bluuebunny/crossref_metadata_2025_split huggingface dataset:
Toxic and teratologic effects of caffeine on explanted early chick embryos
Authors: Lee H. , Nagele R. G. , Pietrolungo J. F. 
Published: June 2005

AbstractThe toxic and teratologic effects of caffeine on chick embryos ex‐planted at stages 4–7 and cultured for 19–22 hours were investigated. Caffeine, at 200–300 μg/ml, significantly increased the incidence of neural tube defects regardless of the developmental stage at treatment. Concentrations of 500 μg/ml or higher inhibited morphogenesis of nearly all organ primordia. In general, the effects of caffeine were concentration dependent and younger embryos were more susceptible to treatment than their older counterparts. Microscopic studies confirmed that the developing neuroepithelium was most sensitive to treatment. Caffeine, at concentrations sufficient to inhibit neural tube closure, caused no apparent alteration in the ultrastructure of cellular components except that apical microfilament bundles were thinner and less conspicuous than usual. Furthermore, caffeine (400 μg/ml) selectively inhibited uplifting of neural folds (and hence, closure of the neural tube) in embryos explanted at stage 8 and cultured for 4–6 and 16 hours. Affected neuroepithelial cells lacked the typical bottle‐shaped characteristic and folded apical surfaces. Overall results of this study suggest that caffeine causes neural tube defects, at least in part, through its inhibitory action on the contractile activity of apical microfilament bundles in developing neuroepithelial cells.
Ontogeny of suckling behavior in rats prenatally exposed to alcohol
Authors: Chen Jaw‐Sy , Driscoll Cynthia D. , Riley Edward P. 
Published: June 2005

AbstractThe effect of prenatal alcohol exposure on nipple attachment behavior was studied at a number of ages in rat pups whose mothers consumed liquid diets containing 35% or 0% ethanol‐derived calories (EDC) or standard lab chow during pregnancy. In the first experiment, nondeprived pups were tested in groups of three (one from each of the prenatal treatment groups) for nipple attachment to an anesthetized lab chow dam. The second experiment examined the influence of the type of test dam (35% EDC, 0%EDC, or lab chow) on nipple attachment behavior. Finally, experiment three evaluated the possibility that the data from the preceeding experiments were the result of either testing the offspring in triads or alcohol‐induced alterations in maternal behavior. Rat pups from all three groups reared by their biological mothers and a group of 35% EDC offspring fosterd at birth to lab chow surrogate mothers were tested alone rather than in triads. The data from all three experiments clearly indicated an age‐related pattern of nipple attachment behavior; the latency to attach was shortest in 6‐ to 12‐day‐old pups and increased rapidly from 13 to 21 days of age. Prenatal exposure to alcohol significantly increased the latency to attach to the nipple and the rank order of attachment at the younger ages (three to nine days of age) but not in the older animals. Also, the prenatal effect of alcohol was independent of the type of dam to which testing was conducted, the social interaction involved in testing triads, or fostering procedures. These results suggest that prenatal alcohol exposure can interfere with the development of normal suckling behavior, which might influence normal growth.
The pathogenesis of brain abnormalities in the fetal alcohol syndrome: An integrating hypothesis
Authors: Kennedy L. A. 
Published: June 2005

AbstractThe most obvious characteristics of the fetal alcohol syndrome are a cluster of minor, physical malformations that are rather nonspecific and that vary greatly in the frequency and severity of expression. The most common characteristrics are general body and organ growth deficits, including microcephaly. The most debilitating characteristics, however, are central nervous system (CNS) dysfunctions, such as behavioral and intellectual impairments, which appear to be closely related to the growth deficits. The mechanisms whereby alcohol exerts its deleterious effects on intrauterine growth and development are being intensively investigated. Because of its pharmacological properties, maternal consumption of alcohol is associated with widespread effects throughout the maternal‐placental‐fetal organism, many of which can secondarily alter the in utero environment. Both direct and indirect mechanisms are discussed with respect to their contribution to alcoholrelated effects on embryofetal growth and development. It is suggested that impairment in the protein synthetic machinery, resulting in cellular growth restriction at critical periods of development is the common mechanism underlying alcohol's teratogenicity. Because the development of the CNS is so prolonged and complex compared to other organ systems, it is exquisitely vulnerable to derangement throughout pregnancy.
The influence of deoxycytidine monophosphate (dCMP) on the cytotoxicity of hydroxyurea in the embryonic spinal cord of the mouse
Authors: Herken R. 
Published: June 2005

