bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative developmental toxicity of cationic and neutral rhodamines in mice
Authors: Hood Ronald D. , Jones Cathy L. , Ranganathan Sulabha 
Published: June 2005

AbstractRhodamines 123 and 6G (Rh 123 and Rh 6G) are cationic fluorescent dyes that inhibit oxidative phosphorylation following their selective accumulation within mitochondria. Neutral rhodamines (e.g., Rh 116 and Rh B) do not share these properties. To determine if cationic and neutral rhodamines differ in their effect on mammalian development, pregnant CD‐1 mice were injected i.p. with Rh 123, Rh B, or Rh 116 at doses of 15 mg/kg/day. The rhodamines were given alone or in combination with 500 mg/kg/day 2‐deoxy‐D‐glucose (2‐DOG), an inhibitor of glycolysis, daily on gestation days 7–10 (copulation plug = day 1). Additional pregnant mice were similarly treated with Rh 6G at a dose of 0.5 mg/kg/day. Controls were given saline equimolar to the dose of 2‐DOG. Treatment with Rh 6G, alone or in combination with 2‐DOG, significantly increased the incidences of prenatal mortality (17% and 35%, respectively) when compared with the control incidence (6%). Treatment with Rh 123 or Rh 6G, alone or with 2‐DOG, inhibited fetal growth. Treatment with the neutral rhodamines had little effect on prenatal survival or growth. Exposure to Rh 6G, with or without 2‐DOG, was associated with high incidences of gross malformations (41% and 61%, respectively). Rh 116 or Rh B, with or without 2‐DOG, and Rh 123 alone were not associated with statistically significant teratogenic effects, but results of the latter treatment were suggestive of such an effect (9.1% grossly malformed fetuses vs. 0% for controls). The incidences of skeletal malformations were significantly increased in the test groups given Rh 6G + 2‐DOG, Rh 123 + 2‐DOG, or Rh 6G alone. These results suggest a relationship between the charge on the rhodamine molecule and effects on the conceptus, and these effects may have been mediated at least in part by interference with mitochondrial metabolism.
Bendectin and human congenital malformations
Authors: Shiono Patricia H. , Klebanoff Mark A. 
Published: June 2005

AbstractThe relationship between Bendectin exposure during the first trimester of pregnancy and the occurrence of congenital malformations was prospectively studied in 31,564 newborns registered in the Northern California Kaiser Permanente Birth Defects Study. The odds ratio for any major malformation and Bendectin use was 1.0 (95% confidence interval 0.8–1.4). There were 58 categories of congenital malformations; three of them were statistically associated with Bendectin exposure (microcephaly—odds ratio = 5.3, 95% confidence interval = 1.8–15.6; congenital cataract—odds ratio = 5.3, 95% confidence interval = 1.2–24.3; lung malformations (ICD‐8 codes 484.4–484.8)—odds ratio = 4.6, 95% confidence interval = 1.9–10.9). This is exactly the number of associations that would be expected by chance. An independent study (the Collaborative Perinatal Project) was used to determine whether vomiting during pregnancy in the absence of Bendectin use was associated with these three malformations. Two of the three (microcephaly and cataract) had strong positive associations with vomiting in the absence of Bendectin use. We conclude that there is no increase in the overall rate of major malformations after exposure to Bendectin and that the three associations found between Bendectin and individual malformations are unlikely to be causal.
Sex difference in digit and palate formation of mouse embryos at midgestation
Authors: Watanabe Toshiaki , Endo Akira 
Published: June 2005

