bluuebunny/crossref_metadata_2025 huggingface dataset:
Teratogenicity and developmental toxicity of valproic acid in rats
Authors: Vorhees Charles V.
Published: June 2005

The teratogenicity and developmental toxicity of valproic acid (VPA) was investigated in Sprague‐Dawley CD rats at doses of 0, 150, 200, 300, 400, and 600 mg/kg administered by gavage on days 7–18 of gestation. The VPA‐600 dose was maternally toxic, causing death in two of four dams. This dose produced 100% embryonic resorption. The VPA‐400 dose was maternally toxic in as much as maternal weight gain was reduced, but no deaths occurred. At this dose five of fifteen litters were completely resorbed, and 52% of all embryos were resorbed. Among survivors, 49% were malformed (68% having skeletal defects and 41% visceral defects). Fetal weight was reduced by 43% in this group. Most of the defects were ectrodactyly, hydronephrosis, cardiovascular defects, hypoplastic bladder, rib and vertebral defects, and other defects of the limbs and tail. The VPA‐300 dose (nine litters) produced fewer defects, larger fetuses, and no increase in resorptions. The defects at this dose were primarily cariovascular, rib, and vertebral. The VPA‐200 dose (12 litters) produced no reduction in fetal weight, no increase in resorptions, and few defects. The defects noted were hydronephrosis, cardiovascular abnormalities, and rib defects, primarily wavy ribs. Additional litters were prepared using doses of 150 and 200 mg/kg and were allowed to deliver and grow until 70 days. These doses produced no reduction in maternal weight gain, no reduction in litter size, birth weight, or sex ratio of the offspring. These doses produced no reduction in offspring weight to day 70, no increase in mortality, and only rare cases (two offspring of each dose) of tail defects. Maternal plasma VPA concentrations on day 18 of gestation showed values in excess of human therapeutic values (50–130 μg/ml) at 400 mg/kg and values at or within the therapeutic range at 150 and 200 mg/kg. The data support the view that VPA is mildly teratogenic in rats at human therapeutic plasma concentrations.
Secular rates and correlates for gastroschisis in California (1968–1977)
Authors: Roeper Peter J. , Harris John , Lee Gerri , Neutra Raymond
Published: June 2005

This study reports on an epidemiological investigation of gastroschisis using birth certificate data from California for the period of 1968–1977. Gastroschisis has been reported to be on the increase in a number of countries. The distribution of the 166 California gastroschisis cases reported during this time period indicated a clear upward secular trend (P < .001) with the rate per 1,000 increasing from .006 in 1968 to .089 by 1977. This secular trend was observed in every maternal age group and for gravidity level 1. Gastroschisis also occurred more frequently among younger mothers (P < .001) and low gravidity mothers (P < .001). Omphalocele, another eventration defect, was also examined but did not display an upward secular trend.
Fetal hydantoin syndrome in rats: Dose‐effect relationships of prenatal phenytoin on postnatal development and behavior
Authors: Vorhees Charles V.
Published: June 2005

Sprague‐Dawley rats were gavaged once daily on days 7–18 of gestation with, 100, 150, or 200 mg/kg of phenytoin. Only the highest dose of phenytoin decreased maternal weight during gestation or increased offspring mortality up to weaning. Offspring were evaluated for activity prior to weaning (pivoting and photocell) and afterwards (figure 8, open‐field, and holeboard), dynamic righting development, maze learning (Biel maze), and visual discrimination (Y maze), and for startle reaction to both auditory and tactile stimuli. The highest dose of phenytoin produced increased activity on all tests of activity, delayed dynamic righting development, impaired Biel maze and Y‐maze learning, and inhibited tactile startle responses. The two lower doses of phenytoin generally showed a dose‐effect relationship with values on most measures intermediate between values for controls and for the highest‐dose group. Dose‐effect relationships were most evident on measures of early activity (both tests), dynamic righting, and Biel maze learning, whereas only trends were evident on measures of later activity, Y maze, and startle. A dose‐related rotational defect was found in a minority of phenytoin offspring, and although these individuals contributed to the behavioral abnormalities observed, they in no instance accounted for the overall pattern of effects seen in the phenytoin offspring. Maternal plasma phenytoin levels at the end of treatment were doserelated. Offspring showed no effects on postnatal growth, total brain weight, or brain protein content as adults. The data support the view that phenytion is a potent behavioral teratogen at doses well below those causing any evidence of gross teratogenicity or embryotoxicity.
High prevalence of defective human embryos at the early postimplantation period
Authors: Shiota Kohei , Uwabe Chigako , Nishimura Hideo
Published: June 2005