AbstractOn day 10 of pregnancy NMRI mice received an intraperitoneal injection of either 500 mg/kg hydroxyurea (HU) or 500 mg/kg HU plus 500, 700, 800, or 900 mg/kg deoxycytidine monophosphate (dCMP). Three hours after application of the substances, the animals received 5 μCi/g 3Hthymidine i.p. One hour later the animals were sacrificed and the embryos were removed. Autoradiographs of the embryos served to determine the percentage of necroses, labelled necroses, mitoses, labelled mitoses, and labelled neuroepithelial cells of the spinal cord. Optimal inhibition of HU effects was achieved by application of 700 mg/kg dCMP. The cytotoxic effects of HU on neuroepithelial cells could be partially but not completely inhibited by simultaneous application of dCMP. The duration of HU‐induced DNA synthesis inhibition was shortened after simultaneous dCMP application. A strong increase of the labelling index and shortening of the G2‐phase duration of neuroepithelial cells after simultaneous application of HU and dCMP was striking as compared to the results obtained from untreated or HU‐treated animals.
Ultrastructural changes in the neural tube of 10‐day‐old mouse embryos exposed to colchicine and hydroxyurea
Authors: Herken Rainer 
Published: June 2005

AbstractThe ultrastructural changes in the neural tube of 10‐day‐old mouse embryos were investigated between 1.5 hr and 4 hr after application of either 1 mg/kg colchicine (Col) or 500 mg/kg hydroxyurea (HU) or simultaneous application of both substances. During the investigated period, the shape of the nuclei of the neuroepithelial cells had changed from elongated to round after Col application. The chromatin in the nuclei was condensed and arranged in clusters. A breakdown of polysomes into ribosomes and an enlargement of the rough ER was observed in the cytoplasm. At the luminal surface, bleb‐like cytoplasmic processes of the neuroepithelial cells containing monoribosomes protruded into the lumen. No cell necroses were visible in the neural tube after Col application. A condensation of chromatin in the nuclei of some neuroepithelial cells was visible 1.5 hr after HU application. Shortly thereafter, cell necroses appeared in the neural tube and 4 hr after HU application the entire spinal cord was strongly damaged. After simultaneous application of Col and HU, the ultrastructural changes in the neuroepithelial cells of the neural tube did not differ from the results obtained after Col application alone. In contrast to the results obtained after HU application alone, no necroses occurred after simultaneous application of Col and HU.
Effects of streptozotocin‐induced diabetes on fetal development of the rat
Authors: Giavini E. , Broccia M. L. , Prati M. , Roversi G. D. , Vismara C. 
Published: June 2005

AbstractThe purpose of this study was to determine whether or not in rats with experimentally induced diabetes there is an increased frequency of congenital malformations; data in the literature are not consistent on this point. Virgin CD females rats were injected with 40–50 mg/kg streptozotocin (Stz) before mating (SIBM group) or on the first day of pregnancy (SI1). Both SIBM and SI1 females were divided into two groups according to their blood glucose levels: severaly diabetic (SD, > 300 mg%) and mildly diabetic (MD, 120–250 mg%). Food and water consumption by the control and MD groups were the same, but the SD females developed polyphagia, polyuria, and polydypsia, which continued to increase throughout pregnancy, as did the blood glucose levels. All the MD females mated and carried to term. In SD females both frequency of mating and fertility were only slightly lower than in the controls. All the females were killed on the 21st day of pregnancy. Pre‐ and postimplantation losses were the same for diabetic and control rats, but SIBM‐SD females ovulated less than other groups. Weights of fetuses of SD dams were lower and blood sugar levels higher than those of the other groups. The placentas of SD rats were significantly heavier and there was cystic degeneration of spongiosa. The incidence of major malformations was minimal ( ∼ 2%) in fetuses of SD females and there were none at all in controls or MD females. In conclusion, our data are in agreement with those of other investigators who have found that rats with experimentally induced diabetes have smaller fetuses and increased placental weight. But our data do not show any increase in incidences of malformations or of fetal loss, which have been reported by some groups. One basis for this disagreement might be the differences in the composition of the diets, especially in mineral salt content. We are currently investigating this possibility.
Anomalous neural differentiation induced by 5‐bromo‐2′‐deoxyuridine during organogenesis in the rat
Authors: Biggers William J. , Barnea Eytan R. , Sanyal Mrinal K. 
Published: June 2005

