bluuebunny/crossref_metadata_2025 huggingface dataset:
Pathogenesis of persistent truncus arteriosus induced by nimustine hydrochloride in chick embryos
Authors: Miyagawa Sachiko , Kirby Margaret L.
Published: June 2005

Nimustine hydrochloride (ACNU) is a nitrosourea derivative anticancer agent which has been shown to cause persistent truncus arteriosus in chick embryos. The objective of this study was to confirm the teratogenic effects of ACNU on the cardiovascular system of chick embryos and to determine whether ACNU induces persistent truncus arteriosus by interfering with neural crest cells. Various doses of ACNU ranging from 10 to 200 μg were injected under the chorioallantoic membrane of chick embryos on the third day of incubation. Saline solution was used as the control. After 10 to 11 days of incubation, 242 (46%) survivors of the 524 treated eggs were obtained. The survival rates of the embryos and the frequencies of cardiovascular anomalies were dose dependent. Of 146 embryos with cardiovascular anomalies, 104 (71%) had persistent truncus arteriosus. Ventricular septal defect and double‐outlet right ventricle were seen in 37 (25%) and one (1%), respectively. Aortic arch anomalies were seen in 116 embryos (79%). Quail‐chick chimeras (chick embryos with quail cardiac neural crest) were treated with 50 μg of ACNU and examined histologically 24 hours later. These chimeras showed dying neural crest cells in the pharyngeal arches. Dying cells were also noted in the neural tube, cranial ganglia, retina, and otocyst. These results suggest that persistent truncus arteriosus in chick embryos treated with ACNU is induced by neural crest cell death.
Embryonic malformations in a case of intrauterine parvovirus B19 infection
Authors: Hartwig N. G. , Vermeij‐Keers C. , Van Elsacker‐Niele A. M. W. , Fleuren G. J.
Published: June 2005

An incomplete embryo of 9 weeks development from a woman infected by human parvovirus B19 during early pregnancy was histologically examined. B19‐DNA was detected in both embryonic and placental tissue by dot‐blot hybridization. Focal vascular endothelial damage was found throughout the entire embryo and placenta together with mononuclear infiltrations around the vessels. In the placenta these mononculear cells belonged for the greater part to the cytotoxic and/or suppressor. T‐cell group. One eye showed lens abnormalities and retinal folds. The other eye was microphthalmic and aphakic and showed dysplasia of the sclera, anterior segment, and retina. The skeletal muscle cells displayed a general eosinophilic degeneration. Focally, similar changes were found in heart muscle and smooth muscle tissue. In several tissues pathologic effects at a cellular level were noted, as intranuclear vacuole‐like inclusions and nuclear ballooning. On the basis of this study it is concluded that human parvovirus B19 may affect several fetal tissues and may even have teratological effects on a developing human embryo.
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

Retinoic 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

Rat 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

Hansch 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

Exposure 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

The 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

The 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

Genetic 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

A 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

A 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

To 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

The 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

Cocaine 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

Long‐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

This 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.
Effects of pulsing electromagnetic fields on the prenatal and postnatal development in mice and rats: In vivo and in vitro studies
Authors: Zusman Igor , Yaffe Perhija , Pinus Helena , Ornoy Asher
Published: June 2005

Electromagnetic fields (EMF) might have various biological effects on the developing embryo. We studied the effects of pulsing electromagnetic fields (PEMF) on the in vitro development of preimplantation mouse embryos and of early somite rat embryos as well as on the in vivo development of rat embryos. We used PEMF at frequencies of 1, 20, 50, 70, and 100 Hz with a tension of 0.6 V/m. The embryos were exposed to PEMF throughout the experimental period. PEMF at frequencies of 20 and 50 Hz were embryotoxic, inhibiting over 50% of blastocysts from hatching and further development, all within 72 h of culture. PEMF at frequencies of 50 and 70 Hz induced 22% and 30% incidence of malformations in 10.5 day old rat embryos after 48 h in culture. The main malformations were absence of telencephalic, optic, and otic vesicles and of forelimb buds. In addition, retarded growth and development manifested by fewer somites, reduction in crown‐rump length, and retarded closure of the neural tube were found in many embryos. No significant pathological changes were found by TEM in PEMF‐exposed embryos. Disappearance of microvilli and collapse of apical parts of endodermal cells were observed by SEM in many yolk sacs of embryos exposed to 50 and 70 Hz PEMF. A slightly reduced litter average, a reduction or increase of weight, and a delay in eye opening was observed among offspring of pregnant rats exposed throughout pregnancy to PEMF at frequencies of 20, 50, and 100 Hz. No malformations were observed among these offspring. The mechanism of PEMF‐induced embryotoxicity and teratogenecity is unknown, as is the mechanism of the “protective effects” of the mother on the rat embryos exposed to PEMF in vivo.
Expression of a new mutation (Axd) causing axial defects in mice correlates with maternal phenotype and age
Authors: Essien Francine B. , Haviland Martha B. , Naidoff Alan E.
Published: June 2005