Thirty‐seven cases of human embryos at the early postimplantation period were procured after induced abortion and examined histologically. Their developmental stages ranged from Carnegie stages 6 to 11, and their standard ages ranged from 14 to 24 days after fertilization. Five cases (13.5%) were grossly abnormal, and seven (18.9%) were degenerating partially or in toto. Gross abnormalities included distorted embryonic disc, disorganized neural groove or tube, and neural tube dysraphism. The high prevalence rate of defective embryos at the early postimplantation period supports the clinical finding that a substantial proportion of human conceptions are eliminated from an early stage of pregnancy, often without the knowledge of the mother. The fate of undifferentiated pathological embryos is uncertain and remains to be determined.
A tier system for developmental toxicity evaluations based on considerations of exposure and effect relationships
Authors: Johnson E. Marshall
Published: June 2005

The backlog of untested chemicals and the rate at which new substances enter the marketplace exceed our capacity for developmental effects testing by standard in vivo methods. However, conservative use of two observations in a manner consistent with present day understandings of abnormal developmental biology can more accurately focus attention and resources on those agents in greatest need of complex testing for effects on in utero development. These two observations are 1) most chemicals are no more toxic to embryonic development than they are to adult homeostasis and 2) most human exposure to chemicals is de minimus, i.e., so small that it is inconsequential. Recently devised in vitro assays to quantitatively rank chemicals according to their developmental hazard index, when used in conjunction with more conventional in vivo methods and appropriate considerations of exposure, permit evaluation of a significantly larger number of chemicals than is currently achieved. The methods described apply a tier approach to establish testing priorities that markedly reduce the time, cost, and number of laboratory animals needed for evaluation of developmental toxicity.
Origin of abnormality in a human simelian foetus as elucidated by our knowledge of vertebrate development
Authors: Chandebois Rosine , Brunet Christian
Published: June 2005

In this paper we attempt to explain the abnormality of a simelian foetus with reference to our present knowledge of vertebrate development. The various developmental defects seem to have a single common origin: the speeding‐up of the progression of cell differentiation in the noto‐chord anlage—which is the organization centre of the embryo—during the regression of the Hensen's node. Cell activity involved in the morphogenetic movements in the chordamesoderm probably stopped before it should have. The elongation of the notochord anlage was not completed, resulting in the defective development of the posterior part of the foetus. A number of pairs of posterior trunk somites were not induced. Consequently (1) the pelvic limb buds, whose posterior parts were missing, fused, bringing in further developmental deviations in the limb skeleton and abdominal muscles; (2) there are no vertebrae between the first sacral vertebra and the misshaped coccyx formed by the tail bud. The derivatives of the posterior endoderm (hindgut, bladder and ureters) were not induced either. The cauda equina is deficient. The absence of functional kidneys and the presence of embryonic urinary tubules in the pelvic cysts which are wrapped up by gut epithelium suggest the induction of the metanephric mesenchyme by ectopic endoderm. The speeding‐up of differentiation in the notochord anlage also probably resulted in the excessive extension of its anterior region which is the organizer of brain structures. This explains the overdevelopment of the nose and of the neuro‐cranium, and the low position of the ear. A gene mutation as well as a mechanical stress are the possible causes of the abnormal behaviour of the notochord anlage.
Ovarian follicular cell hyperplasia in fetal mice treated transplacentally with ethinyl estradiol
Authors: Yasuda Yoshiko , Konish Hiroyoshi , Tanimura Takashi
Published: June 2005

