bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetic assessment of teratologically effective concentrations of an endogenous retinoic acid metabolite
Authors: Satre Michael A. , Penner John D. , Kochhar D. M. 
Published: June 2005

AbstractRetinoic acid is a natural vitamin A derivative that undergoes oxidative metabolism in the body to yield several metabolites, which apparently represent the products of a detoxification pathway. To assess if such metabolic conversions diminished teratogenic potency, one of the major metabolites (4‐oxo‐all‐trans‐retinoic acid) was tested for its teratogenic activity in pregnant ICR mice and further investigated for its pharmacokinetic features to determine if it accumulated in the embryo in concentrations sufficient to elicit a teratogenic response. Administration of single oral doses (10, 25, 50, or 100 mg/kg) of the compound to ICR mice on day 11 of gestation. (plug day = day 0) produced dose‐dependent frequencies of serious fetal anomalies of the type usually associated with the use of retinoic acid and other retinoids. The metabolite was equivalent in teratogenic potency to retinoic acid, and, in the instance of cleft palate frequency, it was even more active. Concentrations of 4‐oxo‐all‐trans‐retinoic acid and its 13‐cis isomer were measured in the maternal plasma and whole embryos at 30 min to 10 hr after administration of the lowest (10 mg/kg) and the highest (100 mg/kg) teratogenic dose of 4‐oxo‐all‐trans‐retinoic acid by means of high‐performance liquid chromatography methodology. Distribution of the compound in the maternal system and transfer to the embryo occurred rapidly with either dose. Peak concentration in the maternal plasma and the embryo persisted for 3–4 hr after the higher dose but not with the lower dose; however, elimination kinetics for the two dose levels were similar. Irrespective of the dose, the half‐life of the compound was longer in the embryo than in the maternal plasma. The values for the area under the concentration vs. time curve in the embryo, 3.5 μg.hr/g after the lower dose and 13.6 μg.hr/g after the higher dose, provided a preliminary estimate of teratologically effective retinoid levels since the two dose levels elicited a minimal (25%) and a maximal (100%) teratogenic response, respectively. From these results we conclude that 1) 4‐oxo‐trans‐RA is a potent teratogen, 2) it may contribute substantially to the teratogenic activity of all‐trans‐RA, and 3) AUC values, as reported here, may serve as a basis for comparison of teratogenic potencies of other retinoids being developed as therapeutic agents.
Growth of 9.5‐day rat embryos in folic‐acid‐deficient serum
Authors: Miller Pamela N. , Pratten Margaret K. , Beck Felix 
Published: June 2005

AbstractRat embryos (9.5‐day‐old) were cultured for 48 hours in serum from diet‐induced folic‐acid‐deficient rats. Resultant embryos were frequently abnormal; many were growth retarded and exhibited a defect in the turning mechanism that inverts the embryo from ventrally to dorsally convex. Affected embryos displayed abnormal twisting or kinking of the neural tube. Gross anaemia was also frequently observed, and the protein content of the embryos was markedly less than that of embryos grown in normal rat serum. Supplementation of the deficient serum with folic acid improved growth and greatly reduced the occurrence of deformities. It virtually eliminated the incidence of gross anaemia but only partially restored the protein content of the embryos to the level observed in those grown in normal rat serum. The effects of the folate deficiency could be eliminated by supplementation with normal rat serum. The data indicate that embryos have a requirement for adequate folate in order for normal growth and differentiation to take place; they also suggest that some of the embryopathic effects of maternal folate deficiency are mediated by secondary effects on maternal metabolism. This may take the form of a disturbance in the production of maternally synthesised growth factors necessary for normal embryonic development.
Structure‐activity relationships in the developmental toxicity of substituted phenols: In vivo effects
Authors: Kavlock Robert J. 
Published: June 2005

