bluuebunny/crossref_metadata_2025_split huggingface dataset:
Maternal zinc deficiency, but not copper deficiency or diabetes, results in increased embryonic cell death in the rat: Implications for mechanisms underlying abnormal development
Authors: Jankowski Margaret A. , Uriu‐Hare Janet Y. , Rucker Robert B. , Rogers John M. , Keen Carl L. 
Published: June 2005

AbstractThe mechanism underlying the teratogenicity of maternal copper deficiency, zinc deficiency, and diabetes are largely unknown. Here we investigated whether these insults are associated with altered patterns of cell death in gestation day (GD) 11.0 rat embryos. Four weeks prior to mating, rats in the copper‐deficient group (CuD) were fed a copper‐deficient diet supplemented with the chelator, triethylenetetramine, to facilitate the depletion of tissue copper stores. Rats in this group were switched to a triethylenetetramine‐free copper‐deficient diet 1 week prior to mating. Dams in the diabetic and control groups were fed a control (8μg copper, 25 μg zinc/g) diet throughout the study. On GD 3.0, one subset of the control dams was assigned to the zinc‐deficient group (ZnD) and fed a zinc‐deficient diet. A second subset of control dams was assigned to a restricted fed group and fed the control diet in quantities consumed by the zinc‐deficient dams. Litters were taken by cesarean section on GD 11.0 Embryos were examined for gross morphology and assessed for patterns of cell death using Nile blue sulfate. Embryos from the CuD dams were characterized by edematous hindbrain. Embryos from the diabetic group were characterized by delayed development. Altered patterns of cell death were only detected in embryos from the ZnD dams. Within the ZnD group, embryos were either characterized by small size, edematous head region, and control patterns of cell death, or normal size, normal morphology, and increased cell death. These different patterns of morphology and cell death in the embryos of ZnD dams were associated with different patterns of maternal food intake. These results support the concept that abnormal cell death may contribute to zinc deficiency‐induced teratogenesis. © 1995 Wiley‐Liss, Inc.
Symmetrical terminal transverse limb defects: Report of a twenty‐week fetus
Authors: Harmon James V. , Osathanondh Rapin , Holmes Lewis B. 
Published: June 2005

AbstractA 20‐Week gestation hydropic Thai fetus is reported who had symmetrical absence of each hand and forefoot with persistence of digit‐like nubbins on each limb. The histologic studies showed there was calcified acellular material in the digit‐like nubbins, consistent with infarcted blood vessels, and cartilaginous structures that represent possibly the distal metacarpal articulating surface. The red blood cell indices of both parents were consistent with their being heterozygous for a hemoglobinopathy, such as α‐thalas‐semia, which is common in Thais. The infarcted blood vessels could be the result of thrombosis of the digital arteries in the fetus due to a hemoglobinopathy such as hemoglobin Bart's, just as rabbit fetuses homozygous forbrachydactylyhave transverse terminal digit amputations following digital vessel occlusions due to macrocytic anemia. This was the only child with symmetrical absence of the hands and feet identified among 123, 489 liveborn and stillborn infants surveyed for major malformations. © 1995 Wiley‐Liss, Inc.
Placental transfer and developmental effects of 9‐cisretinoic acid in mice
Authors: Kochhar Devendra M. , Jiang Heng , Penner John D. , Heyman Richard A. 
Published: June 2005