The occurrence of follicular cell hyperplasia was studied by light and electron microscopy in fetal mouse ovaries exposed to ethinyl estradiol (EE) from day 11 through day 17 of pregnancy. Pregnant mice were given EE in olive oil (0.02, or 0.2 mg/kg of body weight) and were sacrificed on day 18. The female fetuses were examined for ovarian histogenesis. Follicular cell hyperplasia was detected in both of the experimental groups, but the incidence was statistically significant only in fetuses exposed to 0.2 mg/kg of EE. Light and electron microscopic observations of the ovaries showed that the hyperplasia was located in the medullary region, and the follicular cells showed pleomorphism. Accumulation of abundant lipid droplets, enlarged rough endoplasmic reticulum with granular material, dense bodies, and vague masses of fibrous structures were seen in the cytoplasm. These morphological observations indicate that hyperplasia of follicular cells in fetal mouse ovaries at term can be induced by prenatal treatment with EE.
Father's drinking and infant birth weight: Report of an association
Authors: Little Ruth E. , Sing Charles F.
Published: June 2005

Parents' drinking in the month prior to conception was ascertained for 377 infants born to members of a health maintenance organization. If the father had an average of two or more drinks daily, or had at least five drinks on one occasion, a decrease of 137 gm in infant birth weight was predicted, by means of regression analysis. This result was independent of maternal drinking, although infants whose mothers were regular drinkers weighed less at birth. The lower mean birth weights of infants of regular‐drinking fathers was not due to parents' smoking, maternal use of caffeine, marijuana, or other drugs, or 21 other measured variables. This is the first report of an association in humans between father's drinking prior to conception and decreased infant birth weight. However, interpretation of this finding is difficult because the biological mechanisms that might underlie it are obscure.
Fetal toxicity of cadmium chloride: The pharmacokinetics in the pregnant Wistar rat
Authors: Levin Arthur A. , Kilpper Robert W. , Miller Richard K.
Published: June 2005

The pharmacokinetics of a single subcutaneous injection of 40 μmol/kg CdCl2 in pregnant rats on day 18 were studied during an 18‐hour time period. Previous studies demonstrated that this dose of CdCl2 induced fetal death, placental necrosis, and a reduction of uteroplacental blood flow without maternal lethality; direct fetal injections of CdCl2 indicated that the site of toxic action was not in the fetus. Cadmium was rapidly absorbed from the intrascapular subcutaneous depot with the highest blood levels occurring within 5 minutes of injection. The release from the depot appeared to be multiphasic with both rapid and slow absorption components observed in the blood. Uptake of cadmium was greatest in the liver, followed by the placenta, kidney, and pancreas. The best fit to the data was obtained by assuming the existence of two pools of cadmium in the organs: one freely exchangeable with the blood and the other nonexchangeable. Deviations from model predictions were observed for the placenta and adrenals; these deviations are consistent with the concomitant diminished blood flow to these organs. Cadmium uptake by the fetus was also investigated, and the results support the hypothesis that the placenta is relatively impermeable to the toxicant. It is concluded that the rapid and extensive accumulation of cadmium by the placenta may play a role in the development of early placental cellular damage and the eventual induction of fetal death through uteroplacental dysfunction.
Reproductive and developmental effects on rats after prenatal, postnatal, or pre‐ and postnatal exposure to the hypotensive agent losulazine
Authors: Poppe Susan M. , Marks Thomas A. , Mesfin Gebre‐Mariam , Soule Deborah L. , Shaw Charles I. , Morris Diann F. , Black Daniel L.
Published: June 2005