AbstractHansch analysis, a quantitative approach relating the physical‐chemical properties of molecules to biological effects, was applied to a series of substituted phenols tested for developmental toxicity. The physical‐chemical properties included a hydrophobic parameter (log P), an electronic parameter (Hammett sigma), and a bulk parameter (molar refractivity (MR)). Biological activities (potencies) were obtained for 27 congeners in a Chernoff/Kavlock Assay performed in Sprague‐Dawley rats exposed on day 11 of gestation. The potencies discussed in this report are the following: the dose to decrease maternal weight gain by 10 g at 24 and 72 hours after treatment (MTOX1 and MTOX2); the dose to increase postimplantation loss by 1 over the concurrent control value (PLOSS); and the dose required to decrease total litter weight by 10% on postnatal day 6 (BIO6). A quantitative structure‐activity relationship QSAR was developed for the maternal data (1/MTOX1 = (0.0344*log P) + (−0.1503*sigma) + 0.1195; n = 22, r = 0.81, P <.0001), which related increasing lipophilicity and decreasing electron‐withdrawing ability of the substituent on 22 para‐phenols to increasing toxicity. Another QSAR was developed from eight para‐phenols that had the greatest postimplantation loss potencies (i.e., <100 mmol/kg). The model (1/PLOSS = (−0.2676*log P) + (−0.1827*sigma) + (0.0265*MR) + 0.4420; n = 8, r = 0.93, P < .0298) related decreasing lipophilicity and electron‐withdrawing ability and increasing bulk properties to the decreased viability of implantation sites. However, no descriptor was identified that distinguished the more potent from the less potent congeners for postimplantation loss, and no QSAR was found for litter weight on postnatal day 6 (even when limiting the analysis to the more potent congeners). Congeners were also grouped on a qualitative level according to whether they induced a biological effect below a dose of 6 mmol/kg (termed active), between 6 and 11 mmol/kg (moderately active), or greater than 11 mmol/kg (inactive). Overall, 14 of 27 congeners were classified as active in terms of maternal effects, but only 50% of these were active for developmental effects. Seven of the nine overall active developmental toxicants were active maternal toxicants. Four of the developmental toxicants produced a syndrome of effects that may be related to a similar mechanism of or common metabolic pathway. Thus, from both quantitative and qualitative viewpoints, the properties of these phenolic congeners that promote maternal toxicity are different from those that contribute to developmental toxicity. It is therefore likely that the mechanisms of toxicity behind these effects are also different.
Induction of postaxial forelimb ectrodactyly with anticonvulsant agents in A/J mice
Authors: Collins Michael D. , Fradkin Rochelle , Scott William J. 
Published: June 2005

AbstractExposure of A/J mice on day 9.5 of gestation to the derivatives of three acidic anticonvulsant agents, namely dimethadione, sodium valproate, and sodium diphenylhydantoin, each induced postaxial forelimb ectrodactyly predominantly of the right side. This specific malformation has previously been associated with the administration of acetazolamide to rodents; however, several agents can induce this same defect including other carbonic anhydrase inhibitors, carbon dioxide, cadmium, ethanol, ammonium chloride, and 13‐cis retinoic acid. The relative potency of the three agents indicates no direct relationship to the pKa of the acid. Other than ectrodactyly, each of the anticonvulsant agents induced a compound‐specific spectrum of malformations despite the uniform administration time. This finding suggests that these agents are capable of acting via different mechanisms or by the differential spatial and temporal dynamics of a common mechanism.
Effects of TCDD on embryonic ureteric epithelial EGF receptor expression and cell proliferation
Authors: Abbott B. D. , Birnbaum L. S. 
Published: June 2005

AbstractThe potent toxin 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) is teratogenic in mice, producing hydronephrosis and cleft palate. Because of the long half‐life of TCDD, the urinary tract is exposed throughout development after a single dose on gestation day (GD) 10 or earlier. TCDD‐induced hydronephrosis is a consequence of occlusion of the ureter by epithelial cells. Since embryonic growth factors and the epidermal growth factor (EGF) receptor are probably involved in regulation of embryonic cell proliferation, this study examines the effects of TCDD on expression of EGF receptors and proliferation of ureteric epithelial cells in vivo and in culture. After exposure to TCDD by gavage (12, 24, or 30 μg/kg on GD 10; 6 or 24 μg/kg on GD 12) the mean cell depth of the ureteric and bladder epithelia was increased. EGF receptors were detected immunohistochemically in sectioned urinary tracts. The expression of receptors decreased with advancing development in control ureteric epithelia. However, after TCDD exposure the level of EGF receptors failed to decline. The incorporation of 3H‐TdR was observed in sections by autoradiography, and after exposure to TCDD more epithelial cells showed incorporation than was apparent in controls. Transmission electron microscopy (TEM) of embryonic ureters from fetuses exposed to TCDD in vivo showed no cytotoxicity in basal cells and the cells remained undifferentiated, as in controls. Ureters taken from GD 12 embryos and cultured with 1 × 10−10 M TCDD showed ureteric epithelial hyperplasia without cytotoxicity, but at 1 × 10−8 M TCDD evidence of cytotoxicity was observed by TEM. The levels of TCDD found in fetuses after in vivo exposure (204–307 pg/fetus, with 1–2 pg in the urinary tract) compare well with the in vitro level (32 pg/ml), which was most effective in producing hyperplasia of the epithelial cells. The present study correlates a TCDD‐induced increase in cell depth with altered regulation of EGF receptors and excessive proliferation, both in vivo and in cultured embryonic ureters.
Deposition of low dose benzo(a)pyrene into fetal tissue: Influence of protein binding
Authors: McCabe Dorothy P. , Flynn Edward J. 
Published: June 2005

