bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased postimplantation loss and malformations among the F2 progeny of male rats chronically treated with cyclophosphamide
Authors: Hales Barbara F. , Crosman Kellie , Robaire Bernard 
Published: June 2005

AbstractCyclophosphamide, administered to the male rat, produces increased pre‐ and postimplantation loss in the progeny as well as an increase in the numbers of malformed and growth retarded fetuses. The purpose of this study was to determine whether the adverse effects of chronic paternal cyclophosphamide exposure are transmissible to the next generation, the F2 progeny. Adult male rats were treated by gavage daily with saline or with cyclophosphamide (3.4 or 5.1 mg/kg) for 4 or 18 weeks and mated. The male and female offspring in each treatment group (F1 generation) were randomly mated. The resulting pregnant females were killed on day 20 of gestation to evaluate progeny outcome in the F2 generation. There was a significant increase in postimplantation loss among the offspring of the group whose fathers had been treated with cyclophosphamide at a dose of 5.1 mg/kg/day. Exposure to a dose of 5.1 mg/kg/day of cyclophosphamide also resulted in an F2 generation with a significantly decreased mean fetal weight per litter and a significant increase in the number of malformed fetuses. The malformations observed among the F2 progeny included open eyes, omphalocele, generalized edema, syndactyly, gigantism, and dwarfism. Thus, exposure of the father to cyclophosphamide does result in a specific and heritable alteration in the fertility of the surviving “apparently normal” F1 progeny. Interestingly, the adverse consequences of exposure of male rats to cyclophosphamide are similar in the F2 generation to those previously reported for the F1 progeny. © 1992 Wiley‐Liss, Inc.
Interpretation of recurring weak associations obtained from epidemiologic studies of suspected human teratogens
Authors: Khoury Muin J. , James Levy M. , Flanders W. Dana , Erickson J. David 
Published: June 2005

AbstractEpidemiological studies of suspected human teratogens not infrequently lead to recurring weak or moderate associations (relative risks or odds ratios ranging from >1 to 3 for adverse effects and from 1/3 to <1 for protective effects) between specific defects and prenatal exposures. Examples of such associations include cigarette smoking and oral clefts (odds ratios between 1 and 2) and periconceptional multivitamin/folic acid supplementation and neural tube defects (odds ratios from 1/3 to 1). In this paper, we illustrate that low relative risk recurring in well‐designed studies may reflect underlying biologic mechanisms and should not be readily dismissed. Low relative risks could be the result of a combination of the following factors: 1) unmeasured confounding, 2) exposure misclassification (often related to the inability to pinpoint relevant dose and timing), 3) outcome misclassification (related to the etiologic heterogeneity of birth defects), 4) biologic interactions (related to teratogenic effects in population subgroups defined by genetic susceptibility or the presence of other exposures), and 5) differential prenatal survival (related to the combined impact of the exposure and the defect on prenatal survival). These issues can be addressed in epidemiologic studies by using biological markers of exposure and susceptibility, dysmorphologic evaluation of affected infants, subgroup analysis for etiologic heterogeneity, a search for biologic interactions, and the use of prospective cohort studies. Finally, low relative risks in the face of common exposures can reflect an important public health contribution of the exposure to the occurrence of the defect in the population. © 1992 Wiley‐Liss, Inc.
Embryotoxicity of T‐2 toxin and secalonic acid in embryonic chicks varies with the site of administration
Authors: Veselý D. , Veselá D. , Jelínek R. 
Published: June 2005

AbstractA crucial role of the site of administration in the sensitivity of the alternative system using chick embryo for testing embryotoxicity was demonstrated by morphological evaluation of the effects of T‐2 toxin and secalonic acid D, and by incorporation of [14C]sodium acetate radioactivity. Secalonic acid D, administered to 2‐, 3‐, and 4‐day‐old embryos in doses higher than 1 μg produced mostly malformations of the face (bilateral cleft beak, microphthalmia) while the teratogenic effects of T‐2 toxin were being limited to the embryonic trunk of 2‐day‐old embryos (rumplessness) after administering doses higher than 0.001 μg. In case of subgerminal and intraamniotic injections, the doses of both mycotoxins needed for producing embryotoxic effects comparable to those obtained with the more commonly used yolk sac injections appeared to be lower by one and two orders of magnitude, respectively. The results stress the need of using the shortest transport channel of test substances from the site of application to the target tissues of the embryo, when the maximum sensitivity and reproducibility of the test system are to be expected. © 1992 Wiley‐Liss, Inc.
Cocaine and single ventricle: A population study
Authors: Martin M. Louise , Khoury Muin J. 
Published: June 2005