AbstractThe influence of 5‐bromo‐2′‐deoxyuridine (BrdU) on rat embryo development and neurogenesis was investigated using a rat conceptus culture system during organogenesis (pregnancy days 10–13). The embryos and visceral yolk sacs of conceptuses cultured with BrdU were examined for overall growth, morphological anomalies, incorporation of radiolabeled BrdU into DNA, and neurotransmitter enzyme activities in embryos. In addition, neural tubes from cultured whole embryos were isolated and mechanically dissociated into fragments and cultured again to assess neural cell differentiation into neuron‐like cells. BrdU was found to incorporate differentially into embryonic and visceral yolk sac DNA with simultaneous stage‐specific retardation and anomalous organogenesis in proportion to the increasing concentrations used. Neural tube differentiation of cultured embryos was markedly altered, and there were morphologically distinct neural anomalies. The neurite outgrowth from neuroblast cells (type 1) of explanted spinal neural tube fragments from BrdU‐treated embryos was markedly reduced in length and number compared to those from similar areas of embryos grown without BrdU. In contrast, BrdU at the same doses did not affect differentiation of a number of neural tissue‐related enzymes. These results indicate that BrdU incorporation into DNA of primordial embryonic cells significantly affects neurogenesis and differentiation of neurites from neuroblasts, which is a specific neural cytodifferentiation characteristic of neuronal cells.
Subcellular effects of experimental oligohydramnios on the developing rat limb
Authors: Houben Jean‐Jacques , Huygens R. 
Published: June 2005

AbstractIn the rat, the development of the limb bud can be impaired by amniotic puncture. Selective haemorrhages are observed within 1 hour of the treatment. An ultrastructural analysis was undertaken to uncover the cytological changes associated with these haemorrhages. The earliest effect of oligohydramnios is the appearance of a periendothelial oedema which separates the mesodermal cellular processes from the endothelial basal lamina. The loosening of the latter and the distortion of the endothelial cells occur almost simultaneously. Subsequent damage of the mesodermal cells ensues, the ectoderm and the preskeletal condensations remaining unaffected. Only general damage of the embryo affecting all tissues will lead to the complete necrosis of the limb bud and even to foetal death. The great variability of skeletal defects observed in amniocentesis syndrome can be accounted for by the higher resistance of the differentiating cells to a decrease in blood supply.
Steroid contraceptive use and pregnancy outcome
Authors: Pardthaisong Tieng , Gray Ronald H. , McDaniel Edwin B. , Chandacham Arida 
Published: June 2005

AbstractContraceptive use in relation to pregnancy outcome was studied in 8,816 births in Chiang Mai, northern Thailand, by examination of newborn infants and interviews with their mothers. Four thousand twenty‐three women used no contraception before the index pregnancy, 1,229 used the injectable contraceptive Depo Provera (DMPA), and 3,038 used oral contraceptives prior to or during pregnancy. No differences were observed between these groups with respect to still births, multiple pregnancies, and birthweight. Women who used oral contraceptives had unexpectedly low rates of major defects and may have been affected by self‐selection bias, whereas the noncontraceptors had rates similar to other populations. There was a significantly increased association of polysyndactyly among infants of DMPA users relative to the other groups, which was most pronounced in offspring of women under age 30 years, and persisted after exclusion of subjects with a family history or infants with multiple abnormalities. However, in five out of the ten polysyndactyly, cases, the last injection of DMPA occurred more than 9 months before conception, and only three cases had definite gestational exposure. The association of chromosomal anomalies was also significantly increased in infants of mothers who used DMPA. The unrelated nature of these defects, the lack of confirmation from other studies, the distant preconceptional exposure to DMPA in many cases, and chance effects due to multiple statistical comparisons make a causal association unlikely. Other birth defects that had been previously reported in some publications to be associated with progestational steroid exposure, such as neural tube defects, heart malformations, and limb reduction defects, were not found in this study. Further research should evaluate in detail the type and incidence of syndactyly or chromosomal aberrations in exposed groups and appropriate control populations.
Evaluation of the bioeffects of prenatal ultrasound exposure in the cynomolgus macaque (Macaca fascicularis): I. Neonatal/infant observations
Authors: Tarantal A. F. , Hendrickx A. G. 
Published: June 2005