AbstractWe investigated whether there is a difference in timing between the sexes of mouse embryos with regard to digit and palatal formation at midgestation by using a simple method of sex chromatin analysis for rodent embryos. At day 14.4 of gestation, although the mean body weight of male embryos was greater than that of female embryos, digit and palatal formation of female embryos was found to be more advanced than in males when compared according to their body weight. This was contrary to our previous finding of digit formation at the earlier stage (day 12.0 of gestation): namely, that digit development was more advanced in male embryos than in female embryos even when two sexes were compared according to their body weight. Thus, the development of female embryos catches up with that of male embryos at the later stages of midgestation. The period for digit development must be longer in male embryos than in female embryos. If mothers are exposed to some teratogens, a sex difference in incidence of digital defects might be produced.
Interpretation of some median anomalies as illustrated by cyclopia and symmelia
Authors: O'Rahilly Ronan , Müller Fabiola 
Published: June 2005

AbstractAnomalies that involve the median plane are heterogeneous, and their embryological basis varies widely. Cyclopia and symmelia present a number of similarities: 1) They would appear to arise by neither fusion nor merging but mainly through a failure in lateralization. 2) Mesenchymal deficiency is important in both: possibly disturbance of the prechordal plate in cyclopia and failure of the caudal eminence in symmelia. The caudal eminence is an important developmental feature that is only recently becoming clearer in the human embryo. 3) Disturbance of axial material seems to be essential in both. 4) The results of experimental teratogenesis and an analysis of normal human development confirm that these conditions arise early. The teratogenetic termination‐periods in the human are probably 21/2 weeks for cyclopia sensu stricto (a median eye in a single orbit) and 3 weeks for cyclopia sensu lato, i.e., synophthalmia (paired ocular structures in a single orbit); 2 1/2 weeks for symmelia of the upper limbs (e.g., in cephalothoracopagus) and 3 1/2 weeks for symmelia of the lower limbs in a single individual. It is pointed out that in symmelia the limb buds, upper or lower, have failed to separate at their postaxial margins. This is in contrast to dimelia, in which the preaxial borders are missing and the postaxial margins are duplicated (postaxial dominance).
Amelioration of the teratogenicity of cadmium by the metallothionein induced by bismuth nitrate
Authors: Naruse Ichiro , Hayashi Yukimasa 
Published: June 2005

AbstractThe participation of maternal hepatic metallothionein (MT) in the amelioration of cadmium teratogenicity in mice was examined. Pretreatnient with Lisrriulh nitrate (subcutaneously) ameliorated the teratogenicity, including exencephaly and abnormalities of the axial skeleton, caused by a single intraperitoneal injection of cadmium sulfate. Pretreatment with bismuth nitrate for 3 days induced MT drastically in maternal liver and kidney. Six and 24 hr after the injection of cadmium sulfate, the accumulation of maternal hepatic cadmium increased and that in the decidua, including embryos, decreased after pretreatment with bismuth nitrate.Mouse embryos on day 7 of gestation were cultured for 48 hr. Exposure to cadmium sulfate in vitro induced unfused brain fold, which corresponds to exencephaly in vivo. From the in vitro experiment, it was suggested that the teratogenicity of cadmium on day 7 of gestation is a direct action against the mouse embryo. In the present experiment it was suggested that pretreatment with bismuth nitrate induced maternal hepatic and renal MT; cadmium was therefore trapped and detoxicated, and consequently embryos were exposed to a lower concentration of cadmium.
Congenital heart disease among spontaneous abortuses and stillborn fetuses: Prevalence and associations
Authors: Chinn Anne , Fitzsimmons Jack , Shepard Thomas H. , Fantel Alan G. 
Published: June 2005