AbstractA recent case report by Shepard et al. (Teratology 43:113–117, 1991) suggested that single ventricle may result from maternal cocaine ingestion by inducing coronary occlusion in the developing fetal heart. We used data from the Atlanta Birth Defects Case‐Control Study and the Metropolitan Atlanta Congenital Defects Program (MACDP) to investigate the role of maternal cocaine ingestion in the induction of single ventricles. We identified through the MACDP 58 case infants with a single ventricle, 27 who were study subjects in the Atlanta Birth Defects Case‐Control Study, and 31 who were not. We conducted a case‐control study with the 27 Atlanta Birth Defects Case Control Study infants, frequency‐matched to control infants by race, hospital of birth, and calendar quarter of birth. None of the 27 case infants were exposed to cocaine during early pregnancy, but 7 (0.43%) of the control infants were exposed during early pregnancy. Using MACDP data, we conducted an analysis of trends for prevalence of single ventricle in the metropolitan area. No upward trend in single ventricle was detected for 1968 through 1990. Our data suggest that even if maternal cocaine ingestion during pregnancy is a cause of single ventricle, most cases appear to be unrelated to this exposure. © 1992 Wiley‐Liss, Inc.
Descriptive profile of birth defects among livebirths in Singapore
Authors: Thein M. M. , Koh D. , Tan K. L. , Lee H.‐P. , Yip Y. Y. , Tye C. Y. , Phoon W. O. 
Published: June 2005

AbstractA case‐control study of birth defects was carried out in Kandang Kerbau Hospital in Singapore for a three‐year period from January 1986 until December 1988. This paper presents the descriptive profile of birth defects among livebirths seen in that hospital. Out of 44,842 livebirths, 678 babies were found to have birth defects, giving a prevalence of 15.13 per 1000 livebirths (95% CI 14.0–16.2). The musculoskeletal system was the most frequently affected system accounting for 161 cases with a prevalence of 3.59 per 1,000 livebirths (95% CI 3.06–4.19), followed by 111 cases with defects of the gastrointestinal system (2.47 per 1,000 livebirths 95% CI 2.04–2.98), 88 cases of chromosomal disorders (prevalence of 1.96 per 1,000 livebirths 95% CI 1.57–2.42), 78 cases with defects of the cardiovascular system (1.74 per 1,000 live‐births 95% CI 1.38–2.17), 73 cases with defects of the urogenital system (1.63 per 1,000 livebirths 95% CI 1.28–2.05), and 52 cases with defects of the central nervous system (1.16 per 1,000 livebirths 95% CI 0.87‐1.52). The prevalence of cleft lip, cleft palate in isolation, and cleft lip and palate combined was 1.72 per 1,000 livebirths and the occurrence of Down's syndrome was 1 in 700 livebirths. When reviewed 6 weeks postpartum, the rate of false positives at birth was 4%. In a control group of 709 “normal” cases at birth, the rate of cases not detected at birth but detected at 6 week follow‐up, false negatives was 0.84%. © 1992 Wiley‐Liss, Inc.
Rat hepatic glutathione S‐transferase‐mediated embryotoxic bioactivation of ethylene dibromide
Authors: Mitra Ashoke , Hilbelink Don R. , Dwornik Julian J. , Kulkarni Arun 
Published: June 2005

AbstractThe embryotoxic effects of ethylene dibromide (EDB) bioactivation, mediated by purified rat liver glutathione S‐transferases (GST), were investigated using rat embryos in culture. Significant EDB metabolism was observed with rat liver GST purified by affinity chromatography (specific activity of 188 ± 11.3 nmol/min/mg protein). The reaction was enzymatic in nature and the conjugation rate was proportional to the concentration of EDB (up to 0.75 mM) and the enzyme present in the reaction medium. EDB activation by 100 units (1 unit = 1 nmol of glutathione consumed per min) of purified rat liver GST caused a significant reduction in general development as measured by crown–rump length, yolk sac diameter, somite number, and the composite score for different morphological parameters (Brown and Fabro methodology). Structures most significantly affected were the central nervous and olfactory systems as well as the yolk sac circulation and allantois. The results of this study clearly indicate that under in vitro conditions, bioactivation of EDB by GST can lead to embryotoxicity. © 1992 Wiley‐Liss, Inc.
Avian model for 13‐cis‐retinoic acid embryopathy: Morphological characterization of ventricular septal defects
Authors: Hart Robin C. , Winn Kevin J. , Unger Elizabeth R. 
Published: June 2005

