bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of oxygenation in embryotoxic mechanisms of three bioreducible agents
Authors: Barber C. V. , Fantel A. G. 
Published: June 2005

AbstractMany xenobiotics used in the treatment of hypoxic pathogens and tumors require reductive bioactivation under anaerobic conditions for maximal effectiveness and/or toxicity. A number of agents of this type have been shown to be teratogenic in vitro and/or in vivo. Early conceptuses may be vulnerable to these agents because they exist in a relatively anaerobic environment and have the capacity to perform reductive metabolism. It has been hypothesized that the single electron redox potential of bioreducible agents plays a dominant role in the capacity to induce anomalies. We examined the in vitro embryotoxicity in rats of three bioreducible drugs of similar redox potential under normoxic and hypoxic conditions as well as the capacity of those drugs to redox cycle and to damage DNA in embryonic tissue. Adriamycin, mitomycin C, and niridazole were shown to have differential embryotoxic responses in vitro to altered oxygenation. Studies of the bases of drug action showed (1) Adriamycin induces DNA strand breaks at concentrations that correlate well with embryolethality; (2) Mitomycin C does not induce strand breaks, but its dysmorphogenicity is increased by hypoxia; and (3) Niridazole does not produce DNA damage but appears to induce asymmetric malformations by depleting embryonic oxygen through redox cycling. Together the studies show that dysmorphogenic and embryolethal effects may result from separate mechanisms and that oxygenation plays an important role in those mechanisms. © 1993 Wiley‐Liss, Inc.
Ellagic acid embryoprotection in vitro: Distribution and effects on DNA adduct formation
Authors: Frank Anthony A. , Collier John M. , Forsyth Carol S. , Zeng Wenguang , Stoner Gary D. 
Published: June 2005

AbstractEllagic acid (EA) is a naturally occurring plant phenol that was recently demonstrated to protect cultured rat embryos from the embryotoxic effects of N‐methyl‐N‐nitrosourea (MNU). The teratogenic mechanism of action of MNU, as well as other methylating agents, is debated: both cell death and mutation have been proposed. In some model systems, EA has been reported to selectively decrease the mutagenic DNA adduct O6‐methylguanine (O6MG) when compared to the cytotoxic DNA adduct N7‐methylguanine (N7MG). The present study was initiated to determine 1) the distribution of 14C‐EA and 3H‐MNU in the rat whole embryo culture model system and 2) the effects of EA on MNU‐induced DNA adduct formation in this model system. 14C‐EA (50 μM for 2 hr, known embryoprotective concentration; no MNU added) was used to demonstrate access of EA to the embryo within the 2 hr exposure period. The majority of EA (99.5%) remained in the media while tissue concentrations of 57.0 and 47.9 pmol/mg were attained in the yolk sacs and embryos, respectively. Similarly, MNU (75 μM for 1 hr, known effective concentration; no EA added) was distributed between the media, yolk sacs, and embryos at 99.7%, 73.7 and 112.9 pmol/mg, respectively. When non‐radiolabeled EA (50 μM for 2 hr) was used to protect embryos prior to exposure to 3H‐MNU (75 μM for 1 hr), the distribution of MNU in the model system was unchanged. When O6MG and N7MG addjuction rates in yolk sac DNA, embryo DNA, and pooled data were compared between protected (50 μM EA for 2 hr followed by 75 μM MNU for 1 hr), and non‐protected tissues (vehicle for 2 hr followed by 75 μM MNU for 1 hr), EA decreased O6MG formation by 35.2–49.7% while N7MG was not decreased. The decreases in O6MG formation were only statistically significant (P < 0.05) when yolk sac and embryo data were pooled. EA apparently interrupts the embryotoxic pathogenesis of MNU by decreasing O6MG formation within the embryo and/or yolk sac. © 1993 Wiley‐Liss, Inc.
External craniofacial features, body size, and renal morphology in prenatal Brachyrrhine mice
Authors: Ma Wenbin , Lozanoff Scott 
Published: June 2005