AbstractThe prevalence, range, and associations of congenital heart disease (CHD) were studied among 400 spontaneous abortuses between 9 and 40 weeks' gestation. Fifty‐two (13.0%) cases of CHD were detected. To minimize selection bias the specimens were grouped by external appearance and the prevalence expressed accordingly. CHD was detected in 21 (7.3%) of 289 externally normal and 31 (27.9%) of 111 externally abnormal fetuses. Ventricular septal defect (VSD) was the most frequent CHD found in isolation as well as in combination with extracardiac malformations. Seventy‐five percent of isolated CHD was VSD. Forty (69.2%) of the 52 cases of CHD were associated with extracardiac malformations. Chromosomal syndromes were responsible for a minimum of 19.2% of the cases and suspected in up to 36.5%. The most frequent associations involved the musculoskeletal system, central nervous system, abdominal wall, and kidneys. In contrast, studies of liveborn infants have reported 70% of CHD as isolated defects, including many CHD infrequently seen among spontaneous abortuses. This suggests that fetuses with isolated CHD often survive to term, and CHD does not significantly affect the survival of the fetus in utero. Ventricular septum formation may be particularly susceptible to hemodynamic changes and may be indicative of an underlying pathologic condition that also leads to a spontaneous abortion.
Effect of smokeless tobacco on the development of the CD‐1 mouse fetus
Authors: Paulson Ruth , Shanfeld Joseph , Sachs Larry , Price Theresa , Paulson John 
Published: June 2005

AbstractThe objective of this study was to examine the effect of an aqueous extract of smokeless tobacco (ST) on the development of the CD‐1 mouse fetus. Three ST dosages were administered three times daily by gastric intubation during gestational days 1–17: 1 × ST equivalent to a dose of 4 mg nicotine/kg body weight, 3 × ST equivalent to 12 mg nicotine, and 5 × ST equivalent to 20 mg nicotine/kg body weight. Maternal plasma nicotine levels were determined 30 minutes after the second daily intubation at five different times during the gestational period.At these ST dosages, the weight gain of ST‐treated dams was not significantly affected in comparison to treated controls, though the difference was significant (P<.05) in comparison to untreated controls. The mean maternal plasma nicotine level for the low dosage (1 ×) group was 99.0 ng/ml, which reasonably approximates human consumption levels. The 3 × ST and 5 × ST dosages produced higher nicotine plasma values, 398 ng/ml and 623 ng/ml, respectively, were considerably more toxic to the dams, and resulted in 18% and 31% maternal deaths. Fetal weights were reduced by 7.4% (P<.001) in the highest ST dosage group (5 ×), whereas at the 1 × and 3 × dosages fetal weight differences were not significantly different from treated controls. Resorptions increased in a dose‐related manner (P<.05), ranging from 4.7% in the 1 ×, to 6.4% in the 3 × and 8.9% in the 5 × dosage compared to 3.2% in treated controls. External malformations were few and minor in extent. Internal malformations increased in a linear, dose‐related manner (P<.05). Placental weights were unaffected by ST.The results of skeletal examinations were inconclusive. Precocious ossification was seen in 60% and 70% of the parameters measured in the 1 × and 3 × dosage groups, respectively, in comparison to controls. In the 5 × ST group ossification levels were less than in controls for 30% of the parameters measured.Under these experimental conditions the lowest ST dosage (1 ×) produced a negligible effect on the CD‐1 mouse fetus and the dam. The highest ST dose (5 ×) demonstrated embryotoxicity, growth retardation, few malformations, and maternal toxicity. The intermediate dose (3 ×) showed a range of effects between the highest and lowest doses to both the fetus and the dam.
Changes in red nucleus neuronal development following maternal alcohol exposure
Authors: Zajac C. S. , Bunger P. C. , Moore J. C. 
Published: June 2005

AbstractThe red nucleus of Swiss Webster mouse fetuses was examined for morphological changes following maternal ethanol exposure. Pregnant females were given a liquid diet containing 30% or 0% ethanol‐derived calories. Changes in numerical density of neurons and in neuronal nuclear volume were found in the rostral red (RR) nucleus of ethanol‐exposed pups but not in the caudal red (CR) nucleus. Because of the integrative nature of the RR, changes in neuronal morphology that might relate to synaptic connections could affect the behavioral response mechanisms of these off spring.
Discontinuity of primary and secondary neural tube in spina bifida induced by retinoic acid in mice
Authors: Yasuda Yoshiko , Konishi Hiroyoshi , Kihara Takahide , Tanimura Takashi 
Published: June 2005