AbstractIn developing an avian model for 13‐cis‐retinoic acid (13cisRA) embryopathy, we found 13cisRA induced cardiovascular defects, especially Type I ventricular septal defects (VSDs) (Hart et al.: Teratology 41:463–472, '90). As the first step of investigating possible mechanisms, we have examined the light microscopic morphology of RA‐induced cardiovascular defects in chick embryos. Fertilized eggs were injected via yolk sac with 150 μg 13cisRA in dimethylsulfoxide (DMSO), DMSO or mock injection on embryonic day 5 (E5). On E6, E7, or E8, surviving embryos were sacrificed and fixed in 10% formalin. Thoracic blocks were exised, embedded in paraffin and serially sectioned through the heart, base to apex. Slides were stained, screened for tissue orientation, then coded and evaluated without knowledge of treatment group. Examination of serial sections permitted qualitative evaluation of conotruncal ridge volume, mesenchymal organization, necrosis and extent of fusion. Extent of fusion was the only parameter influenced by 13cisRA treatment. On E6, ridge fusion was incomplete in all groups at comparable levels. On E7, ridge fusion in 13cisRA‐treated embryos had not progressed as far proximally as in controls. By E8, there was a significant difference in the extent of fusion between 13cisRA‐treated and non‐RA‐treated groups. We conclude 13cisRA‐induced VSDs resulted from defective conotruncal ridge fusion and that the fusion defects did not result from decreased tissue volume, altered mesenchymal organization or increased necrosis. © 1992 Wiley‐Liss, Inc.
Clinical anophthalmia: An epidemiological study in Northeast Italy based on 368,256 consecutive births
Authors: Clementi Maurizio , Turolla Licia , Mammi Isabella , Tenconi Romano 
Published: June 2005

AbstractWe describe an epidemiological and clinical study of Clinical Anopthalmia in a population of consecutive live and stillborns enrolled in a hospital based registry of congenital malformations in Northeast Italy during the period from 1981 to 1989; 22 cases were detected among 368,256 births yielding a birth prevalence of 0.60 per 10,000 (95% CI 0.34–0.84); 20 cases were associated with at least one other major malformation. Malformation syndrome, association, or sequence was diagnosed in 13, while a non‐recognizable multiple defect pattern was observed in 7/20 (35%). A chromosomal anomaly was present in eight syndromic cases. No significant trend over time, nor space or time clusters, were detected. As most CAn cases are associated with other anomalies recognizable by ultrasound, a decreasing trend in its prevalence at birth is expected in the future. © 1992 Wiley‐Liss, Inc.
Importance of early exposure to 13‐cis retinoic acid to induce teratogenicity in the cynomolgus monkey
Authors: Korte Rainhart , Hummler Hans , Hendrickx Andrew G. 
Published: June 2005