AbstractThe influence of maternal binding of benzo(a)pyrene (BaP) on its disposition into fetal tissue was investigated in pregnant Swiss‐Webster mice. Low doses (10 ng/mouse) of radiolabeled BaP were administered by intravenous injection on day 15 of gestation. BaP was administered along with normal rabbit serum (NRS) (low binding paradigm) or anti‐BaP antiserum (high binding paradigm) and animals killed at various time points. Total radioactivity in the fetus increased with time to peak concentrations in whole fetal homogenates at 12 hours. In contrast, maternal serum, liver, and lung showed a decrease in total radioactivity over the same time period. Total radioactivity/gram of fetal tissue was significantly higher in NRS‐treated animals compared to anti‐BaP—antiserum‐treated animals.Since the levels of the parent compound, BaP, in fetal tissue fell over time similar to maternal liver and lung, the increase in total radioactivity in the fetus was due to an increased concentration of a BaP metabolite fraction in both the low binding and high binding groups. Significantly, a lower level of this metabolite fraction was found in fetal tissue from the anti‐BaP—antiserum‐treated animals.The present study shows that maternal exposure to this environmental pollutant, even at low doses, results in an accumulation of a metabolite‐rich fraction in the fetal compartment, which may contribute to the teratogenic potential of BaP. The data also demonstrate that the amount of this accumulation can be diminished by increasing maternal binding proteins, such as by treatment with anti‐BaP antiserum.
Strain difference of the mouse in manifestation of hydrocephalus following prenatal methylmercury exposure
Authors: Inouye Minoru , Kajiwara Yuji 
Published: June 2005

AbstractGenetic background may influence susceptibility to hydrocephalus. In the present experiment we compared the manifestation of hydrocephalus following prenatal methylmercury exposure among strains of mice which sporadically develop or never develop spontaneous hydrocephalus. Pregnant mice of the B10.D2 congenic strain were given a single oral dose of 10 mg/kg methylmercuric chloride on one of days 14 through 17 of pregnancy and allowed to give birth and rear their litters. The incidence of grossly apparent hydrocephalus in the offspring at 30 days of age following treatment on day 14, 15, 16, or 17 of pregnancy was 67, 88, 75, and 48%, respectively; that of shamtreated and untreated offspring was 5 and 4%, respectively. In addition, there were some brains showing slight dilatation of the lateral ventricles. Pregnant females of C57BL/10 (B10) or DBA/2 (D2) strain were also treated with 10 mg/kg methylmercury on day 15 of pregnancy. The incidence of hydrocephalus at 30 days of age in untreated and dosed B10 mice was 0.8 and 54%, respectively. Hydrocephalus failed to develop in D2 mice. The hydrocephalus is a communicating type. Occlusion of the cerebral aqueduct with glial reaction and caudal displacement of the cerebellum are considered to be secondary changes. The results indicate that the susceptibility to methylmercury‐induced hydrocephalus is under genetic control in mice.
Trisomy 13 in the fetus
Authors: Fujinaga Masahiko , Shepard Thomas H. , Fitzsimmons Jack 
Published: June 2005