AbstractThis report shows by light microscopy the appearance of secondary neurulation separated from primary neurulation and its developmental fate in the spinal cord of mice exposed to retinoic acid in utero. The embryos and fetuses were derived from pregnant mice (ICR strain) given 60, 40, or 0 mg/kg of retinoic acid in olive oil on day 8 of gestation orally and killed 1, 2, or 10 days later. Separation of the primary neural fold from the secondary neural tube was seen in 9‐ and 10‐day‐old embryos: the caudal part of the neuroepithelium of the primary neural fold was disarranged with non‐closed posterior neuropore, and underneath it the secondary neural tissue extended caudally with abnormal notochord. At term, fetuses showed spina bifida, including myeloschisis, myelocele, and diplomyelia (diastematomyelia) with abnormal distribution of ganglionic cells. These cord lesions were located between the third lumbar and second coccygeal levels. The former two cord anomalies were associated with diplomyelia and split the dorsal and ventral portions of the spinal cord with an overlapping zone between the third lumbar and third sacral levels. These findings suggest that the separation from primary neurulation is due to the lesions in both primary neural folds and notochord induced by retinoic acid and that the spinal cord caudal to the third lumbar level originates from both neuroectoderm and mesenchyme‐like cells while that caudal to the third sacral level originates from mesenchyme‐like cells only.
Processes involved in retinoic acid production of small embryonic palatal shelves and limb defects
Authors: Abbott B. D. , Hill L. G. , Birnbaum L. S. 
Published: June 2005

AbstractAll‐trans‐retinoic acid (RA) is teratogenic to the embryonic mouse, producing malformations in many developing systems, including the limb bud and palate. High incidences of limb defects and cleft palate are induced at doses which are not maternally toxic and do not increase resorptions. Exposure to RA on gestational day (GD) 10 results in small palatal shelves, which fail to make contact on GD 14. The formation of small shelves could be a consequence of increased cell death, reduced proliferation, a combination of these effects, or some other effect such as inhibition of extracellular matrix production. After exposure to 100 mg RA/kg on GD 10, proliferation in mesenchymal cells of the palatal shelves was not reduced from GD 12 to GD 14 and the levels of cell death in control and treated shelves did not differ when observed by light and electron microscopy. The present study examines the effects of RA on cell death and proliferation from GDs 10–12 and compares the effects in palatal shelves and limb buds. Embryonic mice were exposed to RA suspended in corn oil (100 mg/kg on GD 10), a dose that was teratogenic but not maternally toxic or embryolethal. Embryos were collected at 4, 12, 24, 36, or 48 hr postexposure, and tissues which form the palate or limb were dissected from the embryos, stained by a modified Feulgen procedure, and whole mounted on slides. Mitotic index (MI) and percentage dead cells were determined for mesenchymal cells of the first visceral arch, maxillary process, or palatal shelf (depending on stage of development) and forelimb buds. In the palatal tissues from GD 10 to GD 12, RA did not significantly alter MI and percentage dead cells was significantly increased only at 4 hr postexposure. Some whole embryos were prepared for scanning electron microscopy (SEM). At 48 hr (GD 12) a reduction in the size of the shelves was not apparent on SEM. In the limb buds, RA did not increase percentage dead cells, but MI was significantly decreased. A decreasing rate of proliferation was detected in control facial tissues as development progressed, and this agrees with findings in rat and chick. Thus it appears that mesenchymal cell death and reduced proliferation are not responsible for the small palatal shelves seen on GD 14. RA did not increase cell death but inhibited proliferation in the limb bud, and this effect may contribute to the retarded development and malformations occurring in the limb.
Biochemical changes in the developing rat central nervous system due to hyperthermia
Authors: Rao G. Subba , Abraham Varkey , Fink Bradley A. , Margulies Nurit , Ziskin Marvin C. 
Published: June 2005