AbstractThe Brachyrrhine (Br) semidominant mouse mutant provides a useful model for studying factors responsible for midfacial hypoplasia. In order to determine early morphogenetic events responsible for midfacial hypoplasia in these mice, prenatal mutants must be differentiated from nonaffected littermates. The purpose of this study was to determine whether prenatal offspring from Br matings could be separated morphologically into groups of normal or midfacially deficient embryos. Thirty embryos resulting from Br matings were collected between day 15 and birth (Theiler stages 23–27). Qualitative observations on craniofacial morphology as well as renal morphology and histology suggested that embryos segregated into two distinct groups. External craniofacial and body measurements, collected from the embryos, as well as renal volumes, determined from computerized reconstructions of the kidneys, were subjected to quantitative analyses. A discriminant function analysis segregated the sample into two groups based primarily on midfacial length and renal volume. Bivariate regression analysis showed that midfacial length and renal volume differed significantly, and cranial length marginally so, between the two groups. The results indicate that a proportion of prenatal offspring from Br matings exhibits midfacial and renal hypoplasia and that these animals segregate completely from nonaffected embryos. © 1993 Wiley‐Liss, Inc.
Expression of the IV (reversed and/or heterotaxic) phenotype in SWV mice
Authors: Layton W. M. , Layton M. W. , Binder Michael , Kurnit David M. , Hanzlik Andrzej J. , Van Keuren Margaret , Biddle Fred G. 
Published: June 2005

AbstractApproximately 50% of iv/iv mice have situs inversus (mirror image reversal of viscera) and 40% have heterotaxia (anomalous arrangement of viscera). The occurrence of heterotaxia is independent of situs. Using the cross‐intercross breeding system to put the iv gene on the SWV background, an occasional presumed iv/ + mouse was found that had an IV (situs inversus and/or heterotaxic) phenotype. Testcrosses of these reversed animals indicated an iv/ + genotype. Since iv is linked tightly to Igh‐C on chromosome 12, we inferred the genotype with a polymorphism of Igh‐C demonstrated using the polymerase chain reaction (PCR). This confirmed them to be iv/ +. The expression of the IV phenotype in animals heterozygous for the iv gene may be due to an interaction of iv with an autosomal recessive gene found in SWV. We have not found the IV phenotype in heterozygous iv/+ mice following placement of the iv gene on six other inbred strains. Rarely, we also found that presumed SWV +/+ mice had the IV phenotype. Test matings of these phenodeviants, corroborated by PCR, have confirmed them to be +/+. Although the phenotypes of the affected SWV +/+ and iv/ + mice resembled those found in iv/iv mice, the occurrence of situs inversus and heterotaxia were not independent of each other, and most of the SWV mice with the IV phenotype had heterotaxia with situs solitus.This infrequent dominant expression of the iv gene has so far only been seen when iv is on the SWV background. These findings are consistent with the idea that this phenomenon is due to the interaction of the iv gene with another gene found so far only in the SWV strain. © 1993 Wiley‐Liss, Inc.
The Teratogenic effects of salicylic acid on the developing nervous system in rats in vitro
Authors: Joschko Marion A. , Dreosti Ivor E. , Tulsi Ram S. 
Published: June 2005

AbstractAspirin ingestion in humans and animals has been reported to lead to a range of undesirable outcomes, including fetal death, growth retardation, and congenital abnormalities. Rat embryos were cultured for 48 h in 100–300 μg/ml of salicylic acid, a metabolite of aspirin, days 9.5–11.5 of gestation. When compared to growth in control embryos, a significant dose‐dependent decrease in crown‐rump lengths, somite numbers, and yolk sac diameters was observed. There was also a significant increase in overall dysmorphology, including eye, branchial arch, and heart anomalies, and an absence of forelimb buds. The neural tube was especially vulnerable and had frequently failed to close. Cellular and ultrastructural examination revealed extensive cell death in the neuroepithelium, with a lesser effect on the mesenchymal cells. Large condensed blebs projected into the ventricular lumen, and cell membranes as well as the basal lamina were severely disrupted, with all cytoplasmic organelles affected in dying cells. It is likely that the extensive cell necrosis and blebbing in the developing neuroepithelium at the site of neural tube fusion may be involved in failed neurulation, while necrosis at other sites in the cranial neuroepithelium may be linked with previously reported intellectual and behavioural abnormalities. © 1993 Wiley‐Liss, Inc.
Effects of fetal dexamethasone exposure on postnatal control of cardiac adenylate cyclase: β‐adrenergic receptor coupling to GS regulatory protein
Authors: Bian Xiaopeng , Seidler Frederic J. , Olsen Catherine , Raymond John R. , Slotkin Theodore A. 
Published: June 2005