AbstractA significant number of fetuses with trisomy 13 are spontaneously or voluntarily lost before birth; however, very few such fetuses have been systemically autopsied. In the present study, ten trisomy 13 fetuses of 130–305 mm in crown‐rump length, estimated gestational age from 108 days to 239 days, were examined following either karyotype or ultrasonographic diagnosis and voluntary termination. Mean maternal age was 35.1 years. The spectrum of anatomical features was similar to that observed in neonates or older infants with trisomy 13, namely, holoprosencephaly, cyclopia, microphthalmia, cleft palate and lip, cardiac defect, polydactyly, and cystic kidney. Kidney weights were significantly increased above normal in eight of nine fetuses. Histologically, the cortex of these kidneys showed increased mitotic activity and blastemic appearance, which extended deep into the medullary areas. The weights and histology of other organs were normal except for slight increases in spleen weight.
Anomalous caudal vena cava passing through the vertebral canal in a calf
Authors: Hiraga Takeo , Abe Mitsuo , Iwasa Kenji , Takehana Kazushige , Higashi Ryusei 
Published: June 2005

AbstractA 15‐day‐old female Holstein‐Friesian calf with an anomalous caudal vena cava was examined macroscopically, roentgenologically, and histologically. The calf, weighing 43 kg, had severe scoliosis. A common renal vein merged into a single venous trunk formed by the union of the left and right common iliac veins. The trunk entered the vertebral canal through the left intervertebral foramen formed by the last (13th) thoracic and the first lumbar vertebrae. The trunk continued along the ventral side of the narrowing spinal cord inside the canal, and then ran out the left intervertebral foramen formed by the 8th and 9th thoracic vertebrae and emptied via the right azygos vein into the cranial vena cava. In contrast, the hepatic vein passed through the foramen vena cava independently of the trunk and entered the right atrium directly. The pathogenesis of the present anomaly may be explained as follows: The right subcardinal vein, failing to make connection with the liver, shunted directly into the right azygos vein derived from the right supracardinal vein. The body axis began to curve before ossification of the vertebrae occurred. Consequently, the developing right supracardinal vein, located close to the spinal cord, is thought to have become enclosed in the vertebrae with the spinal cord during the early fetal stages.
Relative teratogenicity of nitrofen analogs in mice: Unchlorinated, monochlorinated, and dichlorinated‐phenyl ethers
Authors: Magnus Francis B. 
Published: June 2005

AbstractTo determine the role of number and position of chlorine substituents on the developmental toxicity of diphenyl ether analogs of nitrofen, we have evaluated one unchlorinated, three monochlorinated, and five dichlorinated‐phenyl 4′‐nitrophenyl ethers with respect to effects on liver weight and on maintenance of pregnancy in females, and with respect to postnatal survival and the occurrence of small or absent Harderian glands in offspring. None of the diphenyl ethers evaluated in these experiments was as active as nitrofen with respect to any parameter evaluated. Both the position and the number of chlorine substituents affected toxicity, but no simple relationship between number or position of chlorine substituents and either maternal or fetal endpoints was established.
Avian model for 13‐cis‐retinoic acid embryopathy: Demonstration of neural crest related defects
Authors: Hart Robin C. , McCue Peter A. , Ragland William L. , Winn Kevin J. , Unger Elizabeth R. 
Published: June 2005

AbstractThe effects of 13‐cis‐retinoic acid on the developing chick embryo were investigated. Fertilized eggs were injected via the yolk sac with single 50μl doses of either 1.5 μg, 15 μg, or 150 μg of 13‐cis‐retinoic acid in dimethyl sulfoxide on varying days of incubation (embryonic days 2, 3, 4, 5, or 6). Control embryos were given solvent alone or a mock injection. The embryos were examined on day 14 of incubation. The effects of retinoic acid on mortality and total malformations were both dose and developmental‐stage responsive. The defects caused by 13‐cis‐retinoic acid occurred in mesenchymal tissues derived in part from the cranial neural crest ectomesenchyme. The craniofacial and cardiovascular malformations produced in the chick are analogous to those seen in animal models of retinoid teratogenesis and in human fetuses exposed to 13‐cis‐retinoic acid during maternal therapy for cystic acne. Following 13‐cis‐retinoic acid treatment, craniofacial and specific cardiovascular malformations were increased significantly compared to those in matched solvent and mock treated controls. The greatest number of malformations occurred when 13‐cis‐retinoic acid was given after cranial neural crest cell migration was complete. We propose that the primary effect of 13‐cis‐retinoic acid is on region‐specific localization and differentiation of the mesenchymal subpopulation of cranial neural crest cells.
Cocaine as a cause of congenital malformations of vascular origin: Experimental evidence in the rat
Authors: Webster William S. , Brown‐Woodman Patricia D. C. 
Published: June 2005