AbstractThe teratogenic potential of 13‐cis retinoic acid (13‐cis RA) was further assessed in cynomolgus macaques (Macaca fascicularis) following exposure to two different regimens during the preorganogenic period to determine the influence of time of treatment on the 13‐cis RA malformation syndrome established previously (Hummler et al., Teratology, 42:263–272, 1990). In experiment (Exp) 1, 13‐cis RA was orally administered once daily (2.5 mg/kg) on gestational day (GD) 16–25 and twice daily (2 × 2.5 mg/kg) on GD 26–27. In Exp 2, the same oral dose was administered once daily on GD 10–20 and twice daily on GD 21–24. Although the ear was affected at about the same incidence (6/9, 67%) in Exp 1 as previously reported, the defects were less severe. Except for hypoplastic vermis of the cerebellum (2/9, 22%), no other defects were seen. In Exp 2, the teratogenic effects of 13‐cis RA on the craniofacial skeleton (1/9, 11%), external ear (5/9, 56%), and heart (2/9, 22%) were similar to that reported by Hummler et al.; however, no thymus or cerebellar malformations were observed. Analysis of the three different treatments (GD 16–27 in Exp 1, GD 10–24 in Exp 2, and GD 10–27 in Hummler et al.) suggests that the sensitive periods in the macaque are 1) craniofacial skeleton and heart GD 10–24, 2) thymus and cerebellum >GD 24, and 3) external ear GD 16–24, although the defects are less severe following the shorter exposure. Exposure to 13‐cis RA preceding onset of morphological organogenesis appears to be a requirement for 13‐cis RA embryopathy in the cynomolgus monkey. The external ear appears to be both a uniquely sensitive biomarker for 13‐cis RA teratogenicity and an indicator of embryotoxic severity. Finally, the longer period of drug administration (2.5 mg/kg, GD 10–25, and 2 × 2.5 mg/kg, GD 26–27) used by Hummler et al. is more suited to assessment of 13‐cis RA teratogenicity in macaques due to greater concordance with the 13‐cis RA syndrome in humans. © 1993 Wiley‐Liss, Inc.
Young maternal age and smoking during pregnancy as risk factors for gastroschisis
Authors: Haddow James E. , Palomaki Glenn E. , Holman Mary S. 
Published: June 2005

AbstractThree maternal risk factors (maternal age, cigarette smoking, and infant's month of birth) have been reported to be associated with fetal gastroschisis. In order to study these risk factors further, a prospective population‐based study was designed, using 62,103 consecutive second‐trimester singleton pregnancies enrolling in a maternal serum alpha‐fetoprotein screening program between January 1, 1980 and April 30, 1989. Gastroschisis occurred in 21 of those pregnancies. Pregnancies in women younger than 20 years of age were at 7.3 times greater odds for being affected with gastroschisis than pregnancies in women aged 25 or older (95% confidence interval 2.4 to 22). For pregnant women aged 20 to 24 years, the odds were 1.9 times greater (95% confidence interval 0.7 to 5.0). Pregnant women who smoked cigarettes were at 2.1 times greater odds than non‐smokers (95% confidence interval 0.9 to 4.8). When these smoking data were combined with smoking data from two other published studies, the consensus odds ratio was 1.6 (95% confidence interval 1.2 to 2.2). Infant's month of birth was not associated with gastroschisis. Evidence from the present study and other published studies clearly establishes a greater risk for fetal gastroschisis in pregnant women younger than age 20, even after adjustment for smoking status. Cigarette smoking also appears to be a risk factor, when data from this and two previously published studies are combined. © 1993 Wiley‐Liss, Inc.
Developmental toxicity evaluation of diethyl and dimethyl phthalate in rats
Authors: Field Elizabeth A. , Price Catherine J. , Sleet Randolph B. , George Julia D. , Marr Melissa C. , Myers Christina B. , Schwetz Bernard A. , Morrissey Richard E. 
Published: June 2005

AbstractDiethyl phthalate (DEP) and dimethyl phthalate (DMP), phthalic acid ester (PAE) plasticizers, were evaluated for developmental toxicity because of reports in the literature that some PAE were embryotoxic and teratogenic. A previous study (Singh et al., '72) suggested that an increased incidence of skeletal defects in rats might result from gestational exposure to DEP (0.6–1.9 g/kg) or DMP (0.4–1.3 g/kg), ip, on gestational days (gd) 5, 10, and 15. In the current study DEP (0, 0.25, 2.5, and 5%) or DMP (0, 0.25, 1, and 5%) in feed (approximately 0.2–4.0 g/kg/day) were supplied to timed‐mated rats from gd 6 to 15. Treatment with 5% DMP resulted in increased relative maternal liver weight. Also, animals exhibited reduced body weight gain during treatment (5% DEP or DMP) and during gestation (5% DEP). Weight gain corrected for gravid uterine weight was also reduced in animals fed 5% DEP. However, high‐dose treatment with either DEP or DMP resulted in changes in food and water consumption paralleling the body weight reductions, suggesting that apparent toxic effects on maternal body weight may reflect PAE/feed unpalatability. Treatment with 2.5% DEP resulted in only transient changes in body weight during early treatment. The only maternal effects at 0.25 or 1% DMP were minor changes in food and/or water consumption, and there were no effects at 0.25% DEP. Thus, the NOAELs for maternal toxicity were 1% DMP and 0.25% DEP. In contrast to the observed maternal toxicity, there was no effect of DEP or DMP treatment on any parameter of embryo/fetal development, except an increased incidence of supernumerary ribs (a variation) in the 5% DEP group. These results do not support the conclusion of other investigators that DEP and DMP are potent developmental toxicants. Rather, they suggest that the shortchain PAE are less developmentally toxic than PAE with more complex substitution groups, e.g., di(2‐ethylhexyl) phthalate, mono(2‐ethylhexyl) phthalate, and butyl benzyl phthalate. © 1993 Wiley‐Liss, Inc.
The effect of tolbutamide on rat embryonic development in vitro
Authors: Ziegler Marilyn H. , Grafton Thomas F. , Hansen Deborah K. 
Published: June 2005