Abstract9‐cisretinoic acid (RA) is a naturally occurring isomer of all‐transRA. While both isomers can bind with high affinity and activate RA receptors, only 9‐cisRA is the specific ligand for the retinoid X receptors. 9cisRA has also been shown to be much more potent than all‐transRA in inducing digit duplication in the chick embryo wing bud. To gain further insight into its mechanisms, here we investigated the teratogenic activity in pregnant mice of 9‐cisRA and compared it with those of all‐transRA and 13‐cisRA. Using frequency and severity of limb reduction defects as well as palatal clefts in the resultant fetuses as indicators, we found that orally administered 9‐cisRA was one‐half as potent a teratogen as all‐transRA. That 9‐cisRA was intrinsically less active than all‐transRA was deduced by comparing the inhibitory activities of the two retinoids in the limb bud mesenchymal cell micromass cultures using chondrogenesis as an end‐point. Since placental transfer ofcisisomers of RA is generally poor, we monitored the identities and amounts of retinoids in the embryo after administration of 9‐cisRA to the mother. We found that 9‐cisRA undergoes extensive metabolism and isomerization during absorption resulting in a number of metabolites in the maternal circulation within 30 min after administration. Although some of these metabolites remain to be identified, the most abundant RA isomers in the plasma coeluted with 13‐cisRA. The major isomer in the embryo, however, was all‐transRA, which exceeded the embryonic levels of 9‐cisRA and other retinoids in the 13‐cisRA fraction during the 3 hr period of monitoring. We conclude that orally administered 9‐cisRA is a weaker teratogen in mice than all‐transRA and suggest that its isomerization may be an important contributory factor to its teratogenicity. The individual role played by either of the receptor pathways in teratogenesis is unclear and needs further study. © 1995 Wiley‐Liss, Inc.
Anti‐interferon immunoglobulins can improve the trisomy 16 mouse phenotype
Authors: Maroun Leonard E. 
Published: June 2005

AbstractMouse trisomy 16 is a well‐studied model for human chromosome 21 trisomy (Down's syndrome). The late stage trisomy 16 mouse fetus exhibits significant growth retardation, inappropriately opened eyes, and convex rather than concave back curvature. The interferons (α β and γ)have potent growth retarding activity, and sensitivity to these cytokines is controlled by genes that map to mouse chromosome 16 and human chromosome 21. In experiments designed to determine if the interferons induce or aggravate the trisomy phenotype, mice pregnant with trisomy 16 fetuses were injected with a combination of anti‐α,‐β and‐γ interferon lgG. This maternal anti‐ interferon treatment was found to provide measurable benefit to the development and growth of the trisomic fetuses with significant return‐ forward‐ normal values observed for overall fetal growth, eye opening, and back curvature.© 1995 Wiley‐Liss, Inc.
Detection of genotype‐environment interaction in case‐control studies of birth defects: How big a sample size?
Authors: Khoury Muin J. , Beaty Terri H. , Hwang Shih‐Jen 
Published: June 2005

AbstractDetecting interactions between risk factors in case‐control studies of birth defects and other conditions usually requires increasing the sample size beyond that needed to detect marginal effects. A special case of such interaction is genotype‐environment interaction in which the effects of an exposure on disease risk are modified by genetic susceptibility. When case‐control studies are designed to detect marginal effects of an exposure (i. e., in the whole population), under many plausible interaction schemes, no additional case and control subjects are needed to detect genotype‐environment interaction. On the contrary, inclusion of genotypic information generally can improve the statistical power of the original study. Using the example of oral clefts, maternal cigarette smoking, and genetic variation at the transforming growth factor alpha gene, we illustrate sample size and power issues in designing case‐control studies when prior information is available on both the marginal effects of the exposure and the genetic factor.© 1995 Wiley‐Liss, Inc. This article is a US Government work and, as such, is in the public domain in the United States of America
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Evaluation of the reproductive and developmental toxicity of the AT1‐selective angiotensin II receptor antagonist Losartan in rats
Authors: Spence S. G. , Cukierski M. A. , Manson J. M. , Robertson R. T. , Eydelloth R. S. 
Published: June 2005

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 F0 generation. There was no evidence of treatment‐related or dose‐related fetal malformationsHowever, decreased F1 pup 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 F1 pup 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 F1 generation 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 inhibitors are discussed. © 1995 Wiley‐Liss, Inc.
Clusterin expression during programmed and teratogen‐induced cell death in the postimplantation rat embryo
Authors: Little Sally A. , Mirkes Philip E. 
Published: June 2005