Losulazine was administered orally to 21 bred Sprague‐Dawley rats per group at 0, 4, and 8 mg/kg/day by three dosing schedules: gestation day 15 until term (prenatal section); postnatal days 1 to 21 (postnatal section); and gestation day 15 until postnatal day 21 (pre‐ and postnatal section). Dams were allowed to deliver and the number of live and dead pups recorded. Each pup was sexed and weighed on days 0, 4, and 21. Also, pinna detachment and eye opening were monitored. Randomly selected offspring were allowed to mature and then cohabited for assessment of reproductive performance. Dam body weight gain during dosing was reduced in the high dose group of the pre‐and postnatal section. Treated dams in the postnatal and pre‐ and postnatal sections had litters with reduced body weight, delayed development, and decreased survival. In the F1 mating portion of the postnatal and pre‐ and postnatal sections, F1 offspring from losulazine‐treated dams had reduced body weights over the entire study. A dose‐related decrease was found for both the percentage of F1 males that bred and the conception rate of bred F1 females. All F1 females entered estrus at least once, and those that conceived delivered normal litters. Neither microscopic examination of F1 male reproductive organs nor analyses of serum prolactin, luteinizing hormone (LH), and testosterone levels indicated the cause of impaired fertility. Thus, although prenatal exposure only did not result in adverse effects, postnatal exposure to losulazine via lactation affected offspring growth, development, and reproductive capacity.
Effects of Δ9‐tetrahydrocannabinol, phenobarbital, and their combination on pregnancy and offspring in rats
Authors: Abel Ernest L. , Tan S. E. , Subramanian M.
Published: June 2005

△9‐THC, sodium phenobarbital, or a combination of these drugs, were administered to pregnant mice on gestation days 6 to parturition. Levels of △9‐THC in blood approximated levels attained in humans after smoking one to two marijuana cigarettes. Blood cannabinoid levels in mice were not significantly elevated by concurrent drug administration. Both drugs significantly reduced litter size and weight per pup at birth, but the combination of these drugs did not affect these outcomes to a significantly greater degree than either drug by itself. Phenobarbital but not △9‐THC increased resorption rate.
Prenatal alcohol exposure shortens life span in rats
Authors: Abel Ernest L. , Church Michael W. , Dintcheff Barbara A.
Published: June 2005

In a study of the effects of in utero alcohol exposure on life span in rats, pregnant rats were intubated twice daily with 3.5 gm/kg alcohol on gestational days 11–21 or with an isocaloric sucrose solution. These latter animals were pairGlutamate dehydrogenasefed and pairGlutamate dehydrogenasewatered to alcoholGlutamate dehydrogenasetreated animals. A third group served as nontreated ad libGlutamate dehydrogenasefed controls. At birth, all offspring were removed from their biological mothers, culled to eight per litter, and placed with nontreated surrogate dams. AlcoholGlutamate dehydrogenaseexposed animals died at a significantly younger age than pairdGlutamate dehydrogenasefed and ad lib controls and never attained the same maximum body weights as control animals. For females prenatally exposed to alcohol, life span was shortened by about 20 weeks; in male cohorts, life span was shortened by about 2.5–7 weeks.
TC‐83 Venezuelan equine encephalitis vaccine exposure during pregnancy
Authors: Casamassima Anthony C. , Hess L. Wayne , Marty Aileen
Published: June 2005

A human pregnancy exposed to TC‐83 live attenuated Venezuelan equine encephalitis (VEE) virus vaccine resulted in hydrops fetalis and fetal demise. Maternal seroconversion and the finding of a diffuse mononuclear cell infiltrate on postmortem examination are suggestive of a causative role for TC‐83 vaccine.
Teratogenic effects of retinoic acid and dirmethylsulfoxide on embryonic chick wing and somite
Authors: Larsen Heidi L. , Janners Martha Y.
Published: June 2005

In order to document the stage(s) at which the embryonic chick wing bud is sensitive to vitamin A teratogenesis and the kinds of defects produced by vitamin A insult to the embryonic chick wing, 1‐μg doses of retinoic acid (1 μl RA in 90% DMSO at a concentration of 1 μg/μl) were locally applied to the right wing bud of chick embryos at stages 17–23 (Hamburger and Hamilton: J. Morphol., 88:49‐92, '51), and the resulting limb skeleton anatomy was observed at 10 days of incubation. Local application of RA at stages 17–20 resulted in distal wing skeleton defects. There were significantly more wing skeleton defects among embryos treated at these stages with RA solution than among solvent (DMSO)‐treated control embryos and than among untreated control embryos. Wings of embryos treated with RA at stages 21–23 were always normal. Scapular and vertebral defects were seen at 10 days of incubation among embryos which had been treated prior to stage 21 with both the RA solution and the solvent control. Statistical analysis and histological data suggest that scapular and vertebral defects were caused by DMSO‐in‐duced damage to somites.
The effects of in vivo administration of teratogenic doses of vitamin A during the preimplantation period in the mouse
Authors: Pillans P. I. , Folb P. I. , Ponzi S. F.
Published: June 2005

