bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early biochemical detection of adverse effects of a neurobehavioral teratogen: Influence of prenatal methylmercury exposure on ornithine decarboxylase in brain and other tissues of fetal and neonatal rat
Authors: Slotkin Theodore A. , Pachman Steven , Kavlock Robert J. , Bartolome Jorge 
Published: June 2005

AbstractOrnithine decarboxylase (ODC), an enzymatic regulator of macromolecule synthesis, has proven useful as a biochemical marker for teratologic events. Daily administration of methylmercy (0.5 or 1 mg/kg s.c.) to pregnant rats during the second and third trimesters had a profound effect on ODC in whole fetus that was detectable as early as 13 days of gestation. Levels of enzyme activity in fetal brain also showed a marked increase centered about gestational day 17 as well as a significant elevation during early postnatal life; in the latter case, the cerebellum appeared to be a major target for methylmercury‐induced aberrations. These effects were accompanied by little or no alteration in general growth rate, brain weights, or weights of other tissues (liver, heart, lung). Furthermore, no other tissue displayed such dramatic effects on ODC activity. Lowering the dose of methylmercury by an order of magnitude (0.05 to 0.1 mg/kg), levels which are associated with almost purely neurobehavioral effects of the teratogen, still resulted in clear‐cut elevations of both whole fetus ODC and fetal and neonatal brain ODC. These results indicate that a sensitive biochemical detection procedure used in the fetus/neonate can successfully predict the subsequent tissue‐specific damage to neurotransmitter systems and behavior resulting from methylmercury.
The effect of prenatal procarbazine treatment on brain development in the rat
Authors: Johnson J. M. , Thompson D. J. , Haggerty G. C. , Dyke I. L. , Lower C. E. 
Published: June 2005

AbstractGroups of pregnant Sprague‐Dawley rats were treated orally with procarbazine, an antineoplastic drug, at dose levels of 0, 1.0, 2.5, 5.0, 7.5, and 10.0 mg/kg/day from days 12 through 15 of gestation. Following normal delivery, offspring were raised until day 21 and sacrificed, and their brains removed and weighed. A dose‐dependent micrencephaly, characterized by hypoplasia of the cerebral hemispheres, was seen starting at 2.5 mg/kg/day. In a second study, groups of pregnant female rats were given a single dose of 10 mg/kg procarbazine on gestation day 12, 13, 14, or 15. Micrencephaly occurred in 21‐day‐old offspring from all groups, with the greatest effect induced on days 13, 14 and 15. Analysis of brain region weights revealed a maximum reduction in neocortex weight in offspring from groups treated on days 13 and 14. The hippocampus, cerebellum, and diencephalon‐midbrain were also reduced in size, depending on the day of treatment, while the corpus striatum and ponsmedulla were spared. In a final study, embryos from females treated on gestation days 12 through 15 were removed, fixed, and sectioned at 24‐hour intervals starting on gestation day 13. Necrosis and cellular degeneration were observed with decreasing severity in the telencephalon, diencephalon, mesencephalon, and medulla. The neocortex of 20‐day treated fetuses was characterized by a thickening of the ventricular zone and reduced cellularity of the cortical plate.
Developmental and cytogenetic effects of caffeine on mouse blastocysts, alone or in combination with benzo(a)pyrene
Authors: Spindle Akiko , Wu Kitty 
Published: June 2005

AbstractMouse blastocysts were treated with caffeine and/or benzo(a)pyrene (BP), and the effects on development and on induction of sister chromatid exchanges (SCEs) were examined. Caffeine interfered with blastocyst development in a dose‐related manner. At 4 mM, the highest concentration tested, caffeine interfered with development of blastocysts to all four endpoints: hatching, trophoblast outgrowth, inner cell mass (ICM) growth, and two‐layer (primary endoderm and ectoderm) differentiation of ICMs. At 2 mM, caffeine reduced the incidence of both ICM growth and differentiation but did not affect hatching or formation of trophoblast outgrowths. At 1 mM, caffeine interfered only with ICM differentiation. Cell proliferation was least sensitive to caffeine and was reduced at concentrations of ≥2 mM. Induction of SCEs was most sensitive to caffeine exposure; an increase in SCE frequency was observed at 0.1 and 0.5 mM. When caffeine was added to cultures with BP (1 μM, a concentration that was not embryotoxic and did not induce SCEs), both embryotoxic effects and SCE frequency were increased. The enhancing effect on SCE induction was particularly marked; as little as 0.1 mM caffeine was sufficient to cause doubling of induced SCE frequencies when added to cultures with BP.
The embryotoxicity of gossypol
Authors: Beaudoin Allan R. 
Published: June 2005

