bluuebunny/crossref_metadata_2025_split huggingface dataset:
Maternal toxicity—a possible factor in fetal malformations in mice
Authors: Khera K. S. 
Published: June 2005

AbstractThe assumption that major fetal malformations are indicative of a chemical's teratogenic potential was not supported by a literature review of teratology studies conducted in mice. In these studies, dose levels of test agents that manifested maternal toxicity as suggested by reduction in dam's body weight, clinical signs of toxicity, or deaths, also invariably caused reduction in fetal body weight, increased resorptions, and rarely fetal deaths. In several such studies, conducted with maternotoxic doses of structurally unrelated test agents, a consistent pattern of fetal defects was discovered. These defects included exencephaly, open eyes, hemivertebrae, fused arches or centra of lumbar or thoracic vertebrae, fused, missing or supernumerary ribs, and fused or scrambled sternebrae. These defects were absent at drug dosages that were distinctly nontoxic for the mother. In a few studies conducted at two or more maternally toxic doses, the degree and severity of maternal toxicity showed a positive correlation with the incidence and severity of above fetal defects. It is hypothesized that maternal toxicity, on its own, may have an etiologic role in these fetal defects.
Teratogenic effects of avidin‐induced biotin deficiency in mice
Authors: Watanabe Toshiaki , Endo Akira 
Published: June 2005

AbstractTeratogenic effects of maternal biotin deficiency were examined at different levels of severity by adding three levels of avidin (10, 20, or 40 mg/kg) in the basal diet. There was a considerable increase of fetuses with multiple congenital malformations (micrognathia, cleft palate, and micromelia) with increasing amounts of avidin. The dose‐response relationship was observable in the incidence of each malformation as well. The body weight of live fetuses was also significantly reduced. However, the dams did not exhibit any typical signs of biotin deficiency, such as loss of hair, dermatitis, or nervous irritability. These results suggest that biotin is important for early embryonic development in the mouse.
Reproductive and genetic effects of continuous prenatal irrediation in the pig
Authors: Erickson B. H. , Martin P. G. 
Published: June 2005

AbstractThe stem germ cells of the prenatal pig are highly vulnerable to the cytotoxic effects of ionizing irradiation. This study was conducted to determine whether sensitivity to killing was also marked by a sensitivity to mutation and how prenatal depletion of the germ‐cell population affects reproductive performance. Germ‐cell populations were reduced by continuously irradiating sows at dose rates of either 0.25 or 1.0 rad/day for the first 108 days of gestation. The prenatally irradiated boars were tested for sperm‐producing ability, sperm abnormalities, dominanat lethality, reciprocal translocations, and fertility. Prenatally irradiated females were allowed to bear and nurture one litter, then tested for dominant lethality in a second litter; germ cell survival and follicular development were assessed in their serially sectioned ovaries. Sperm production was not significantly affected in the 0.25‐rad boars, but boars irradiated with 1.0 rad per day produced sperm at only 17% of the control level. Incidence of defective sperm was 4.9% and 11.1% in the 0.25 and 1.0 groups, respectively. Four of the 1.0‐rad boars were infertile, but prenatal irradiation apparently caused neither dominant lethality nor reciprocal translocations in fertile males. Number of oocytes was reduced to 66 ± 7% of control in the 0.25‐rad gilts, but reproductive performance was unaffected and no dominant lethality was observed. Only 7 ± 1% of the oocytes survived in the 1.0‐rad group. Reproductive performance was normal for the first litter, but four of the 23 sows tested were infertile at the second litter and a significant incidence of dominant lethality was observed. Whether this was a direct irradiation effect or the consequence of severe oocyte depletion is discussed. Diminished reproductive capacity rather than mutation appears to be the major consequence of continuous prenatal irradiation in the pig.
An anatomical study of human otocephaly
Authors: Lawrence Daniel L. , Bersu Edward T. 
Published: June 2005