AbstractClusterin appears to play a role in multiple cellular processes including reproductive cell function, lipid transport, complement regulation, and endocrine secretion. In addition, clusterin has been shown to be associated with both developmental and induced cell death. We have used immunohistochemistry and in situ hybridization to study the relationship between clusterin expression, normal programmed cell death (PCD) in the developing rat limb bud, and abnormal cell death induced by hyperthermia in day 11 rat embryos. Immunohistochemical localization of clusterin in day 14‐16 limb buds showed that the most intense immunostaining was associated with the condensing mesenchyme of the developing digit, a tissue exhibiting low levels of PCD. Moreover, areas of digital cell death, confined to future interphalangeal spaces, were devoid of clusterin immunostaining. Clusterin immunostaining was also observed in the interdigital mesenchyme and partially overlapped the cell death that occurs in this tissue during the early development of the digits. Although clusterin immunostaining overlaps areas of interdigital cell death, most apoptotic cells in the interdigital mesenchyme and underlying the surface ectoderm were not associated with clusterin immunostaining. We also examined the expression of clusterin in day 11 rat embryos exposed to 43°C, an exposure that induces extensive cell death primarily in the developing neuroepithelium. In control embryos cultured at 37°C, clusterin mRNA and protein were expressed at high levels in the heart, a tissue that is completely resistant to the cytotoxic effects of hyperthermia. Within 2.5 hr after an exposure of 43°C, clusterin mRNA showed a dramatic induction in the prosencephalic mesenchyme and only a modest induction in the prosencephalic neuroepithelium. Although less dramatic, clusterin immunostaining was also induced in the prosencephalic mesenchyme, a tissue that is relatively resistant to the cytotoxic effects of hyperthermia. Our results suggest that clusterin is not associated with either PCD or hyperthermia‐induced cell death. Nonetheless, our results suggest that clusterin plays some role in the differentiation of digital cartilage/bone and possibly in the protection of specific embryonic cell types (heart, mesenchyme) from hyperthermia‐induced cell death. © 1995 Wiley‐Liss, Inc.
Induction of hsp72 in heat‐treated rat embryos: A tissue‐specific response
Authors: Fisher Benjamin R. , Heredia Dinorah J. , Brown Kenneth M. 
Published: June 2005

AbstractPrevious studies have demonstrated that heat exposure on gestation day 10 (GD10) resulted in disrupted somite development in rat embryos 24 hr after exposure and in thoracic skeletal malformations in neonatal rats examined 3 days postpartum. The production of abnormal somites was correlated with the location of skeletal elements that developed from the affected somites. Heat has also been shown to induce changes in genetic expression whereby new proteins are synthesized and the expression of constituent proteins may be repressed. In the present study, heat‐induced alterations in proteins synthesis during rat organogenesis that may be associated with previously observed malformation was investigated. GD10 rat embryos were expose in utero to a heat treatment previously demostrated to produce skeletal malformations; maternal core temperature was raised and maintained at 42‐42.4°C for 5 min. In addition, explanted GD10 embryos were cultured in vitro and exposed to temperatures of 42‐42.5°C for 15 min. At various times postexposure, embryos were labeled with 35S‐methionine and processed for SDS‐PAGE. In both in vivo and in vitro heat‐treated embryos, a transient enhanced de nove synthesis of 70‐ and 90‐kD proteins was observed 1‐8 hr after exposure. Actinomycin D studies were conducted to determine whether transcription of new mRNA was required for the enhanced synthesis of the 70‐ and 90‐kD proteins was observed 1‐8 hr after exposure. Actinomycin D studies were conducted to determine whether transcription of new mRNA was required for the enhanced synthesis of the 70 ‐and 90‐kD proteins in heat‐treated embryos. Results from these studies demonstrated that the expression of these proteins was transcriptionally regulated. The 70‐kD protein was identified, using Western blot analysis, as a eukaryotic inducible stress protein (hsp72), and the presence of this protein was detected between 2 and 27 hr postreatment. Immunohistochemical results indicated that following heat shock, hsp72 accumulates in the neuroectodermal tissues of the embryos. The data demonstrate that although heat‐induced expression and accumulation of the hsp72 precedes aberrant somite morphology, the lack of hsp72 accumulation in the somite mesoderm may explain the sensitivity of this tissue to heat. © 1995 Wiley‐Liss, Inc.
Ethanol‐induced teratogenesis: Free radical damage as a possible mechanism
Authors: Kotch Lori E. , Chen Shao‐Yu , Sulik Kathleen K. 
Published: June 2005