AbstractTolbutamide (TOLB) is a sulfonylurea used to treat non‐insulin‐dependent diabetes mellitus and is a suspected teratogen. However, it is not possible to discriminate between potential teratogenic effects of TOLB and malformations produced by either drug‐induced hypoglycemia or the diabetic state itself. We examined the direct effect of TOLB on rat embryos cultured in a rodent whole embryo culture system. CD strain rat embryos were cultured for 48 h beginning on day 9 of gestation (plug day = day 0). Tolbutamide was added at various concentrations (90–3,600 μM). At the end of culture, viable embryos were examined for morphological score, number of somite pairs, crown‐rump and head lengths, and DNA and protein content. Tolbutamide produced doserelated decreases in all endpoints at concentrations (2,250–3,600 μM) which are two to four times the human therapeutic concentration. Sera from TOLB‐treated rats were adjusted to contain equal concentrations of glucose and insulin and then used for embryo culture. Serum from TOLB‐treated rats had no observable effect on embryonic development. The mechanism for the embryotoxic effect of TOLB is unknown; however, the drug was previously demonstrated to alter activity of purified yeast glutathione reductase (GR). Because GR may be important for normal embryonic development, the effect of TOLB on this enzyme activity in cultured rat embryos was evaluated. Tolbutamide (2,700 μM) reduced embryonic GR activity by 35–57%. These results indicate that TOLB has a direct embryotoxic effect at levels 2 to 4 times the usual therapeutic serum concentrations on developing rodent embryos which may be mediated by GR inhibition. © 1993 Wiley‐Liss, Inc.
Glucose causes lengthening of the microvilli of the neural plate of the rat embryo and produces a helical pattern on their surface
Authors: Shepard Thomas H. , Park Hyoung Woo , Pascoe‐Mason Julie 
Published: June 2005

AbstractProminent microvilli have been observed on the surface of neural plates in the embryos of many species. Since glucose is the main source of energy for embryos before neural tube closure and the onset of vascular circulation, it was of interest to study the relationship between these microvilli and glucose utilization in the neural plate. By applying microdrops of amniotic fluid to chemstrips, which colorimetrically measure glucose by glucose oxidase reaction, we determined that day 10 rat amniotic fluid glucose level was 31.6 ± 1.6 mg/dl. On day 10 and within about 20 min from removal of the decidual sites, no glucose was found in the amniotic fluid.By use of a scanning electron microscope, the microvilli of the day 10 neural plate were found to have a 10‐fold increase in length during a 40‐min exposure to Hanks' solution at 21–23°C. Similarly exposed embryos in Hanks' without glucose did not have microvillus elongation. However, under whole embryo culture conditions at 38°C no extension of the microvilli was found. In the closed neural tube of the day 10 embryo, the microvilli were stubby and did not elongate with glucose exposure. Similarly, day 11 and 14 embryos had short microvilli which did not elongate with direct exposure to glucose at 21–23°C. The short microvilli on the surface of the closed neural tube on day 11, 14, and 16 were associated with low glucose concentrations in the neural tube fluids. By use of a field emission scanning electron microscope, the surfaces of the microvilli in the extended position were seen to be covered by a right‐handed helical array of globular objects the size of large molecules.The findings support the hypothesis that microvillar length may modulate glucose uptake. Shortening is associated with low concentrations of glucose in closed neural tubes, and lengthening occurs at glucose exposures of 100 mg/dl. © 1993 Wiley‐Liss, Inc.
Tail short variable: Characterization of a new mouse mutant, and its possible analogy to certain human vascular disruption defects
Authors: Seller Mary J. , Wallace Margaret E. 
Published: June 2005

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, Inc.