To examine the effects of vitamin A administered during the preimplantation period, pregnant C3H mice were exposed to teratogenic doses of the vitamin 60 h after copulation. Fetuses were examined for gross abnormalities on the 18th day of gestation and viability, cell number, mitotic index, and chromosome structure were assessed in 81‐h blastocysts to determine whether embryotoxic effects were apparent in the preimplantation embryo. There was a reduction in the fetal weight of 18‐day fetuses treated in this manner with 15,000 and 30,000 IU vitamin A (p < 0.0003 in each case), and doses of 10,000 IU and greater were associated with a significantly higher incidence of gross abnormalities. Malformations included exophthalmos, anophthalmia, microphthalmia, exencephaly, exomphalos, and limb defects. Administration of 30,000 IU vitamin A resulted in resorption and intrauterine death in 70% of cases. There was no indication that vitamin A adversely affected 81‐h blastocyst viability, cell number, mitotic index, and chromosome structure. The findings suggest that the teratogenic effects that were noted later in fetal life were the result of an action on the developing fetus of the vitamin at a stage later than 81‐h and are consistent with the relative resistance of the preimplantation embryo to toxic injury. Persistence of vitamin A, either in the mother or the embryo, is the most likely explanation for the later expression of toxic injury, which is characteristic of the effects that are noted as a result of exposure to the teratogen during the period of organogenesis.
Hyperthermia‐induced exencephaly in mice: Effect of multiple exposures
Authors: Chernoff G. F. , Golden J. A.
Published: June 2005

Pregnant LM/Bc female mice were given a 10‐minute hyperthermic exposure in a 43°C waterbath during the period of neural tube closure. On day 15.5 of gestation, the females were killed, and the fetuses were examined for exencephaly. Following a single treatment on day 8.0, 8.5, 8.75, or 9.0 of gestation 1.7, 13.6, 2.9, and 0.8% of the respective fetuses displayed exencephaly. With two treatments, one on each of gestational days 8.5 and 8.75, or three treatments, one on each of gestational days 8.5, 8.75, and 9.0, the percentage of exencephalic fetuses increased to 28.3 and 59.3%, respectively. The increased response to multiple treatments was not due to an increase in the number of susceptible embryos but rather was due to the increased number of treatments. The results of this study suggest that with increasing numbers of treatments, the embryo's ability to recover from the hyperthermic exposure is lessened, resulting in an increase in exencephaly.
Methodological proposal in behavioural teratogenicity testing: Assessment of propoxyphene, chlorpromazine, and vitamin A as positive controls
Authors: Saillenfait A. M. , Vannier B.
Published: June 2005

Pregnant Sprague‐Dawley rats received either 80 mg/kg d‐propoxyphene HCl or 20 mg/kg chlorpromazine HCl or 80,000 and 160,000 IU/kg vitamin A palmitate daily between the 6th and 20th days of gestation. Vehicle control groups were similarly treated with saline or corn oil and considered as negative controls. Offspring were examined for physical landmarks, neuromotor development, and behaviour using righting reflex, swimming, negative geotaxis, open field, rotarod, water maze, and nocturnal activity. This test battery included biochemical measurements. No reduction in parental weight and physical offspring development was observed. All these treatments produced long‐term changes in more than one test. Vitamin A palmitate (160,000 IU/kg) was judged as the best positive control with this test battery for future investigation of the behavioural teratology of drugs.
Developmental‐stage‐dependent radiosensitivity of neural cells in the ventricular zone of telencephalon in mouse and rat fetuses
Authors: Hoshino Kiyoshi , Kameyama Yoshiro
Published: June 2005