AbstractTo investigate the possibility of a free radical mechanism for ethanol‐induced teratogenesis, gestational day 8 mouse embryos were exposed for 6 hr in whole embryo culture to a teratogenic dosage of ethanol alone (500mg%) or in conjunction with an antioxidant, superoxide dismutase (SOD; 300 U/ml). For subsequent analysis, some embryos were examined at the end of this 6‐hr period, while others were removed to control medium and cultured for an additional time period. Ethanol exposure resulted in increased superoxide anion generation and increased lipid peroxidation (as noted 6 hr after initial ethanol exposure) and in excessive cell death (as noted 12 hr after initial exposure) in the embryos. Following a total of 36 hr in culture, a high incidence of malformation, including failure of the anterior neural tube to close in 63% of the ethanol‐exposed embryos, was noted. The ethanol‐induced superoxide anion generation, lipid peroxidation, excessive cell death, and dysmorphogenesis were diminished in embryos co‐treated with SOD, suggesting that the teratogenicity of ethanol is mediated, at least in part, by free radical damage. © 1995 Wiley‐Liss, Inc.
Severe limb defects and craniofacial anomalies in a fetus conceived during acitretin therapy
Authors: De Die‐Smulders Christine E. M. , Sturkenboom Mirjam C. J. M. , Veraart Joep , Van Katwijk Cees , Sastrowijoto Prapto , van der Linden Ed 
Published: June 2005

AbstractWe describe a 20‐week‐old fetus with multiple congenital anomalies exposed to acitretin in the first trimester of pregnancy. Acitretin and its ethylester etretinate are both vitamin A congeners; drugs of this group are well‐known teratogenic agents. Since the marketing of acitretin only one report on human teratogenicity associated with acitretin has been published. The present male fetus showed severe symmetric anomalies of upper and lower limbs, craniofacial anomalies, ear anomalies, and an atrioventricular septal defect (ASD). Although the craniofacial anomalies resemble the abnormalities described in classical “retinoic acid embryopathy,” limb anomalies were seldomly reported after maternal use of vitamin A congeners. However, in laboratory animals limb defects were frequently observed after retinoid exposure in utero. This case emphasizes again that extreme care and precaution are needed before prescribing a potentially teratogenic drug to a fertile woman. © 1995 Wiley‐Liss, Inc.
In vitro assessment of the effect of methanol and the metabolite, formic acid, on embryonic development of the rat
Authors: Brown‐Woodman Patricia D. C. , Huq Fazlul , Hayes Louise , Herlihy Carolyn , Picker Kelvin , Webster William S. 
Published: June 2005