AbstractThe frequency of use of ultrasonography for evaluating the developing embryo/fetus has continued to rise although the possible risks from exposure still remain uncertain. The cynomolgus macaque (Macaca fascicularis) is currently being used in our laboratory as a model to assess these risks. In utero exposure was performed utilizing a commercial real‐time mechanical sector scanner with a 7.5 MHz scanhead (ATL, MK 600). Maximum acoustic power output for this unit is as follows: I(SPTA) = 12.0 mW/cm2, I(SPPA) = 98 W/cm2, and Im = 137 W/cm2. Animals exposed to ultrasound (N = 16) were scanned five times weekly on gestational days (GD) 21–35±2 for 10 minutes/exam (m/e), three times weekly on GD 36–60±2 for 10 m/e, and once weekly on GD 61–150±2 for 20 m/e. Controls (N = 14) were “scanned” with the unit placed on standby. Assessment of simian Apgar scores at 1, 5, and 10 minutes of life revealed higher scores for treated animals at 10 minutes (P⩽0.045); greater scores in muscle tone (P±0.013) and color (P±0.016) were observed. Evaluation of morphometrics at birth including weight, biparietal diameter, occipitofrontal diameter, head circumference, hand and foot lengths, humerus and femur lengths, arm circumference, chest circumference, tail length, skinfold thickness, and crown‐rump length (CRL) indicated a significant reduction in only two parameters, birth weight (P±0.027) and CRL (P±0.033). Hematologic analysis at 2±1, 9±1, and 16±1 days of life revealed a significant difference in white blood cell counts (WBCs). Treated animals displayed lower WBCs with reductions in numbers of segmented neutrophils and monocytes at all ages observed. Hematologic differences were not significant by 5–6 months of age. No abortions, gross malformations, or stillbirths were observed in the exposed animals.
Effects of phosphoramide mustard and acrolein, cytotoxic metabolites of cyclophosphamide, on mouse limb development in vitro
Authors: Hales Barbara F. 
Published: June 2005

AbstractPhosphoramide mustard and acrolein are toxic and reactive metabolites of the widely used anticancer drug and known teratogen cyclophosphamide. To study the mechanism(s) involved and to determine which of the active metabolites of cyclophosphamide is responsible for the production of limb malformations, the effects of exposure of cultured limb buds to phosphoramide mustard and acrolein were investigated. Fore‐ and hindlimbs were excised from ICR mice on day 12 of gestation and cultured in roller bottles for 6 days. Limbs were exposed to either phosphoramide mustard or acrolein (10 or 50 μg/ml) for the first 20 hours of the culture period. Exposure to phosphoramide mustard produced limb reduction malformations in both the fore‐ and hindlimbs; total limb bone area was greatly reduced, while the relative contribution of the paw to this area in forelimbs was increased. There was a fourfold reduction in both DNA and RNA; protein content was reduced only by one‐half. Alkaline phosphatase activity was significantly decreased in fore‐ and hindlimbs exposed to phosphoramide mustard, whereas creatine phosphokinase activity was only reduced in hindlimbs in the limbs exposed to the higher concentration of phosphoramide mustard. Exposure to acrolein also produced malformed limbs with a mangled appearance; however, total limb bone area and the relative contribution of the long bones versus paw structures were not altered. Acrolein exposure had little effect on growth parameters such as DNA (decreased only in hindlimbs exposed to 50 μg/ml), RNA (increased in hindlimbs exposed to 50 μg/ml), or protein content. Alkaline phosphatase and creatine phosphokinase activities were not altered in acrolein‐exposed fore‐ or hindlimbs. Thus, phosphoramide mustard and acrolein have dramatically different effects on developing limbs in vitro; this observation may indicate that they have different targets and/or mechanisms of action as teratogens in the limb. The effects of phosphoramide mustard are very simlar to those of “activated” cyclophosphamide (4‐hydroperoxycyclophosphamide).
Lack of teratogenicity of trans‐2‐ene‐valproic acid compared to valproic acid in rats
Authors: Vorhees Charles V. , Acuff‐Smith Karen D. , Weisenburger Walter P. , Minck Daniel R. , Berry James S. , Setchell Kenneth D. R. , Nau Heinz 
Published: June 2005