AbstractThis study describes the gross anatomic variations observed in a 32‐week male fetus diagnosed as having otocephaly. Special attention was given to the muscular, peripheral nervous, and vascular systems of the entire body. External features included approximation of the ears on the front of the neck, underdevelopment of the lower jaw, and a small oral cavity. The mandible, maxillae, and zygomatic bones were smaller than normal and appeared shifted in a ventrocaudal direction. The middle ear ossicles were fused and abnormally positioned. The tongue was positioned abnormally and malformed. The muscles of mastication were fused in the midline and formed the floor of the oral cavity. The variations were similar to the spectrum of abnormalities reported in two cases in the literature. Because of this finding, it is possible that the causative events leading to these deviations were similar in the three cases. Possible mechanisms are considered which could lead to the observed malformations seen in these cases. There were also several muscle and nerve anomalies outside of the head region.
Cerebral dysraphia (future anencephaly) in a human twin embryo at stage 13
Authors: Müller Fabiola , O'Rahilly Ronan 
Published: June 2005

AbstractCerebral dysraphia was studied histologically and by graphic reconstruction in a twin at stage 13, and comparisons were made with the normal (discordant) twin. The normal, bidirectional closure of the rostral neuropore was investigated in several embryos, from which it was concluded that the situs neuroporicus is represented by the future commissural plate rather than by the (adult) lamina terminalis. In the abnormal twin the neural tube was open over part of the midbrain and forebrain, although the situs neuroporicus was closed. The experimental production of anencephaly by Giroud and co‐workers was reviewed, and comparisons between embryonic staging systems in the rat, mouse, and human were made. Three corresponding phases are found in the human: (1) cerebral dysraphia, occurring before or during Carnegie stage 11 (approximately 23–25 days); (2) exposure of a highly developing and well‐differentiated brain during the remainder of the embryonic period; and (3) degeneration of the exposed brain throughout the fetal period, resulting in anencephaly. Hence the abnormal twin described here is believed to represent a precursor of typical anencephaly, and is the earliest example of purely cerebral dysraphia so far recorded.
Acetazolamide teratogenesis: Association of maternal respiratory acidosis and ectrodactyly in C57BL/6J mice
Authors: Weaver Timothy E. , Scott William J. 
Published: June 2005

AbstractExposure of C57BL/6J mice to CO2 during a critical period of gestation results in predominatly right‐sided, postaxial, forelimb ectrodactyly in the offspring. The incidence and severity of CO2–induced limb malformations has been shown to be dependent on the concentration of inspired CO2, the developmental age of the embryo at exposure and the duration of CO2 exposure. Offspring of acetazolamide‐treated C57BL/6J mice also display this highly specific form of ectrodactyly (Green et al., '73). Since the drug has been shown to elevate tissue CO2 tension (Mithoefer and Davis, '58), the teratogenic effect of acetazolamide may be related to induction of a hypercapnic embryonic environment.
Fetal alcohol syndrome in the ferret (Mustela putorius)
Authors: McLain Daniel E. , Roe Daphne A. 
Published: June 2005

AbstractGastric intubation of 1.5 g ethanol/kg maternal body weight produced a significant teratogenic response in ferrets (Mustela putorius) treated once daily from gestational days 15 through 35. This response was evident by a rise in the frequency of fetuses with one or more malformations (21%), and by a rise in the frequency of litters with one or more malformed fetuses (50%). Palatoschisis and greater relative intermedial canthi distance observed in this study are diagnostic features of the fetal alcohol syndrome (FAS). Although mean (±SEM) peak blood alcohol levels of 207 ± 9 mg/dl did not affect other reproductive parameters, high doses of alcohol (3.0 g/kg) resulted in the inability of treated females to consume adequate food or water, in the complete resorption of litters, and in significant maternal mortality (88%). Fetal deaths occurred prior to gestation day 17 in the high‐dose alcohol group. Based on objective evaluation of differences among ethanol‐treated, pair‐fed sucrosetreated, and untreated ad libitum diet controls, the ferret would seem a valuable alternative animal species for future studies of FAS.
Interactions of salicylate, dietary zinc, and genetic strain in teratogenesis in rats
Authors: Hackman Robert M. , Hurley Lucille S. 
Published: June 2005