AbstractIn utero development was analyzed in pregnancies that resulted from matings between gossypol‐treated male rats and untreated female rats and in pregnancies in which gossypol was administered to the pregnant rat only. Gossypol treatment of males had no effect on the outcome of pregnancy. There was no significant effect on resorption, fetal growth, or malformation rate. Similarly, gossypol administered to pregnant dams at stages during organogenesis had no observable effect on pregnancy. Under the conditions of this experiment, gossypol administered to either the breeding male rat or the pregnant female rat had no demonstrable adverse effect on development in utero.
The effects of L‐ and D‐carnitine administration on cardiovascular development of the chick embryo
Authors: Kargas Steve A. , Gilbert Enid F. , Bruyere Harold J. , Shug Austin L. 
Published: June 2005

AbstractA single 1.0‐ml volume of L‐ or D‐carnitine solution, at several selected mmole concentrations, was applied to the extraembryonic membranes of 3‐ and 4‐day chick embryos in ovo. Hamburger‐Hamilton stages of chick development ranged from 17 to 23. During the 17–18th days of incubation, embryos were dissected, and both survival and intracardiac anomaly rates were determined. Only at extremely high doses, both stereoisomers of carnitine exhibited a statistically significant toxigenic effect (p < 0.001) as measured by a sharp decrease in survival rate when compared to chick Ringer's saline controls. Furthermore, since the anomaly rates became significant only near the LD50's, this indicated that intracardiac anomalies were induced only at toxic doses. Therefore, it is suggested that cardiovascular teratogenicity may be the result of toxicity. Below the LD50, anomaly rates were not significantly different from those of control embryos. In comparison, L‐ and D‐carnitine were significantly different from one another (p < 0.001) both in survival rate and percent affected embryos at a dose of 0.5 mmole. In summary, exogenous carnitine administration to the chick embryo does not appear to be deleterious to the developing cardiovascular system.
The effect of oxygen concentration on the teratogenicity of salicylate, niridazole, cyclophosphamide, and phosphoramide mustard in rat embryos in vitro
Authors: Greenaway J. C. , Mirkes P. E. , Walker E. A. , Juchau M. R. , Shepard T. H. , Fantel A. G. 
Published: June 2005

AbstractComparisons were made of rat embryos cultured at 5% or 20% oxygen in the presence of salicylate (SAL), cyclophosphamide (CP), niridazole (NDZ), or phosphoramide mustard (PM). Multiple regression analyses were used to compare the effects of drug concentration, oxygen concentration, and the product of drug times oxygen concentration on malformation incidence, viability, and protein content of embryos cultured for 24 hours. Drug concentration significantly affected malformation incidence or severity and protein content (P < 0.001) for the four drugs tested. Oxygen concentration significantly affected protein content for the four compounds (P < 0.001) but affected malformation incidence only with NDZ. Furthermore, the interaction of oxygen concentration and drug concentration significantly affected the malformation incidence in the presence of NDZ (P < 0.001), and protein content (P < 0.001) and viability (P < 0.001) in the presence of CP.The pattern of significant effects of the independent variables (drug concentration, oxygen concentration, and drug times oxygen concentration) is consistent with the hypotheses of oxygen‐dependent metabolism (or lack of metabolism) of the drugs in question. NDZ, which is thought to be converted to reactive intermediates by an oxygen‐inhibited nitroreductase, was more toxic at reduced oxygen tension. CP, which is activated by an oxygen‐dependent P‐450 system, was more toxic with increased oxygen tension. Significant effects of the independent variables on embryos exposed to SAL or PM were consistent with the effects on control embryos, notably, increased protein content with increased oxygen.
Morphology of early fetal deaths and their chromosomal characteristics
Authors: Byrne Julianne , Warburton Dorothy , Kline Jennie , Blanc William , Stein Zena 
Published: June 2005

