:1995

数据来源: WILEY

摘要:

AbstractPrevious developmental and reproductive toxicity studies conducted in rats with Losartan, a potent AT1subtype selective angiotensin ll receptor antagonist, noted treatment‐related effects on the pups of dams treated beyond the second trimester through lactation, as demonstrated by increases in pre‐ and postweaning pup deaths and decreased pup body weight [Spence et al. (1995) Teratology51: 000–000]. The studies presented here were designed to define the critical period for the induction of neonatal toxicity and to examine the effects of Losartan on Kidney development when the drug is administered to the dam beyond the second trimester through lactation. In a developmental toxicity study with postweaning evalution, pregnant rats were administered 5, 20, and 100, mg Losartan/kg/day on gestation days 6 through 15 (GD 6–15). There were no adverse effects on the F1generation as assessed by mortality, clinical signs, weight gain, external examinations, developmental signs, behavioral tests, and gross or microscopic examination of the kidney. In a fostering/cross‐fostering study, pregnant rats were administered 100 mg Losartan/kg/day on GD 15 through lactation day 20 (LD 20)Following delivery, pups from dams treated with Losartan were fostered to control dams, pups from control dams were fostered to Losartan‐treated dams, and pups were also fostered to dams within the same group. Maternal exposure to Losartan during lactation increased the incidence of pup deaths on postnatal days 1–3 (PND 1–3), caused decreased pup weights on PND 7, and decreased performance in the auditory startle test in females and increased performance on the second swim maze test in males, relative to controls. Maternal exposure to Losartan during gestation was associated with decreased pup weight on PND 21 and effects observed on male performance in the swim maze test. Treatment during gestation was also associated with decreased pup cardiac weight as well as drug‐induced histopathological changes of the kidneys from F1 pups, including medial hypertrophy of intracortical arterioles and dilatation of the renal pelvis. While the cardiac and renal vascular effects disappeared with time, significant renal lesions were still evident by PND 90. In a late‐gestation/lactation study with renal evaluation, pregnant rats were administered 0. 5, 1. 0, 5. 0, 20, and 100 mg Losartan/kg/day on GD 15‐LD 20. maternal toxicity was evident as decreased body weight gain in the 100 mg Losartan/kg/day group. Developmental toxicity was also evident in the 100 mg/kg/day group as decreased pup weights and histopathological kidney changes (dilatation of the renal pelvis, edema of the renal papilla, medial hypertrophy of intracortical arterioles, and chronic renal inflammation and irregular scarring of the renal parenchyma). Combined, these studies demonstrated that the critical period for Losartan‐induced development toxicity (decreased pup weights and increased pup mortality) is GD 15‐LD 20, while the critical period for Losartan‐induced kidney lesions is GD 15‐20. The relevance of these findings to the development of the renin/angiotensin system in rats is disc

ISSN:0040-3709    

DOI:10.1002/tera.1420510603

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

年代:1995

数据来源: WILEY

摘要:

AbstractLosartan, an AT1‐selective angiotensin ll receptor antagonist, was evaluated in female rats for effects on fertility reproduction, and perinatal and postnatal development. In a range‐finding study, pregnant rats were treated orally from gestation days 6–17 (GD 6–17) with doses of 25, 75, 150, 225, and 300 mg Losartan/kg/day. There were treatment‐related decreases in maternal body weight gain, slight treatment‐related decreases in hemoglobin concentration, and slight treatment‐related increases in serum urea nitrogen in the 225 and 300 mg/kg/day groups. In a fertility study, female rats were treated for 15 days prior to mating, during mating, and GD 0–19 with doses of 25, 100, and 300 mg Losartan/kg/day. The initial dose of 300 mg/kg/day was lowered to 200 mg/kg/day at the start of mating due to excessive body weight loss during the premating treatment interval. There were no treatment‐related effects on reproductive performance, mating, or fertility indices in the F0generation. There was no evidence of treatment‐related or dose‐related fetal malformationsHowever, decreased F1pup body weights were observed in all drug‐treated groups. In the 100 and 300/200 mg/kg/day groups there were treatment‐related increases in F1pup mortality and alterations in the pattern of postweaning body weight gains. There was also a delay in developmental signs in the 100 and 300/200 mg/kg/day groups, which were likely secondary to the decreased weight of the pups in these groups. In a development toxicity study, pregnent rat were administered 50, 100, and 200 mg Lasartan/kg/day on GD 6–17 There was no evidence of developmental toxicity in any dose group. Maternal toxicity was evident in the 200 mg/kg/day group as a treatment‐related decrease in body weight gain during gestation. In a late‐gestation/location study pregnant rats were administered 10, 25, and 100 mg Losartan/kg/day on GD 15 through lactation day (LD 20). There were treatment‐related decreases in maternal body weight gain during gestation and lactation in the 100 mg/kg/day groups. Decreased pup weight were noted in all dose groups, and pre‐ and postweaning pup deaths were observed in the high dose group which were comparable to those observed in the female fertility study. The lack of fetal body weight effects at 100 mg Losartan/kg/day in the developmental toxicity study, with treatment ending on GD 17, indicates that adverse effects observed in the F1generation in the fertility and late‐gestation/lactation studies were due to exposure during late gestation and/or lactation. Similarities between the developmental and reproductive toxicity of Losarton and angiotensin‐converting enzyme inhibitor