AbstractThe influence of dietary zinc concentration on salicylate teratogenesis was studied in Wistar and Sprague‐Dawley rats. Females were fed purified diets containing 0.4, 4.5, 9, 100, or 1,000 μg zinc/gm diet, or a stock diet (Purina Rat Chow) from day zero to day 21 of gestation, when they were killed and the fetuses were examined. On day 9, rats were given saline or 250, 500, or 750 mg sodium salicylate/kg body weight by gavage. Increasing drug dose caused increased frequency of malformed or resorbed fetuses, while increasing dietary zinc reduced the teratogenic effects of salicylate, but in different patterns in the two strains. The teratogenic effect of zinc deficiency also varied by strain. Statistical analysis showed that the frequency of malformed fetuses was significantly affected by levels of dietary zinc or salicylate dose, and interactions of zinc × salicylate and genetic strain × zinc. Frequency of resorption was affected by strain, zinc, salicylate, and interations of strain × salicylate, zinc × salicylate, and strain × zinc × salicylate. Frequency of resorption was affected by strain, zinc, salicylate, and interactions of strain × salicylate, zinc × salicylate, and strain × zinc × salicylate. Frequency of abnormal sites (malformed or resorbed) was affected by strain, zinc, salicylate, and interactions of strain × salicylate, zinc × salicylate, and strain × zinc × salicylate. The results suggest that marginal zinc deficiency in certain pregnant women might increase the possibility of salicylate teratogenicity.
Reproduction and fetal development in rats exposed to nitrous oxide
Authors: Mazze Richard I. , Wilson Anne I. , Rice Susan A. , Baden Jeffrey M. 
Published: June 2005

AbstractThe effects of 24 hours of nitrous oxide exposure on reproductive indices and fetal development were examined in Sprague‐Dawley rats. Four different experiments employing four concentrations of nitrous oxide—0.75%, 7.5%, 25% and 75%—established that the threshold of toxicity was greater than 25%. At 75% nitrous oxide there was a significant increase in early and late resorptions, and a consistent teratogenic effect (e.g., runts, occular malformations, limb deformities). Neither the stress of shipping dams while pregnant nor the witholding of food during nitrous oxide exposure resulted in additional adverse effects. Exposure to 25% nitrous oxide was associated with increased deoxyuridine suppression values; however, adverse reproductive effects were not seen at this nitrous oxide concentration. The results of this and other studies which have examined the reproductive and teratogenic effects of nitrous oxide do not contraindicate its use in operating rooms nor, when necessary, as an anesthetic for pregnant surgical patients.
Ethanol teratogenicity in mice: An electron microscopic study
Authors: Bannigan John , Cottell David 
Published: June 2005

AbstractIn this study, the neuroepithelium (NE) cells of the mouse embryo were examined with the electron microscope at various intervals after maternal injection of 0.03 ml/g body weight 25% (v/v) ethanol on day 9 of gestation (plug day = day 1), by the intraperitoneal route. Within 1 hour of treatment, the mitochondria of the NE cells became greatly swollen but could recover. Recovery occurred in two phases: a rapid one during the second hour after treatment, followed by a more gradual one that lasted until 12 hours after treatment. About 5 hours after treatment, dying and fragmenting cells were seen in the NE of all embryos examined. The debris from this necrosis was phagocytosed by neighbouring healthy cells. Also at 5 hours after treatment there was an apparent expansion of the intercellular space of the NE and an enlargement of the apical pseudopodial processes of the NE cells. The latter two changes may have been the result of failure of energy‐dependent cell fluid homeostasis consequent to mitochondrial dysfunction. All of these changes were reversed by 15 hours after treatment. Although all embryos examined had abnormalities of the NE, including cell necrosis, at 24 hours after treatment only 28% had failed to complete neural tube formation. Hence, either the degree of ethanol‐induced damage varies between embryos in the same litter, or the sensitive period is so restricted that variations in stage of development within a litter can account for the lack of concordance between the presence of cellular damage and the subsequent occurrence of a neural tube defect.
Diflunisal‐induced maternal anemia as a cause of teratogenicity in rabbits
Authors: Clark Robert L. , Robertson Richard T. , Minsker David H. , Cohen Sheila M. , Tocco Dominick J. , Allen Henry L. , James Mary L. , Bokelman Delwin L. 
Published: June 2005