Pregnant ICR mice were treated with single whole‐body X‐radiation at a dose of 0.24 Gy on day 10, 13, or 15 of gestation. Fetuses were obtained from mothers during 1 and 24 hours after irradiation. Pyknotic cells in the ventricular zone of telencephalon were counted in serial histological sections. Incidence of pyknotic cells peaked during 6 and 9 hours after irradiation in each gestation day group. Then, dose‐response curves were obtained 6 hours after 0–0.48 Gy of irradiation. All three dose‐response curves showed clear linearity in the dose range lower than 0.24 Gy. Ratios of radiosensitivity estimated from the slopes of dose‐response curves in day 10, 13, and 15 groups were 1, 1.4, and 0.4, respectively. These demonstrated that ventricular cells in the day 13 fetal telencephalon were the most radiosensitive among the three different age groups.

In order to confirm the presence of the highly radiosensitive stage common to mammalian cerebral cortical histogenesis, pregnant F344 rats were treated with single whole‐body γ‐irradiation at a dose of 0.48 Gy on day 13, 14, 15, 17, or 19 of gestation. The incidence of pyknotic cells in the ventricular zone of telencephalon was examined microscopically during 1 and 24 hours after irradiation. The peak incidence was shown 6 hours after irradiation in all the treated groups, and the highest peak incidence was shown in day‐15‐treated group. The developmental stage of telencephalon of day 15 rat fetuses was comparable to that of day 13 mouse fetuses. Thus, the highest radiosensitivity in terms of acute cell death was shown in the same developmental stage of brain development, i.e., the beginning phase of cerebral cortical histogenesis, in both mice and rats.
Teratogenicity of tellurium dioxide: Prenatal assessment
Authors: Perez‐D'Gregorio Rogelio E. , Miller Richard K.
Published: June 2005

The effects of multiple maternal subcutaneous injections of tellurium dioxide (TeO2) suspended in olive oil (0–1,000 μmol/kg) from day 15 to day 19 of gestation were evaluated in the Wistar rat. External and internal soft‐tissue examinations were performed on day 20 fetuses. Multiple maternal injections, at doses higher than 10 μmol/kg, resulted in a dose‐related appearance of hydrocephalus, edema, exophthalmia, ocular hemorrhage, umbilical hernia, undescended testis, and small kidneys in fetuses on day 20 of gestation. At 500 μmol/kg, reduction in maternal weight gain was also observed. At this level, the incidence of the above anomalies was 100%. The 100 μmol/kg dose of Te, which did not produce apparent maternal toxic responses, resulted in a 100% incidence of hydrocephalus and edema but no fetal mortality. Thus, tellurium can be teratogenic to the rat fetus without concomitant maternal toxicity. Also, the fetal period may be more sensitive than the organogenic period for the induction of hydrocephalus. Such evidence is consistent with the development of the choroid plexus and an effect of TeO2 on the production/resorption of cerebrospinal fluid.
Chronic ethanol exposure in the embryonic chick heart: Effect on myocardial function and structure
Authors: Ruckman Roger N. , Messersmith Donna J. , O'Brien Susan A. , Getson Pamela R. , Boeckx Roger L. , Morse Dennis E.
Published: June 2005