AbstractCocaine hydrochloride was administered to pregnant Sprague‐Dawley rats as a single intraperitoneal dose or as two doses 1–4 hours apart. A single dose administered on day 16 of gestation was teratogenic in a dose‐dependent manner, with 40 mg/kg being a no‐effect dose and 50 mg/kg the lowest teratogenic dose; 80 mg/kg was lethal to the dam. Forty‐eight hours after exposure to a teratogenic dose on day 16 of pregnancy, the fetuses showed severe hemorrhage and edema in the their extremities, particularly the footplates, tail, genital tubercle, and upper lip/nose. When the fetuses were examined on day 21 of gestation, the main externally visible malformations were reduction deformities of the limbs and tail. When two doses of cocaine were administered 1–4 hours apart, the incidence of affected fetuses increased as the time interval between the two doses decreased. Two doses of cocaine administered 2 hours apart were not teratogenic on day 9, 10, 11, 12, 13, or 14 of gestation but did induce reduction deformities on days 15, 16, 17, 18, or 19. The same dose administered 1 hour apart was teratogenic on days 14–19. In general, cocaine administration on gestational days 14, 15, or 16 induced more severe and more widespread hemorrhage and edema than administration on days 17, 18, or 19. In the latter cases, damage was restricted to the distal parts of the hindlimb digits and the tail. The results show that in the rat cocaine is only teratogenic during the late organogenic or postorganogenic period. It exerts its teratogenic effect by inducing hemorrhage and edema in the fetuses, which lead to necrosis and disruption of existing and developing structures, particularly the limbs. It is proposed that cocaine causes severe constriction of the uterine vasculature, leading to an hypoxic response in the placental/fetal unit, which causes the observed hemorrhage and edema.
Extrinsic fetal akinesia and skeletal development: A study in oligohydramnios sequence
Authors: Palacios José , Rodriguez José I. 
Published: June 2005

AbstractLong‐bone morphometry and cephalometry were performed in 13 newborns with oligohydramnios sequence (OS) in order to establish whether or not skeletal changes existed in extrinsic fetal akinesia similar to those observed in the fetal akinesia deformative sequence (FADS) (i.e., hypoplastic long bones and micrognathia). Oligohydramnios sequence was caused by bilateral renal agenesis in five cases and obstructive uropathy in eight cases. Twenty‐one stillborns and newborns who had died from conditions other than renal anomalies or congenital malformations were used as controls. Normal longitudinal and periosteal long‐bone growth and absence of micrognathia were found in OS patients. Skeletal differences between FADS and OS may be explained not only by timing, duration, and degree of reduced motility but also, and more importantly, by the normal muscular stress in OS patients.
Abnormal limb regeneration in adult newts exposed to a pulsed electromagnetic field
Authors: Landesman Richard H. , Douglas W. Scott 
Published: June 2005

AbstractThis investigation examined two questions: (1) whether or not forelimb regeneration results in a faithful replacement of the distal skeletal pattern and (2) what effect exposure to a pulsed electromagnetic field (PEMF), the type reported to facilitate healing of human non‐united bone fractures, would have on the process of limb regeneration. Of the native forelimbs, 98% (132 out 134) had a skeletal pattern that showed little difference with the only variation being the range of carpal bones (5–8). Following a 4–5 month postamputation period, the skeletal pattern of the normal regenerates was examined. While 72% (135 out of 188) of these forelimbs resembled the native group, 28% (53 out of 188) were abnormal. These abnormalities consisted of the loss of a digit, fused carpals, and long bone defects which occurred singly or in combination with one another. Exposure to a PEMF for the first 30 days postamputation, followed by a 3–4 month postamputation period, produced in addition to the normal (60%, 144 out of 240) and abnormal forelimbs (28%, 67 out of 240), a group of forelimbs with unique gross defects (12%, 28 out of 240). These defects, occurring singly or in combination, included the loss of two or more digits with associated loss of carpals, absence of the entire hand pattern, and abnormalities associated with the radius and ulna. We can offer no explanation for these observations.