AbstractDiflunisal [5‐(2,4‐difluorophenyl)‐salicylic acid] is a new analgesic antiinflammatory drug that, when administered orally to rabbits at 40 and 60 mg/kg/day, caused terata, most commonly axial skeletal defects. These same dosage levels also caused a severe maternal hemolytic anemia following a dramatic decrease in erythrocyte ATP levels. The teratogenicity, anemia, and depletion of ATP were unique to the rabbit among species examined. To test the possible causality between the teratogenic effects and anemia induced by diflunisal, a single dose of 180 mg/kg diflunisal was administered to rabbits on gestation day 5. This treatment produced an anemia that persisted through gestation day 15 in addition to causing the characteristic axial skeletal defects. Since diflunisal was cleared from maternal blood before gestation day 9, the critical day for induction of similar axial skeletal defects by hypoxia, the skeletal malformations probably resulted from maternal hypoxia secondary to anemia and not from a direct and specific effect of the drug on the embryo. In addition, we observed that the diflunisal level in the embryo was less than 5% of the peak maternal blood level probably as a result of high plasma protein binding of diflunisal in the maternal blood (>98%). This relatively low placental transfer may explain the lack of diflunisal teratogenicity in rats and mice compared to aspirin which crosses the placenta more readily. These studies demonstrate that a species that exhibits unusually severe drug‐specific maternotoxicity is probably an unsuitable model for the prediction of the teratogenic potential of that drug in humans.
D‐penicillamine‐induced cleft palate in mice
Authors: Myint Ba 
Published: June 2005

AbstractThe teratogenic potential of the lathyrogen, D‐penicillamine (DP), was assessed in pregnant mice, especially with respect to its ability to produce cleft palate. The dosage and the duration of treatment as they relate to the induction of cleft palate were also studied. Two different doses of DP were administered orally for either 5 or 4 consecutive days during the critical period of palatal closure. D‐penicillamine (DP) at a dose level which does not have any apparent maternal toxic effects produced cleft palate in the offspring, and this teratogenic effect depended more upon the duration of treatment than the dosage administered. Inhibitory effects on the formation of bone matrix were observed at the base of the palatal shelf. It is suggested that DP is potentially an osteolathyrogenic agent. The mechanism of induction of cleft palate in DP‐treated mice was explored by histological studies using light microscopy. Delayed elevation of the palatal shelves was observed and is considered to be the cause of the induction of cleft palate. No other external malformations could be detected in DP‐treated fetuses.
Cardiovascular birth defects and antenatal exposure to female sex hormones: A reevalution of some base data
Authors: Wiseman R. A. , Dodds‐Smith I. C. 
Published: June 2005

AbstractA re‐evaluation of the base data as reported by Heinonen et al. from the Drug Epidemiology Unit of the Boston Collaborative Perinatal Project (CPP) was undertaken in order to examine particularly three matters which were not fully considered in the publication. These were, first, the timing of administration of sex hormones during the index pregnancy, which is relevant to determining whether any statistical association reported between sex hormone exposure and malformations could be causal; second, the incidence of serious maternal vaginal bleeding in early pregnancy, which could be an indication of threatened abortion, which in turn in associated with an increased malformation rate, and in addition is an indication for sex hormone administration; and third, the incidence of malformations or other adverse outcome in previous pregnancies, which, if present, might play a material role in the risk of malformation in the index pregnancy. Examination of the records of the 19 cases described by Heinonen et al. as hormone‐exposed/cardiac‐malformed revealed that no preparation containing hormone was administered in two patients, that five cases were given hormones too late in the index pregnancy to have any effect on cardiac organogenesis (which by general consensus begins on day 19 and ends at the latest on day 50 of gestation), that two cases were given hormones too early and two cases had Down's Syndrome. Thus eight children were exposed to hormones during the critical period of cardiac organogenesis, out of 17 actual hormone takers (47%). The description of vaginal bleeding did not allow any conclusions regarding differential rates of threatened abortion. It was found that the incidence of major malformations was 17% in the index group and 4% in the non‐malformed group. This suggests that the hormone‐exposed patients who gave rise to children with cardiac malformations were a highly selected group. The re‐evaluation therefore reveals that the incidence of exposure to sex hormones during the critical period of cardiac organogenesis was not significantly different statistically in those women whose children had cardiac lesions as compared to those without such lesions. It is suggested that the result of this re‐evaluation should direct the attention of epidemiologists to the quality of their base data. Re‐examination of the base data of the Boston CPP does not support their reported association between the exposure to female sex hormones during pregnancy and the occurrence of cardiac malformations.
Cartilage‐staining technique for the examination of unskinned fetal rat specimens previously processed with alizarin red S
Authors: Boardman J. P. , Mitala J. J. , Carrano R. A. , Iuliucci J. D. 
Published: June 2005