AbstractThe teratogenicity of trans‐2‐ene‐valproic acid (300 and 400 mg/kg) was compared with that of valproic acid (VPA; 300 mg/kg) and controls (corn oil) administered by gavage to Sprague‐Dawley CD rats on embryonic (E) days 7–18. At the 300 mg/kg dose, trans‐2‐ene‐VPA produced no change in maternal weight, number of implantations, proportion of resorptions, proportion of malformations, or fetal weight. By contrast, the same dose of VPA (300 mg/kg) reduced maternal weight during gestation, increased malformations (12.0% vs. 0.7% in controls), and reduced fetal body weight by 25.1%. An even higher dose of trans‐2‐ene‐VPA (400 mg/kg) produced a reduction in maternal body weight during treatment and reduced fetal body weight (by 7.9%), but did not increase resorptions or malformations in the fetuses. On day E18, maternal serum drug concentrations of VPA were higher in the VPA‐treated group compared with those of trans‐2‐ene‐VPA in the trans‐2‐ene‐VPA‐treated groups at 1 hr posttreatment. At 6 hr posttreatment the reverse was seen. trans‐2‐ene‐VPA may be absorbed more rapidly and distributed differently than VPA. Overall, the data support the view that trans‐2‐ene‐VPA at equal or higher doses than VPA is not teratogenic in rats.
Relationship between fetal weight and malformation in developmental toxicity studies
Authors: Ryan Louise M. , Catalano Paul J. , Kimmel Carole A. , Kimmel Gary L. 
Published: June 2005

AbstractExposure to developmental toxicants may cause fetal malformations, increase prenatal death rates and reduce fetal weight at term. However, there has been little formal study of the relationship among these effects. Certainly, no statistical methods are currently available to jointly analyze these effects of exposure. As a preliminary step in developing such methods, simple exploratory analyses were conducted using a series of ten studies conducted for the National Toxicology Program. Because fetal weight and malformation status were both reported for all live fetuses, the data permitted an exploration of the correlation between these two outcomes. The data show a clear pattern wherein malformed fetuses tended to be lighter at term than nonmalformed fetuses. While these patterns cannot be used to draw inferences regarding the biological relationship between fetal weight and malformation, they do suggest the potential value in developing statistical models for the joint effect of exposure on fetal weight and malformations.
Craniofacial alterations in adult rats prenatally exposed to ethanol
Authors: Edwards Harold G. , Dow‐Edwards Diana L. 
Published: June 2005

AbstractThe rat was studied to determine whether gestational exposure to moderate amounts of ethanol produces permanent craniofacial malformations. Pregnant Long‐Evans rats were fed a liquid diet containing 35% ethanol‐derived calories or an isocaloric liquid diet between gestation days 6 and 20. Various dimensions of skulls and mandibles from adult male offspring were measured. All measurements taken in the parasagittal and coronal planes were significantly smaller in the ethanol‐exposed rats than in the offspring of pair‐fed controls. None of the vertical measurements was significantly altered. This report demonstrates that gestational exposure to ethanol in rats, at doses which produce lasting behavioral effects, also produces a specific constellation of craniofacial dysmorphisms without concomitant decreases in body weight.