AbstractIn the adult, glucocorticoids have been shown to upregulate β‐adrenergic control of adenylate cyclase by a variety of mechanisms; glucocorticoids are also thought to play a role in development of cardiac adrenergic function. In the current study, pregnant rats were given 0.2 mg/kg of dexamethasone on gestational days 17, 18, and 19 and the effects on the development of cardiac β‐receptors and their linkage to the stimulatory G‐protein, GS, were examined at 4 days postpartum. β‐Receptor numbers and affinity were unaffected by dexamethasone exposure, nor was there any change in the ability of the GTP analog, Gpp(NH)p, to shift the affinity state of the receptor. Addition of Gpp(NH)p to cardiac membranes enhanced basal and isoproterenol‐stimulated adenylate cyclase activity, but the total response to isoproterenol, with or without Gpp(NH)p, represented a very small fraction of total enzymatic activity. Quantitative analysis of GS indicated no changes attributable to dexamethasone treatment. Although prenatal dexamethasone has been shown to increase adenylate cyclase reactivity to β‐adrenergic input, the effect appears to be at the level of the catalytic subunit of adenylate cyclase, rather than at receptor or G‐protein stages. Abbreviations: ANOVA, analysis of variance, Gpp(NH)p, 5′‐guanylimidodiphosphate. © 1993 Wiley‐Liss, Inc.
Teratogenesis associated with oxydemeton‐methyl in the stage 12 chick embryo
Authors: Lenselink Daniel R. , Midtling John E. , Kolesari Gary L. 
Published: June 2005

AbstractThe teratogenic potential of oxydemeton‐methyl (ODM) was investigated using a stage specific localized topical method of application to the stage 12 chick embryo. A dose of 0.01, 0.05, 0.10, 0.50, 1.0, or 2.0 mg/embryo was applied to the vitelline membrane directly above the stage 12 embryo. The embryo was then returned to the incubator and monitored daily until stage 41 (15 day). At stage 41 the embryo was autopsied and examined for gross external and internal malformations, wet weight, and crown‐rump length. Experimental data was compared to unopened and saline treated controls. At doses less than 0.50 mg/embryo, survival rates were high (>80%) but when that dose was exceeded, the survival rate fell significantly (P<0.001). A dose‐dependent increase in malformation rate was seen in all treatment groups with 0.10 mg/embryo, producing a maximum malformation rate (19/33) with minimum mortality (3/36). Crown‐rump lengths and wet weights were significantly less than controls in all treatment groups (P<0.001). Anomalies were primarily seen in the musculoskeletal (ventral midline, limb, and neck) and cardiovascular (ventricular septum and aortic arches) systems. Thoracogastroschisis and ventricular septal defects were the most common combination of malformations. Our data suggest that ODM is teratogenic when topically applied to the stage 12 chick embryo. © 1993 Wiley‐Liss, Inc.
Fetal development in the rat following disruption of maternal renal function during pregnancy
Authors: Kavlock Robert J. , Logsdon Tina , Gray Jacqueline A. 
Published: June 2005

AbstractPregnant Sprague‐Dawley rats received subcutaneous injections of mercuric chloride (1–4 mg/kg) on either gestation day 7, 9, 11, or 13 to determine effects of altered maternal renal function on embryonic and fetal development. Maternal renal function, assessed by urinanalysis, was markedly disrupted for at least 48 hours after treatment and resulted in decreased maternal body weight gain. Residual effects on maternal kidney weight were evident on GD 21 when the females were killed and the fetuses removed and examined for visceral and skeletal development. We did not observe an increased incidence of malformations in the offspring for exposure on any day of gestation. Maternal exposure to mercuric chloride slightly impaired fetal growth over several gestational exposures periods and changed the pattern of rib formation when exposure occurred early in organogenesis. The extent of the changes could not, however, be related to the immediate degree or duration of altered maternal renal function. Rather, we found correlations between lasting effects of exposure as measured by maternal renal weight on GD 21 and supernumerary lumbar rib induction on GD 7 and 9; while for the relationship with fetal weight, the strongest correlation with maternal kidney weight occurred following exposure on GD 9 (p<0.01), with weaker correlations (p<0.10) for GD 7 and 13 exposures. Maternal serum urea was negatively correlated with fetal weight from the GD 7 exposure. This study supports the concept that some specific forms of maternal toxicity may be associated with limited manifestations of developmental toxicity, but, in general, embryonic development was observed to proceed normally in the presence of marked disruptions in maternal renal physiology. Maternal toxicity, especially as routinely measured in developmental toxicity studies, cannot be looked upon as a single disease. Instead, each manifestation must be examined for what it signifies to the physiology and well being of the female and for cause‐and‐effect relationships with fetal observations. Maternal toxicity and developmental toxicity should not be etiologically linked solely because of their concurrent appearance on the dose‐response curve. © 1993 Wiley‐Liss, Inc.This article is a US Government work and, as such, is in the public domain in the United States of America.
Toxicokinetics and structure‐activity relationships of nine para‐substituted phenols in rat embryos in vitro
Authors: Fisher Henry L. , Sumler Martha R. , Shrivastava S. P. , Edwards Brenda , Oglesby Linda A. , Ebron‐McCoy Marian T. , Copeland Frank , Kavlock Robert J. , Hall Larry L. 
Published: June 2005