AbstractA novel staining technique has been devised that permits a cartilage examination of unskinned fetal rats that have been previously processed for skeletal examination with alizarin red S. The procedure consists of rinsing alizarin red S‐stained specimens in distilled water and placing the specimens in a 3% acetic acid solution. A transfer of the stain from bone to adjacent cartilage occurs, producing purple‐stained cartilaginous structures that can be differentiated from still‐discernible bone structures.
Effects of lead and hyperthermia on prenatal brain growth of guinea pigs
Authors: Edwards M. J. , Beatson Jenny 
Published: June 2005

AbstractThe effects of lead at blood levels of 100 μg/100ml or less on the brains of young animals have not been clearly defined, and little is known of its effects and interactions with other agents on prenatal brain development. This study examined the effects of subclinical doses of lead acetate given to pregnant guinea pigs on the development of the embryo brain. At 9 A.M. on day 20 or 21 of pregnancy, guinea pigs were given 6, 12.5, or 25 mg/kg body weight of 0.5% lead acetate in distilled water by intraperitoneal injection. Some of the animals at each dose rate were also exposed to hyperthermia at 11 A.M. on the day of injection and the following day. Another group was exposed to hyperthermia without lead treatment. A saline‐treated control group was used for comparison. Mean levels of lead in blood 1 hour after dosing ranged between 65 and 128 μg/100 ml and at 24 and 72 hours between 65 and 96 μg/100 ml. Brain weights of newborn guinea pigs in the 12.5‐ and 25‐mg lead acetate group were significantly reduced compared with control values. Body weights of all groups receiving lead were not significantly differently different from those of controls. There was no indication of interaction between hyperthermia and lead acetate in doses of 6 or 12.5 mg/kg. At 25 mg/kg plus hyperthermia, there appeared to be a strong synergistic response, with an incidence of 88% micrencephaly compared with 5% in the group given 25 mg/kg without hyperthermia and 46% in the hyperthermia without lead group. The results indicate that subclinical levels of lead can retard prenatal brain growth, and this effect is potentiated by hyperthermia.
Moderate prenatal carbon monoxide exposure produces persistent, and apparently permanent, memory deficits in rats
Authors: Mactutus Charles F. , Fechter Laurence D. 
Published: June 2005

AbstractThe effects of moderate (150 ± 2 ppm) prenatal carbon monoxide (CO) exposure (maternal HbCO concentrations of 15.6 ± 1.1%) on learning and memory were assessed in young and aged adult rats using a two‐way active avoidance paradigm. In experiment 1, the prenatal CO‐exposed rats at 120 days of age acquired a conditioned avoidance response equally well as control animals in a 100‐trial session. However, following a 24‐hr interval the CO‐exposed rats failed to demonstrate significant retention of the task as indicated by the absence of significant improvement in performance over the previous day; control subjects did show significant retention. In experiment 2, in which 120‐day‐old animals received 50 training trials per day until a criterion of ten consecutive avoidance responses was met, the prenatal CO‐exposed subjects again acquired the task as well as control animals. When tested for retention 28 days later, a significant memory impairment was again observed in terms of trials required to reattain the avoidance criterion as well as in total percent avoidance responding. In neither experiment did an analysis of initial or average latency to escape the footshock stimulus reveal any significant alterations. These latter results suggest that the observed performance impairment reflected a memory deficit and not a disruption of sensory, motor, or motivational factors. In experiment 3, prenatal CO‐exposed rats approximately 1 year of age (300–360 days of age) showed impairment relative to air‐exposed controls in both the original learning and retention of the two‐way avoidance response. Again, however, there was no evidence for alterations in performance factors per se. Collectively these data indicate that while young adult rats prenatally exposed to 150 ppm CO demonstrate an associative deficit restricted to memory impairment, aged adults similarly exposed during the prenatal period display a more pronounced deficit similar to that recently reported for animals tested as juveniles. The importance of parametric manipulations in uncovering long‐term toxicity is also discussed.