AbstractThe morphologic features of a consecutive series of 3,472 singleton spontaneous abortions are described. Of the total, 21% consisted of wellformed fetuses (over 30 mm long), 27.9% had no identifiable fetal tissues, 34.2% consisted of fetal membranes only, and the remainder, 16.8%, consisted of a variety of embryonic types. The rate of focal malformations among embryos over 10 mm in length and among fetuses was 16.4%. The overall rate of chromosome anomalies in the 1,356 karyotyped specimens was 39.8%. The vast majority, 94%, occurred in embryos less than 30 mm, and in specimens whose development had not proceeded beyond differentiation of fetal membranes. The rate of chromosome anomalies among nonmalformed fetuses (greater than 30 mm) was only 1.7%. However, the presence of limited embryonic development was not a good predictor of the presence of a chromosome anomaly. Slightly over half (56%) of all specimens less than 30 mm long had chromosome anomalies; for individual classes of such specimens the rate ranged from 45% to 81%. The morphologic category with the highest rate of karyotypic anomalies had an excess of monosomy X abortuses. A gradient of developmental level could be associated with the degree of intrauterine mortality of each chromosome anomaly; i.e., conceptuses with karyotypes that occur at term had a greater degree of embryonic development than karyotypes that are never seen among term births. Thus, trisomies 13, 18, and 21 were more often associated with fetuses, and less often with tissue fragments than other trisomies. Focal malformations were multiple and severe in abortuses with triploidy, trisomies 13 and 18, and monosomy X and mild in trisomy 21. With the exception of monosomy X the malformations were similar to, and not more severe than those reported from, term births with the same anomaly. The high rate of intrauterine mortality in conceptuses with chromosome anomalies could be ascribed to their failure to develop past the embryonic stages. However, the presence of an equally large fraction of chromosomally normal abortions with the same degree of rudimentary development suggests the existence of early and profound developmental problems that are not associated with anomalies of the chromosome complement.
The effect of graded hypoxia on the embryonic chick heart
Authors: Ruckman Roger N. , Rosenquist Glenn C. , Rademaker Deborah A. , Morse Dennis E. , Getson Pamela R. 
Published: June 2005

AbstractEmbryonic ventricular function in the chick was measured in response to graded levels of hypoxia. Myocardial contractility, as measured by cinephotoanalysis and expressed as shortening fraction, was significantly depressed after 1 hour of moderate hypoxia (6% O2) and after 5 hours of milder (16% O2 and 11% O2) levels of hypoxia (P < .05). Microscopy confirmed associated myocyte damage with cell death noted after 5 hours of moderate hypoxic stress. Heart rate change was not related to the severity of hypoxia. The greatest level of tachycardia was noted with conditions of mildest hypoxia (16% O2). The data confirm that cardiac contractility, as measured by shortening fraction, is depressed on exposure to hypoxia, with impairment of function related to the severity of the hypoxic conditions.
Transfer of valproic acid and its main active unsaturated metabolite to the gestational tissue: Correlation with neural tube defect formation in the mouse
Authors: Nau Heinz 
Published: June 2005

AbstractThe pharmacokinetics of the antiepileptic drug valproic acid (2‐proply‐pentanoic acid; VPA) and its main active metabolite 2‐en‐VPA (2‐propyl‐2‐pentenoic acid) in mouse serum and gestational material were studied and correlated with the drastic differences between the two compounds in their embryotoxicity. The peak levels of VPA reached after 0.5 hours were only slightly higher than that of 2‐en‐VPA (both in mother and gestational material). The free concentrations of VPA and 2‐en‐VPA in maternal serum also peaked at 0.5 hours. After that time the free maternal serum levels of 2‐en‐VPA decreased much more rapidly than the concentrations in the gestational materials. The area under the concentration/time curves (AUC) values of 2‐en‐VPA in mother and embryo were lower than corresponding values of VPA; the higher clearance of 2‐en‐VPA was predominantly due to an increased volume of distribution. Since we have previously shown that the peak concentrations and not the AUC values of VPA correlated with the teratogenicity of this compound, our present data indicate that the low teratogenic and embryotoxic potential of 2‐en‐VPA is a result of the intrinsic activity of this compound and not of lower peak concentrations reached in mother and embryo.
Synergistic interaction of 2,3,7,8,‐tetrachlorodibenzo‐p‐dioxin and hydrocortisone in the induction of cleft palate in mice
Authors: Birnbaum L. S. , Harris M. W. , Miller C. P. , Pratt R. M. , Lamb J. C. 
Published: June 2005