A new autosomal mutation, Axd (axial defects), is described. Axd segregates in a simple Mendelian fashion, and it is dominant with incomplete penetrance and variable expressivity. The phenotype of Axd heterozygotes ranges from a variety of tail anomalies to visibly normal tails. Approximately 12% of neonates from curly‐tail (CT) F1 (Axd/ + ) × F1 (Axd/ +) matings exhibit open neural tube defects (NTD) in the lumbosacral region and 16% have curly tails. Mean litter sizes and resorption rates comparable to wild type indicate that homozygosity for Axd is not obligately lethal. Genetic background plays a major role in Axd expression. Strains such as BALB/cByJ allow the highest penetrance of the mutation in single dose (46%), whereas, in CF‐1 mice Axd is recessive. The tail phenotype of heterozygous Axd/ + dams, in part reflective of their genetic background, correlates with the incidence of NTD in F2 offspring: CT mothers produce significantly more neonates with frank NTD than normal tail mothers. At the one embryonic period examined for this study (D13/D14 post‐coitus), an 85% higher incidence of total axial defects is observed than among the F2 at birth. Unchanging litter size and the relative increase in phenotypically normal offspring by birth suggest that Axd acts by delaying posterior neural tube closure. One of the most significant findings in this study is that maternal age influences the survival of Axd embryos in utero. Axd/ + dams older than 8 months yield fewer mean implants, higher resorption rates, and fewer viable embryos with axial defects than do Axd/ + dams younger than 8 months. Axd is not allelic to nor linked to the Sp (splotch) gene which also affects neurulation.
Examination of the eyelid closure defect in trisomy 16 mice
Authors: Lipski David A. , Bersu Edward T.
Published: June 2005

A characteristic feature of trisomy 16 mouse conceptuses is a failure of their eyelids to close. This defect was investigated by examining ocular development in serially sectioned heads of trisomy 16 and normal littermate fetuses from 10 to 18 gestational days. Other heads were examined by using scanning electron microscopy. Between 10 and 15 days, trisomy 16 ocular structures were delayed, but there was no striking abnormal morphology. At 16 days, when the eyelids were closed and fused in normal mice, trisomic eyes had a large cell mass near the inner canthus that protruded between the open lids. The mass was covered by bulbar conjunctiva and cells of the mass were continuous with developing corneal tissue. The mass was not present in the eyes of normal mice on any gestational day and was not present in trisomic eyes at 17 and 18 days, when the lids began to show varying degrees of closure. Based on its positioning at the inner canthus, the mass may represent a transient hyperplasia of the developing semilunar fold which physically impedes lid closure in the trisomic conceptuses. Previously, the defect has been attributed to the trisomy 16 conceptus's overall pattern of growth retardation and delayed development. Masses such as those seen in the trisomic eyes have not been observed in other murine lid‐gap defects that have been investigated. A second finding in this study is that trisomic eyes are positioned more superiorly in the head than normal eyes. This variation may be related to alterations in cranial base morphology that are associated with trisomy 16.
Risk factors for gastroschisis
Authors: Goldbaum Gary , Daling Janet , Milham Sam
Published: June 2005

The prevalence at birth of gastroschisis, a rare abnormality of the abdominal wall, appears to have increased over the past decade. To characterize risk factors that might explain this increase, birth certificates for Washington State residents were compared for 62 infants born with gastroschisis during the years 1984 to 1987 and 617 randomly selected unaffected infants matched for birth year. After simultaneously adjusting for 14 potential risk factors, 4 factors stood out. Infants born during January, February, or March were at greater risk than infants born in any other months (odds ratio 2.2, 95% confidence interval 1.1, 4.1). Mothers less than 25 years old were at greater risk than mothers 25 years and older, with the highest risk to mothers less than 20 years old (odds ratio 4.1, 95% confidence interval 1.4, 12.0). Women who smoked during pregnancy were at greater risk than women who did not smoke (odds ratio 2.0, 95% confidence interval 1.03, 3.8). Finally, mothers receiving inadequate prenatal care were at greater risk than mothers receiving adequate prenatal care (odds ratio 2.1, 95% confidence interval 0.99, 4.6). Unidentified behavioral and environmental exposures may explain the associations with month of birth, maternal age, and prenatal care. However, smoking during pregnancy is a plausible risk factor that should be examined further as an explanation of the apparently increasing prevalence at birth of gastroschisis in developed nations.
Evaluation of drug intake during pregnancy in the Hungarian case‐control surveillance of congenital anomalies
Authors: Czeizel Andrew , Rácz János
Published: June 2005