ISSN:0040-3709    

DOI:10.1002/tera.1420510604

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

年代:1995

数据来源: WILEY

摘要:

AbstractThis study was designed to examine the developmental dose response for all‐trans retinoic acid (TRA) administered at presomite stages in mouse embryos. Previous studies using hamsters [Shenefelt (1972) Teratology5: 103‐118] have shown that developmental stages corresponding to those present early on gestational day (GD) 7 in mice are most sensitive to retinoid‐induced teratogenesis. Our preliminary studies showed that at this treatment time, gavage dosages of 7. 5 mg/kg maternal body weight administered to C57B1/6N mice, an inbred strain, resulted in severe craniofacial malformations representing the holoprosencephaly, aprosencephaly spectrum. Additionally, in an outbred mouse strain, CD‐1, exencephaly was induced by dosages of 2. 5 mg/kg TRA and above. Readily detectable abnormalities of the eyes, including anophthalmia and severe microphthalmia and iridial colobomata, were induced by even lower doses of TRA in the C57B1/6N strain. Incidences of micro/anophthalmia were 6. 7%, 8. 1%, 12. 9% and 32. 4% at 0, 0. 313, 0. 625, and 1. 25 mg/kg, respectively. The dosages required to induce significant incidences of exencephaly (2. 5 mg/kg) and severe ocular abnormalities (125 mg/kg) on GD 7 in mice are approximately 50‐100‐fold less than those that are commonly used to examine the teratogenicity of this compound at later developmental stages in this species. The trend toward an increase in the incidence of severe ocular malformations at the lowest dose examined and the fact that subtle ocular malformations were not taken into account for this study suggest that even lower dosages may be effective. Practical implications of this study include (1) the obvious need to conduct threshold dose determination studies at the most sensitive developmental stage in a sensitive strain/species, and (2) the need for careful surveillance of human populations for brain and ocular malformations (not necessarily those falling within the realm of retinoic acid embryopathy) following retinoid exposure during early stages of pregnancy. © 1995 Wil

ISSN:0040-3709    

DOI:10.1002/tera.1420510605

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

年代:1995

数据来源: WILEY

摘要:

AbstractOur objective in the present study was to determine the effects of alcohol on stages when the limb buds and renal primordia develop in the TO mouse and to see if aspirin pretreatment would prevent these organ systems from being malformed as was shown by Randall et al. ('91) in the C57 mice. On one of days 9‐12 of gestation, groups of TO mice were injected intraperitoneally (IP) with a single dose of 200 mg/kg of aspirin, or a proportionate volume of physiological saline. An hour later, half of the aspirin‐treated animals received a single dose of 0. 03 ml/g of freshly prepared 25% (v/v) solution of absolute alcohol and the other half received a proportionate volume of saline. Half of the saline‐treated animals received a single dose of 0.3 ml/g of saline or a proportionate volume of alcohol solution. All animals were killed on day 18 of gestation. Alcohol significantly increased embryonic resorption and caused remarkable intrauterine growth retardation (IUGR). It also induced arched palate, cleft palate and deformities of the digits with haematomas in a modest number of embryos. Aspirin alone did not have teratogenic effects. Pretreatment with aspirin significantly augmented alcohol‐induced resorption, IUGR, cleft palate and digital malformations associated with haematomas. Chronological observations on the development of the treated limbs showed the occurrence of vascular stasis, haematomas, edema and cell death at early stages. Subsequently, digital rays were either destroyed (ectrodactyly) or remained hypoplastic (brachydactyly). It appears that limb development in the aspirin‐ and alcohol‐treated TO mouse embryos is largely affected by vascular disruption. These data provide further evidence to our earlier observation that alcohol and aspirin interact in the production of malformations and that the teratogenic effects of alcohol in the TO mouse are possibly not mediated via treatment related prostaglandin elevation. © 1995 Wil