AbstractRat embryos at 10 days of gestation were exposed to 43°C for 8 minutes by submerging the exteriorized right uterine horn in heated saline solution and then reinserting the uterine horn into the abdominal cavity. At 15 days, the fetuses were removed, and cells from the cerebral hemispheres were dissociated and grown as primary cultures. Embryos from the left uterine horn served as controls. No morphological changes were observed between the cultures of cells from control and heat‐exposed embryos at different days in culture. However, exposure of embryos to hyperthermia at 10 days significantly affected the developmental pattern of activities of acetylcholine esterase associated with cholinergic neurons and of 2′,3′‐cyclic nucleotide phosphohydrolase associated with oligodendrocytes and myelin membrane formation. These results suggest that hyperthermia at 10 days of gestation in the rat may lead to an impairment in the development of neurons and oligodendrocytes in the central nervous system.
Parameters determining isotretinoin teratogenicity in rat embryo culture
Authors: Ritchie Helen , Webster William S. 
Published: June 2005

AbstractAt the in vitro threshold serum concentration of 500 ng/ml, isotretinoin induces defects of visceral arch development in 9.5‐day rat embryos grown in culture for 48 h. Experiments were performed to determine the minimum period of exposure necessary to induce these arch defects and whether an increase in concentration of isotretinoin could compensate for reduced exposure time. The results showed that a minimum 6‐h exposure to 500 ng/ml immediately prior to cranial neural crest migration was necessary to induce severe defects of the second visceral arch in a majority of embryos. Maximal increase in isotretinoin concentration to 16,000 ng/ml did not compensate for shorter exposure periods.These results suggest that to cause malformations of the visceral arches, the embryo must be exposed to isotretinoin for a minimum period of time regardless of the concentration of isotretinoin above the threshold.
Preventive effects of phenoxybenzamine on nitrous oxide‐induced reproductive toxicity in Sprague‐Dawley rats
Authors: Fujinaga Masahiko , Baden Jeffrey M. , Suto Akira , Myatt John K. , Mazze Richard I. 
Published: June 2005

AbstractIn previous studies, we have shown that the reproductive toxicity of N2O in rats is prevented by the co‐administration of either halothane or isoflurane, whereas treatment with folinic acid, which should reverse the effects of N2O on DNA production, does not prevent toxicity. These results cast doubt on the commonly held theory that inactivation of methionine synthase is the sole cause of N2O‐induced reproductive toxicity, and suggest the need for other hypotheses. One such possibility is that N2O causes adverse reproductive toxicity secondary to its sympathomimetic effects. As a first step to test this theory, we studied the effects of phenoxybenzamine (PX), an alpha‐1 adrenergic antagonist, on N2O‐induced reproductive toxicity using a well‐established in vivo rat model. On day 8 of gestation (plug day = day 0), 130 timed‐pregnant Sprague‐Dawley rats were injected s.c. with either 0.5 ml of either 0.9% saline (control and N2O alone groups) or PX (0.5, 5, or 50 μg/kg) in 0.9% saline, the latter the maximum tolerated PX dose. They were then exposed to either air (control) or 60% N2O for 24 hours (all other groups). On day 20 of gestation, cesarean sections were performed and the fetuses were removed and examined for either visceral of skeletal abnormalities. Compared with control, treatment with N2O alone resulted in increased incidences of fetal resorptions, major and minor visceral abnormalities, and minor skeletal abnormalities. The most common major abnormalities were various forms of altered body laterality (20/72 fetuses; 28%). The two highest PX doses partially reduced the incidence of resorptions but none of the PX doses prevented major teratogenic effects. These results suggest that stimulation of alpha‐1 adrenergic receptors accounts for some of the adverse reproductive effects of N2O. It should be noted that although the concentration of N2O used in the present study is in the clinical range, N2O is rarely administered to surgical patients for more than a few hours. Our main aim was to study the mechanisms involved in the reproductive toxicity of longterm N2O exposure and not for any concerns that short‐term (a few hours) exposure represented a reproductive risk.