The data of the Hungarian Case‐Control Surveillance of Congenital Anomalies, 1980–1987, were evaluated concerning drug intake during pregnancy in 10,698 index patients, 21,546 negative controls, and 828 positive controls (Down syndrome). Excluding pregnancy supplements, the proportion of no drug use was about 30% and the mean number of drugs used was 2.0 in the negative control group. These figures did not differ significantly from data of study and positive control groups. The analysis of most commonly used drugs indicated an extremely high proportion of hormonal support therapy. The teratogenic effect of several human teratogenic drugs was confirmed. However, their use is relatively rare and their attributable risk within the etiology of congenital anomalies is low, at about 0.3–1.0%. At present the teratogenic risk of drugs in humans is exaggerated and it has several unfortunate consequences: negligence in necessary drug use, unnecessary anxiety in pregnant women, and termination of planned pregnancies without any reasonable cause.
Lethal and teratogenic effects after exposure to X‐rays at various times of early murine gestation
Authors: Müller W.‐U. , Streffer C.
Published: June 2005

Various well‐defined stages during completion of the second meiotic division and early organogenesis of mouse embryos were X‐irradiated with doses of 1–4 Gy (100–400 rad). The major risk was prenatal mortality with radiation sensitivity changing markedly with dependence on the developmental stage irradiated; in the case of day 1 even within hours. The surviving fetuses did show a significantly enhanced frequency of malformations on day 19 of gestation (mostly gastroschisis and some exencephalies). This was true for all stages between days 1 and 8; only sensitivity again changed considerably. The radiation doses used in this study are markedly higher than doses that can be expected from radiation diagnostics, but exposure is in a range comparable to doses that can occur in radiation therapy (e.g., Morbus Hodgkin).
A decade of rabbit fertility data: Study of historical control animals
Authors: Feussner Elizabeth L. , Lightkep Gerald E. , Hennesy Rosemary A. , Hoberman Alan M. , Christian Mildred S.
Published: June 2005

Reproductive data for 1795 artificially inseminated Hra: (NZW)SPF control rabbits in 93 developmental toxicity studies conducted from 1980 through 1989 were summarized. Data were obtained during terminal Caesarean‐sectioning procedures performed on animals which survived to day 29 of gestation and during postmortem evaluation of does which aborted, delivered prematurely, or were found dead. Significant seasonal variation was not observed. Average pregnancy rate, percentage of rabbits that aborted, and percentage of rabbits that delivered prematurely throughout the decade were 86, 2.0, and 1.6%, respectively. Average numbers of corpora lutea, implantations, live fetuses, dead fetuses, early resorptions, and late resorptions for each doe that survived to scheduled termination were 10.8, 7.8, 7.1, 0.02, 0.49, and 0.15, respectively. The various vehicles used, routes of administration, and a variety of maternal and paternal factors were compared with the fertility data, and no correlations were observed. Rabbits that aborted earlier in gestation had fewer implantations than does which aborted late or delivered prematurely. Does which resorbed 100% of their conceptuses had fewer corpora lutea and implantations when compared with rabbits in the remainder of the population. Rabbits pregnant at scheduled termination which had a low number of corpora lutea or implantation sites had higher than expected pre‐ and postimplantation losses relative to the population as a whole. Does with a high number of corpora lutea had significantly higher preimplantation loss relative to the general population. This may indicate the presence of a “ceiling value” for the number of ova that can become fertilized and/or implant when the ovulation rate is high and which probably varies according to strain as well as a number of factors related to the individual rabbit. Based upon the results of this study and the work of a previous author, a minimum of four corpora lutea may be necessary for the successful maintenance of pregnancy in the New Zealand white rabbit. The minimum number of corpora lutea required may be strain dependent and may bear a relationship to the normal litter size of the strain. © 1992 Wiley‐Liss, Inc.
Developmental toxicity study in rats treated with the anticonvulsant, ralitoline
Authors: Dostal Lori A. , Anderson John A.
Published: June 2005