AbstractGlucocorticoids cause cleft palate in sensitive mouse strains by interfering with the proliferation of mesenchymal cells in the palatal shelves; 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) also causes cleft palate, but its effects involve the epithelial cells. The purpose of this study was to examine the interaction of TCDD and the glucocorticoid hydrocortisone in the induction of malformations. Pregnant C57BL/6N mice were treated on gestation days 10–13 with TCDD (0 or 3 μg/kg, p.o.), hydrocortisone (0, 25, 50, or 100 mg/kg, s.c.) or a combination of TCDD and hydrocortisone. The dams were killed on gestation day 18 and the mice were analyzed for maternal and fetal toxicity and soft tissue malformations. TCDD alone had no effect on litter size, fetal weight or viability, or maternal weight gain. This dose of TCDD is essentially a threshold dose and it did not produce cleft palate in this study, but all the TCDD‐treated fetuses had hydronephrosis, the most sensitive indicator of TCDD teratogenicity. Hydrocortisone alone caused dose‐related decreases in fetal weight and maternal liver/body weight ratios, and dose‐related increases in cleft palate (0, 5, 10, and 30%). No effects of hydrocortisone were detected on litter size or fetal viability, but maternal weights were affected. Combination of all doses of hydrocortisone with TCDD resulted in a 100% incidence of cleft palate, accompanied by a decrease in litter size and fetal weight and an increase in fetal mortality related to the dose of hydrocortisone. TCDD tended to reverse the decrease in liver/body weight ratio seen with hydrocortisone alone. Morphological assessment of the palatal shelves late on gestation day 14 revealed that the embryos exposed to both TCDD and hydrocortisone resembled hydrocortisone alone. The synergism observed between these two teratogens may be due to changes in the receptors which mediate sensitivity to the induction of cleft palate.
Pharmacological studies on the potentiation of phenytoin teratogenicity by acetaminophen
Authors: Lum Joseph T. , Wells Peter G. 
Published: June 2005

AbstractAn in vivo murine model was developed to measure maternal phenytoin biotransformation along with the covalent binding of phenytoin to fetal tissues in the same fetuses which were assessed for fetal anomalies. Acetaminophen was administered to pregnant CD‐1 mice 1 hour prior to phenytoin, both given i.p. at varying doses and gestational times between days 11 and 13. Dams were killed between days 12 and 19. Metabolites reflecting the enzymatic bioactivation of phenytoin were quantified in maternal plasma and urine with high‐performance liquid chromatography (HPLC). Acetaminophen pretreatment caused a threefold increase in phenytoin‐induced fetal cleft palates without increasing resorptions. The covalent binding of radiolabeled phenytoin to fetal and placental tissues measured on day 13 was increased twofold and threefold, respectively, by acetaminophen pretreatment. Phenytoin covalent binding measured on day 16 was significantly increased in the livers of fetuses with cleft palates, but not in the livers of dams with fetuses having cleft palates. Binding to fetal brain on day 16 was over fourfold higher than that in maternal brain. Acetaminophen pretreatment differentiated dams into poor and extensive metabolisers of phenytoin, with only the latter group carrying fetuses with cleft palates. The incidence of fetal cleft palates correlated positively with maternal urinary levels of phenytoin (r = + .81, P < .01) and its dihydrodiol metabolite (r = + .61, 0.05 < P < .1), and negatively with levels of para‐hydroxylated phenytoin (r = −.85, P < .01). These findings related both to the mechanism of phenytoin teratogenicity and its potentiation by acetaminophen.
Acetazolamide does not disrupt limb regenerate morphogenesis in the salamander, Plethodon cinereus
Authors: Dinsmore Charles E. , Maren Thomas H. 
Published: June 2005

AbstractAcetazolamide, a potent and highly specific inhibitor of carbonic anhydrase, is teratogenic in mammalian embryos and when administered during early limb development causes unique limb defects in a time‐ and dose‐dependent manner. The regenerating urodele limb is often considered to be a good experimental analog of limb development and, if it employs the same mechanisms of tissue interactions during pattern formation, should be susceptible to teratogens which selectively disrupt developmental limb patterning. This study demonstrates that while carbonic anhydrase inhibition is toxic to the red‐backed salamander, Plethodon cinereus, it does not have the same teratogenic effect on limb regeneration as seen in mammalian limb development. Several points are considered as to why the regenerating limb, at least in this salamander species, may not be suitable for studying this class of teratogen.
Amniogenic band anomalies in a fifth‐month fetus and in a newborn from maternal oophorectomy during early pregnancy
Authors: Tanaka Osamu , Koh Toshikiyo , Otani Hiroki 
Published: June 2005