AbstractThe purpose of this study was to examine the toxicokinetics of embryo uptake following exposure to a variety of chemically related phenols in rat embryo culture. The uptake of nine radiolabeled para‐substituted phenols by day 10(9–13 somite stage) rat embryos in vitro was determined from 1 to 42 hrs after being placed in culture media containing various phenols. Uptake was rapid, having a half‐life of 3 hr or less, with 7 of the nine compounds having uptake half‐times of less than one hour. The equilibrium concentration in the embryo ranged from 53 to 136% of the media concentration, indicating only a factor of 2 in maximum discrimination against the compound for any of the phenols studied. The fraction of radioactivity remaining unbound in the media decreased with increasing log P (octanol/water partition coefficient). The binding was calculated to be 50% for log P = 1.77 from the fitted regression equation and decreased by a factor of 5.9 for every decade increase in P.When hepatocytes were also present in the media the equilibrium concentration in the embryos was less than when hepatocytes were absent. With the limited data, four of the phenols appeared to have no (i.e., zero) equilibrium level when hepatocytes were present. Thus the metabolites produced by the hepatocytes appeared to have less affinity for the embryo than the parent phenol. Toxicodynamic information as given by the effective concentration of the phenol in the embryo to cause somite or tail teratological effects was best predicted by the measured unbound fraction. © 1993 Wiley‐Liss, Inc.This article is a US Government work and, as such, is in the public domain in the United States of America.
A morphological and family study on isolated terminal transverse type of congenital limb deficiency in Hungary, 1975–1984
Authors: Czeizel A. E. , Vitéz M. , Kodaj I. , Lenz W. 
Published: June 2005

AbstractA population‐based and validated data set of 195 cases with isolated terminal transverse‐type congenital limb deficiency was evaluated in Hungary, 1975–1984. Terminal transverse types of congenital limb deficiency are not usually associated with non‐limb defects, and typically only one limb is affected. Upper limb is more frequently affected than lower (9:1) in monomelic cases. The left side and females are affected more often in upper limbs while lower limb defects are evenly distributed between right and left sides and both sexes. Familial occurrence was not found. © 1993 Wiley‐Liss, Inc.
Facial features of infants exposed prenatally to cocaine
Authors: Fries Melissa H. , Kuller Jeffrey A. , Norton Mary E. , Yankowitz Jerome , Kobori Joyce , Good William V. , Ferriero Donna , Cox Victoria , Donlin Susan Seto , Golabi Mahin 
Published: June 2005

AbstractThirty two infants referred for in‐patient genetics evaluation at the University of California at San Francisco, 1987–1992, were found to have a history of maternal cocaine use. Genetics reports and medical records were reviewed on all these infants to identify features distinctive for cocaine exposure. Among these 32 cases, 14 infants were exposed only to cocaine; 18 were exposed to alcohol and cocaine. The infants evaluated displayed a distinctive phenotype, consisting of neurologic irritability, large fontanels, prominent glabella, marked periorbital and eyelid edema, low nasal bridge with transverse crease, short nose, lateral soft tissue nasal buildup, and small toenails. Features consistent with the fetal alcohol syndrome appeared distinct and coexistent with the other described facial findings. Other severe abnormalities included cleft lip/palate, atypical facial cleft, abnormal BSER, intraventricular hemorrhages, arthrogryposes, and genitourinary abnormalities. Forty percent of the infants were born prematurely; 28% were small for gestational age; 43% showed head circumference values less than the 10th percentile. We conclude that these findings may be distinctive for a diagnosis of fetal cocaine syndrome; such findings should be further established by a future blinded prospective study of mothers and neonates.© 1993 Wiley‐Liss, Inc.
Effects of low level prenatal 60Co gamma‐irradiation on postnatal growth and behavior in mice
Authors: Wang Hong , Chen Deqing , Gao Changwen , Zhou Xiangyan 
Published: June 2005