The developmental toxicity of the anticonvulsant compound, ralitoline, was investigated in Sprague–Dawley rats administered oral doses of 0, 15, 60, 120, 180, or 240 mg/kg on days 6 through 15 of gestation. An untreated control group and a vehicle control group pair‐fed to the high dose group were included. Maternal and fetal parameters were evaluated on day 21 of gestation. Fetuses were examined for external, visceral, and skeletal malformations and variations. Maternal death occurred at 180 and 240 mg/kg. Dose‐dependent decreases in body weight, food consumption, and water consumption were observed at 60 mg/kg and above. Body weight gain during treatment was similar in the pair‐fed and 240 mg/kg groups. Dose‐related CNS signs (hypoactivity, ataxia, prostration, and/or convulsions) were observed at 60 mg/kg and above. Decreased numbers of live fetuses and increased postimplantation loss were observed in a dose‐related manner at 120, 180, and 240 mg/kg while no changes occurred in pair‐fed controls. Fetal body weights and placental weights were decreased in pair‐fed controls and in the 120, 180, and 240 mg/kg groups. The percent fetuses per litter, and the percent litters with external/visceral malformations, were significantly increased at 120, 180, and 240 mg/kg compared with vehicle and pair‐fed controls. Dose‐related increases in cardiovascular malformations, specifically of the aortic arch (interrupted, stenotic, extra vessel), were apparent at 120 mg/kg and above. The incidence of skeletal variations was increased at 120 mg/kg and above. This study demonstrates the developmental toxicity, including teratogenicity, of the anticonvulsant compound, ralitoline, in rats at maternally toxic doses, and demonstrates a lack of developmental toxicity at lower doses which were less maternally toxic. © 1995 Wiley‐Liss, Inc.
Increased risk for transverse digital deficiency after chorionic villus sampling: Results of the United States multistate case‐control study, 1988–1992
Authors: Olney Richard S. , Khoury Muin J. , Alo Celan J. , Costa Pamela , Edmonds Larry D. , Flood Timothy J. , Harris John A. , Howe Holly L. , Moore Cynthia A. , Olsen Carolyn L. , Panny Susan R. , Shaw Gary M.
Published: June 2005

Although numerous infants have been reported with transverse limb deficiencies after their mothers had undergone chorionic villus sampling (CVS), it has been unclear whether the procedure caused these defects. We report of the first multistate case‐control study to assess and quantify the risk for specific limb deficiencies associated with CVS. Case subjects were 131 infants with nonsyndromic limb deficiency ascertained from 7 population‐based birth defect surveillance programs, and born from 1988–1992 to mothers 34 years of age or older. Control subjects were 131 infants with other birth defects. We ascertained exposure to CVS from medical records and maternal and physician questionnaires. We assessed rates and timing of exposure to CVS, and estimated relative and absolute risks for anatomic subtypes of limb deficiency. The odds ratio for all types of limb deficiency after CVS from 8–12 weeks′ gestation was 1.7 (95% confidence interval, 0.4–6.3). For specific anatomic subtypes, the strongest association was for transverse digital deficiency (odds ratio = 6.4; increased 95% confidence interval, 1.1–38.6). The risk for transverse digital deficiency with earlier gestational exposure (P < 0.01 for trend). We estimated that 1 per the absolute risk for transverse digital deficiency in infants after CVS was 2,900 births (0.03%). Exposure to CVS was associated with a sixfold increase in risk by for transverse digital deficiency. The causality of this association is supported of its strength, specificity, biologic plausibility, and consistency with the results limb previous studies. Although some centers already inform patients about risk for limb deficiency, this study quantifies the magnitude of risk associated with CVS from 8–12 weeks′ gestation. © 1995 Wiley‐Liss, Inc.
Flow cytometric detection of abnormal fetal erythropoiesis: Application to 5‐fluorouracil‐induced anemia
Authors: Zucker Robert M. , Elstein Kenneth H. , Shuey Dana L. , Rogers John M.
Published: June 2005