AbstractA fifth‐month fetus and a newborn with amniogenic band anomalies were examined at autopsy. Both specimens were obtained from women who had undergone oophorectomy during early pregnancy. The dead male fetus was aborted spontaneously, and had a micrognathia, a right club foot, and a constriction ring on the left lower leg. The left fingers 2, 3, and 4 were attached to the placenta by a fibrous string. No internal anomaly was noted. In the other case, a male newborn was delivered at the 39th week of gestation and had an agenesis of the calvarium, a cleft lip with palate, an amputation of the right toe, and constriction rings on right fingers 3 and 4 and left finger 3. The placenta was attached to the left temporooccipital region of the head by a fibrous string. Also present was an atrial septum defect and a horseshoe kidney. Possible etiology is discussed in relation to the “amniogenic bands” hypotheses.
Effect of Shigella toxin on preimplantation mouse embryos in vitro
Authors: Olsen Wenche Marie , Storeng Ritsa 
Published: June 2005

AbstractPreimplantation mouse embryos at the 4‐cell to 8‐cell stage were exposed to Shigella dysenteriae toxin at concentrations of 0.001‐100 pg/ml in vitro. The effect of the toxin was studied by morphological observation of the embryos to the blastocyst stage, by assessing protein synthesis with 14Cleucine incorporation, and by measuring embryonic adenosine triphosphate (ATP) content.Preimplantation mouse embryos were highly sensitive to the toxin. All variables investigated were adversely influenced by the toxin. After a lag period of 24 hr, 0.01 pg/ml toxin inhibited development to the blastocyst stage and protein synthesis. Toxin concentrations of 1.0 pg/ml resulted in a significant decrease in ATP content.
Neonatal behavioral toxicity in rats following prenatal exposure to methanol
Authors: Infurna Robert , Weiss Bernard 
Published: June 2005

AbstractAlthough methanol (MEOH) may assume a significant role as a fuel, which implies wide availability, little is known of its toxicity apart from acute poisoning episodes in human adults. Even less is known about its toxicity in developing organisms. This experiment studied the early behavioral development of rats whose mothers had consumed MEOH during gestation by measuring the responses of suckling (postnatal day 1) and nest‐seeking (postnatal day 10). Primigravida Long‐Evans rats were divided into three groups (N = 10). Two of the groups consumed drinking solutions of 2% MEOH instead of distilled water either on gestational days 15–17 (MEOH 1) or 17–19 (MEOH 2). No maternal toxicity was apparent as measured by weight gain, gestational duration, and daily fluid intake. Daily MEOH consumption averaged 2.5 gm/kg over the 3‐day period in both MEOH groups. Litter size, birth weight, and infant mortality did not differ among the three groups. Postnatal growth and date of eye opening were unaffected. MEOH pups required longer than controls to begin suckling on postnatal day 1. On postnatal day 10, they required more time to locate nesting material from their home cages. These data suggest that prenatal MEOH exposure induces behavioral abnormalities early in life that are unaccompanied by overt toxicity.
Leydig cell hyperplasia in fetal mice treated transplacentally with ethinyl estradiol
Authors: Yasuda Yoshiko , Konishi Hiroyoshi , Tanimura Takashi 
Published: June 2005

AbstractPregant female mice were given ethinyl estradiol on days 11 through 17 of gestation. On day 18 the dams were killed and the male fetuses were examined for testicular differentiation. Three of 12 males from dams treated with the highest dose of ethinyl estradiol showed cryptorchild testes with uterine tubes. Light and electron microscopic evaluation of the testes, both cryptorchid and normal, demonstrated foci of hyperplasia of Leydig cells showing cytoplasmic and nuclear pleomorphism, increase in lipid droplets, and decrease in smooth endoplasmic reticulum and ribosomes when compared to testes from control fetal mice. Morphometric determinations of the testes indicated that the number of Leydig cells in a unit area (mm2) in the interstitial tissue showed a dose‐response relationship to ethinyl estradiol in the normal testes. The number of Leydig cells in the testes exposed to the highest dose of estrogen showed a significant difference between cryptorchid and normal testes: the former had fewer Leydig cells than the latter. These morphological observations indicate that hyperplasia of Leydig cells of fetal mouse testis at term can be induced by transplacental treatment with ethinyl estradiol and suggest that a malignant transformation into a Leydig cell tumor is possible.