AbstractPregnant Kun Ming strain mice were exposed to a total dose of 0, 0.1, 0.2, or 0.4 Gy from 60Co γ‐rays from the 13th to the 18th days of gestation. An overall delay of the appearance of two physiologic markers (pinna detachment, eye opening) and the age of acquisition of four reflexes (surface righting, air righting, auditory startle, visual placing) was observed in offspring exposed to 0.2 or 0.4 Gy in utero. Postnatal growth retardation, shortened length of hanging time, inhibited exploratory activity in the hole board test (decreased number of head‐dipping), and hyperactivity in the open field test (shortened latency to leave the center area and increased number of squares entered) were also found among the offspring exposed to 0.2 Gy or more in utero. The results indicate that 0.1–0.2 Gy may represent a threshold range in mice for certain physiologic and behavioral effects resulting from continuous exposure to 60Co γ‐rays on the 13th–18th days of gestation. © 1993 Wiley‐Liss, Inc.
Activation of apoptosis in early mouse embryos by 2′‐deoxyadenosine exposure
Authors: Gao Xiang , Blackburn Michael R. , Knudsen Thomas B. 
Published: June 2005

AbstractAdenosine deaminase (ADA) catalyzes the irreversible hydrolytic deamination of adenosine and deoxyadenosine to nontoxic derivatives. The importance of this reaction in the female reproductive tract of mice is suggested by pronounced utero‐placental expression of ADA, and by embryolethality of the potent ADA‐inhibitor deoxycoformycin (dCF) on day 7–8 of gestation. The present study investigated the effects of dCF, adenosine, and deoxyadenosine on the mouse neurula. Morphological cell death was monitored by the acridine orange reaction (AOR), and biochemical cell death by internucleosomal DNA cleavage (IDC). A strong AOR appeared in day 7–8 embryos between 3 and 4.5 hr post‐exposure to dCF in utero; there was no apparent effect on day 6 or day 9 embryos. Most embryonic tissues were responsive, although the heart and extraembryonic membranes were resistant. Up to 75% of the embryonic chromatin was degraded in a regular pattern in concert with the AOR. Immediate activation of “whole‐body” apoptosis was reproduced in short‐term whole embryo culture with 0.1 mM deoxyadenosine in the presence of 0.01 mM dCF. This was not activated by exposure to dCF alone nor to adenosine; however, high concentrations of adenosine completely blocked the response to deoxyadenosine, whereas niacinamide inhibited the AOR without changing IDC. The cytotoxic effect of deoxyadenosine was correlated with an expansion of embryonic dATP pools determined by high‐performance liquid chromatography analysis. The results suggest that deoxyadenosine is the embryotoxic metabolite which accumulates in the antimesornetrium of pregnant mice treated with dCF. Exposure to this metabolic toxin activates apoptosis in day 7–8 embryos through an adenosine‐sensitive, NAD‐dependent mechanism. © 1994 Wiley‐Liss, Inc.
Comparison of four spatial maze learning tests with methylnitrosourea‐induced microcephaly Rats
Authors: Akaike M. , Ohno H. , Tsutsumi S. , Omosu M. 
Published: June 2005

AbstractThe usefulness of four spatial maze learning test methods, single T‐maze, Biel water maze, Morris water maze, and radial eightarm maze, was compared using rats with different degrees of microcephaly, which were induced by single intraperitoneal injection with 3 and 5 mg/kg of methylnitrosourea (MNU) on day 13 of gestation. The single T‐maze test did not detect a learning defect in either MNU group. In the Biel water maze test, the swimming time and number of errors were increased in the 5 mg/kg group, but these parameters were comparable to the control values in the retention and path B (reverse course) tests. On the Morris water maze task, the 5 mg/kg group required longer swimming time and distance to reach the goal. In the retest with the goal set on an opposite side, the swimming distance in the 5 mg/kg group was as long as the value in the original test. The radial eight‐arm maze test detected fewer correct choices in both MNU groups, which showed different responses on this task. The brain weights in the 3 and 5 mg/kg groups were approximately 80 and 60% of the control value, respectively. The cerebral cortex weights were 77 and 50% of the control value, and the hippocampus weights were 78 and 51%. Among the four maze tests, only the radial eight‐arm maze test could detect the effect of both doses of MNU. This shows that the method has the highest sensitivity to spatial learning defect in MNU‐induced microcephalic rats. © 1994 Wiley‐Liss, Inc.