We sought to determine whether flow cytometric analysis of circulating fetal blood cells could be used to rapidly detect perturbations of fetal erythropoiesis. In addition, we wanted to determine whether this approach would allow sample collection by exsanguination instead of fetal cardiac puncture, a difficult technique used to prevent contamination of samples with maternal erythrocytes. To monitor fetal erythropoiesis from gestational day (GD) 14–20, we analyzed the cell size, RNA content, and percentage of circulating liver‐derived reticulocytes relative to yolk‐sac‐derived erythroblast. As a model toxicant, we choose 5‐fluorouracil (5‐FU), since we previously observed that maternal administration at 20–40 mg/kg on gestational day (GD) 14 produced fetal anemia on GD 16–17, as evidenced by dose‐dependent decreases in the cell counts, hematocrit, and hemoglobin content of fetal blood obtained by cardiac puncture. We report herein that 48 hr after maternal 5‐FU administration, both cardiac and peripheral blood samples exhibited a dose‐dependent decrease in the relative percentage of reticulocytes, indicating a reduced rate of reticulocyte release from the fetal liver. Moreover, at 30 and 40 mg/kg, reticulocytes exhibited increased size and reduced RNA content on GD 16, but elevated RNA content (indicative of premature release) by GD 18. These data suggest that 5‐FU inhibits both erythroid cell proliferation and RNA synthesis reversibly, resulting in an anemia that triggers compensatory release of immature reticulocytes. Thus, by using flow cytometry to analyze fetal blood, we were able to detect and characterize 5‐FU‐induced perturbations of fetal erythropoiesis. In so doing, flow cytometry afforded the advantages of rapid determination of individual cell type, size, and RNA content, and the ability to exclude contaminating maternal erythrocytes from analysis, thereby eliminating the need to acquire samples through the time‐consuming technique of fetal cardiac puncture. © 1995 Wiley‐Liss, Inc.
Social interactions and solitary behaviors in a pair of captive sand cats (Felis margarita)
Authors: Bennett Sarah Williams , Mellen Jill D.
Published: June 2005

This study examined the behavior and activity of two captive sand cats at the Washington Park Zoo in Portland, Oregon. Sex differences in behavior were examined and the direction and frequency of social interactions were determined. An attempt was made to determine behavioral signs of estrus. A scan sampling data collection technique was used to find the percentage of time spent by each cat in each behavior. Simultaneously, the frequency of social behaviors was recorded. The cats spent the greatest percentage of their time pacing and resting; social interactions occurred very infrequently. The only significant sex difference in behavior was that the male marked and urinated/defecated more than did the female. Temporal distribution in the usage of the enclosure was examined. It was found that when one cat was active, the other tended to be inactive. No overt behavioral signs of estrus were evident other than the actual observance of copulation. However, the percentage of time spent in each behavior was examined when the female was assumed to be in estrus (days when copulation was observed) versus nonestrous periods. The female was found to pace and locomote significantly more during estrous periods.
Protein variation, fitness, and captive propagation
Authors: Hedrick Philip W. , Brussard Peter F. , Allendorf Fred W. , Beardmore John A. , Orzack Steven
Published: June 2005

We examine the possibility of utilizing protein variation (allozymes) as a tool in the preservation and breeding of endangered and captive species. We believe that allozymes provide estimates of the relative amounts of genetic variation within and among populations. However, because of the difficulties encountered in evaluating both heterozygosity and fitness, we conclude that estimates of individual heterozygosity derived from allozyme studies are poor criteria for selecting individuals for breeding in captive propagation schemes. Furthermore, breeding plans designed to maintain rare allozymes in captive populations represent an unwise strategy for the propagation of most rare and endangered animal species. We believe that successful reintroduction is most likely when genetic variation is preserved as found in natural populations.
Ancestry of alleles and extinction of genes in populations with defined pedigrees
Authors: Thompson E. A.
Published: June 2005

The paper presents, without mathematical formalities, two computational approaches to the analysis of pedigrees. One provides a method for inferring the ancestry of rare alleles observed in a population. The other provides the probabilities that specified combinations of founder genes survive to this current population. The emphasis in both approaches is upon the importance of joint probabilities. If some founder genes survive, others have smaller probability of doing so also. If an allele descends from a given founder to a current individual, it is likely to appear also in individuals sharing the same lines of descent.
Genetic drift and the loss of alleles versus heterozygosity
Authors: Allendorf Fred W.
Published: June 2005

Most studies of the loss of genetic variation caused by bottlenecks in population size have used heterozygosity as a measure of genetic variation. In this paper, I compare the effects of bottlenecks on the loss of alleles, as well as the reduction in heterozygosity. Population bottlenecks of short duration will have little effect on heterozygosity but are expected to reduce severely the number of alleles present. Heterozygosity provides a good measure of the capability of a population to respond to selection immediately following a bottleneck. However, the number of alleles remaining is important for the long‐term response to selection and survival of populations and species.