AbstractInhalation studies in rats have indicated that methanol is embryotoxic at levels that are only mildly maternally toxic. In the present study, the embryotoxicity of methanol and its metabolite, formic acid, was evaluated using rat embryo culture. The results showed that both methanol and formic acid have a concentration‐dependent embryotoxic effect on the developing rat embryo in vitro. The no‐effect concentration of methanol was 211.7 μmol/ml culture medium, while embryotoxicity was observed at 286.5 μmol/ml. The no‐effect concentration of formic acid was 3.74 μmol/ml, while a concentration of 18.66 μmol/ml was associated with severe embryotoxicity. When embryos were grown in sera containing 18.66 μmol sodium formate/ml or in sera adjusted with hydrochloric acid to pH values similar to those achieved with formic acid, the results indicated that both low pH and formate contributed to the observed embryotoxicity of formic acid. When the levels of methanol found to be embryotoxic in the present study is compared to blood levels in the human following controlled industrial exposure there appears to be a large margin of safety. However, plasma methanol levels are only one aspect of methanol toxicity in the human. Of greater significance is the formate level and the associated acidosis. However, it appears that embryotoxicity due to low pH ro high formate levels would only occur after very severe methanol intoxication. Based on these in vitro studies, current industrial safety limits would appear to provide protection for the developing embryo. © 1995 Wiley‐Liss, Inc.
Pharmacokinetics of teratogenic antibodies administered to rats
Authors: Fawcett Lynda B. , Beckman David A. , Fawcett Paul T. , Brent Robert L. , Lloyd John B. 
Published: June 2005

AbstractThe serum levels of total and visceral yolk sac (VYS)‐reactive sheep IgG have been determined following injection of a teratogenic sheep anti‐VYS antiserum. After intravenous injection, levels of VYS‐reactive IgG fell rapidly, with 75% of the amount in the injection removed in the first 5 min, and 90% by 60 min. By contrast, 90% or more of the total sheep IgG was still present at these times. A similar difference in clearance was seen after intraperitoneal injection, although the serum levels also reflected the presence of a pool of antiserum in the peritoneum and the simultaneous influx and efflux of IgG into and from the circulation. The clearance pattern was similar in pregnant and nonpregnant rats; it is concluded that antibodies against VYS‐specific antigens comprise a very small fraction of VYS‐reactive antibodies in the antiserum. ELISA and Western blot analysis indicated extensive cross‐specificity with antigens present in rat tissues other than the VYS. Similar teratogenic effects were observed after intravenous or introperitoneal injection of the antiserum at 8.5 days of gestation; we conclude that the proximal effect likely begins within the period immediately after the injection. The results are also considered within the context of published reports that the VYS shows structural and functional damage for several days after intraperitoneal administration of antiserum at 8.5 days. © 1995 Wiley‐Liss, Inc.
Comparison of two approaches to analyzing correlated binary data in developmental toxicity studies
Authors: Have Thomas R. Ten , Hartzel Tracy 
Published: June 2005

AbstractRecently developed statistical methodology is presented for analyzing correlated developmental toxicity data where multiple measures are obtained on individual units such as rat pups. Of particular interest is the assessment of the homogeneity of effects from chemical exposure across different outcomes such as malformation types or non‐ossification of forepaw digits. Such contrasts are referred to as within‐cluster effects, as they represent differences between observations within a cluster (e.g., pup). Between‐cluster effects correspond to comparison of observations from different clusters, e.g., pups exposed to varied doses of chemicals or carcinogens. Two classes of statistical models are available for estimation of these distinct types of effects: (1) cluster‐specific models in which regression adjustments are made for cluster effects, and hence all parameters are interpreted as within‐cluster effects; and (2) population‐averaged models in which no explicit adjustments are made for cluster, and thus all parameters are interpreted as group differences without regard to whether they represent between‐ or within‐cluster effects. Many models in the developmental toxicity literature are population‐averaged logistic regression models ignoring variation among clusters which may be significant under strong influences of genetic and environmental factors. Under such conditions, confidence interval‐based inference for effect homogeneity will depend upon the class of models. These issues are illustrated with data from two developmental toxicity studies: (1) a National Toxicology Program study of the effects of in utero exposure to di(2ethylhexyl)phthalate among three malformation outcomes in mouse pups; and (2) a study conducted by Hartsfield to investigate the effects of anticonvulsant phenytoin on the risk of non‐ossification among digits of the left and right forepaws in rat pups. © 1995 Wiley‐Liss, Inc.