ISSN:0040-3709    

DOI:10.1002/tera.1420510606

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

年代:1995

数据来源: WILEY

摘要:

AbstractN‐acetoxy‐2‐acetlylaminofluorene(N‐Ac‐AAF) is an alkylating agent that forms DNA adducts at C‐8 is guanine and causes single strand breaks. It has abnormal development have not been investigated. Previous studies have indicated that other DNA alkylating agents cause cell death during embryonic development although the types of cell death were not characterized. Using a whole embryo culture system, gestation day 10 rat embryo were exposed to several concentrations (5, 50 and 200 μg/ml)of N‐Ac‐AAF at several times points after expire was begun (5,10,24 hours), the embryos were removed from culture from culture and examined to identify location, type and quantity of cell death, relative to programmed cell death observed in control embryos. Vital staining with Nile blue sulphate revealed that the location of N‐Ac‐AAf‐ include cell death included the forebrain region, tail and areas of programmed cell death Examination of tissue section from both control and treated embryos indicated that the location of apoptotic cell death revealed by in situ DNA nick end ‐labelling was generally consistent with the cell death pattern observed by vital staining of whole embryos. Agarose gel analyses indicated that all concentration of N‐Ac‐AAF caused DNA fragmentation, and Quantification demonstrated a dose response. Examination of treated embryos (50 and 200μg/ ml) by transmission electron microscopy revealed that, by 5 hours after exposure, cells with class, ultrastructural features of apoptosis were present. In conclusion, multiple method have all indicated that, regardless of exposure level, apoptosis was the predominant from of cell death. Because opotosis also occurs in developmental cell death, it is possible that apotosis induced by N‐Ac‐AAF is due to an alternation in cell fate via premature or ectopic induced of the cell deat

ISSN:0040-3709    

DOI:10.1002/tera.1420510607

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

年代:1995

数据来源: WILEY

摘要:

AbstractFor topographical analysis of developing embryos, investigators typically rely on scanning electron microcopy (SEM) to provide the surface details not attainable with light microscopySEM is an expensive and time consuming technique, however, and the preparation procedure may alter morphology and leave the specimen friable. We report that by using a high‐resolution compound epilfluorescence microscope with inexpensive low‐power objectives and the flurochrome acridine orange, we were able to obtain surface image of fixed or fresh whole rat embryos and fetal palates of considerably greater topographical detail than those obtained using routine light microscopy. Indeed the resulting high‐resolution image offered not only superior qualitative documentation of morphological observation, but the capability for detailed morphometry via digitization and computer‐assisted image analysis. © 1995 Wiley

ISSN:0040-3709    

DOI:10.1002/tera.1420510608

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

年代:1995

数据来源: WILEY

摘要:

AbstractExposure of the human of the fetus to physician‐prescribed diethylstilbestrol and other synthetic estrogens (collectively referred to as “DES”) led to an important iatrogenic epidemic In the United States alone, at least four million fetuses and their mother had a substantial exposed these estrogens now known to be mild carcinogens and potent teratogens. Mothers exposed to DES may have a somewhat higher risk of breast cancer than women who were not exposed. The sequelae of in utero exposure of daughters include clear cell adenocarcinoma of the vagina and cervix, various gross anomalies of the genital tract that are associated with adverse outcomes of pregnancy, vaginal adenosis and other vaginal epithelial changes, and other possible health effects that have not yet been fully evaluated. Among sons exposed in utero to DES, no increase in the incidence of any cancer has been reported, but several anomalies of the genital tract have been described, and it is possible that some social behaviors are modified Although the grandchildren of the DES‐exposed daughters and sons have not been shown to have any abnormalities, some of them have been the products of short gestations. Future research, being funded by the National Cancer Institute, will permit monitoring of the DES‐exposed population to dertermine whether any other abnormalities will become apparent in them. © 1995 Wiley

ISSN:0040-3709    

DOI:10.1002/tera.1420510609

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

年代:1995

数据来源: WILEY

ISSN:0040-3709    

DOI:10.1002/tera.1420510610

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

年代:1995

数据来源: WILEY