To investigate the effect of chronic ethanol exposure on the embryonic chick heart, chick embryos were exposed daily to one of seven graded doses of ethanol or to saline only (shams) from 0 to 96 hr of incubation. One hour before and after exposure at 72 hr, and 1 hr before and after exposure at 96 hr, embryos were analyzed for changes in heart function, embryo tissue ethanol content, occurrence of anomalies, and embryo weights. At both 71 and 73 hr of incubation (during cardiogenesis), when compared to shams, heart rate (HR) in embryos receiving ethanol doses > 0.0375 ml increased significantly (P < .05) with commensurate increases in injected ethanol. Additionally, at 73 hr, depressed cardiac contractility, measured as shortening fraction, was noted at doses ≥ .0375 when compared to shams. While slight increases in shortening fraction (SF) across dose were noted at 95 and 97 hr, only random doses were statistically significant from shams, with no specific trend in either HR or SF at this postcardiogenesis stage. Within each time group, gas chromatography analysis of embryo tissue ethanol content demonstrated a linear relationship between dose injected and tissue ethanol content retrieved. With increasing dose and stage, viability decreased. Weights of ethanol‐injected embryos were not significantly different from shams within each time group. Our studies of the response of the embryonic chick heart to ethanol indicate both dose and stage susceptibility, with greater susceptibility to ethanol injury during active cardiogenesis.
Genetic differences in the frequency of acetazolamide‐induced ectrodactyly in the mouse exhibit directional dominance of relative embryonic resistance
Authors: Biddle Fred G.
Published: June 2005

Eleven of the common inbred strains of the mouse were surveyed for their teratogenic response to acetazolamide that was administered three times per os at 1,000 mg/kg (9 A.M. and 4 P.M. on day 9 and 9 A.M. on day 10). The products of conception were examined for gross malformations on day 15. One strain, SJL/J, exhibited maternal toxicity to the dosage regime and was excluded from the survey. Five strains exhibited significantly increased resorption rates after treatment. All strains responded with the expected malformation of postaxial forelimb ectrodactyly with a right‐sided predominance. Nine of the strains could be assigned to one of four mutually exclusive classes of frequency of ectrodactyly and the tenth strain (BALB/cByJ) showed overlap between the two intermediate classes. The data suggest major genes determine the difference in sensitivity to ectrodactyly rather than a polygenic mode of inheritance. Induced cleft lip was found in four strains and one of these strains, SWR/J, exhibited a significantly higher frequency. The strain differences in sensitivity to induced resorption, forelimb ectrodactyly, and cleft lip were genetically independent. A reciprocal cross study was conducted with five of the strains from the four classes of frequency of ectrodactyly response in order to determine gene action. A significant maternal effect on the ectrodactyly response was found only with one of the strain pairs in the ten sets of reciprocal crosses with the five strains. When there was a significant difference between two strains, the F1 embryos exhibited dominance of relative resistance to ectrodactyly. The directional dominance of relative resistance to acetazolamide‐induced ectrodactyly suggests that regulatory genes control the embryonic differences in frequency of ectrodactyly response to acetazolamide. By analogy with other metric traits of development that exhibit directional dominance, the genetic variation in ectrodactyly response that has been observed so far in the mouse embryo may not be involved with the primary target of acetazolamide teratogenesis.
Prenatal death and malformations after irradiation of mouse zygotes with neutrons or X‐rays
Authors: Pampfer S. , Streffer C.
Published: June 2005

Female mice (strain: “Heiligenberger Stamm”) were irradiated with neutrons (7 Me V) or X‐rays when embryos were at the early zygote stage; uterine contents were examined on gestation day 19 for prenatal mortality and malformed fetuses. For both radiation qualities, the dose dependent survival curve fitted well to a simple exponential equation; the neutron relative biological efficiency (RBE) value was 2.3. The major fraction of deaths induced by exposure to neutrons or X‐rays occurred before implantation. Aside from dead embryos, malformed fetuses were observed 19 days p.c. (postconception). The number of malformed fetuses increased with a linear‐quadratic function of neutron or X‐ray dose. Malformations were mainly gastroschisis, although omphaloceles and anencephalies were also observed. The neutron RBE value for the induction of malformations varied from 2.0 to 2.8 in the dose range tested. Except after 75‐cGy neutrons, no significant increase in the proportion of stunted or skeletally malformed fetuses was noted. Our results indicated that the reaction of preimplantation embryos to irradiation could be more complex than the simple “all‐or‐none” response considered so far.
Neuron development in the superior colliculus of the fetal mouse following maternal alcohol exposure
Authors: Zajac C. S. , Bunger P. C. , Moore J. C.
Published: June 2005

Pregnant Swiss Webster mice were given a liquid diet with ethanol (EtOH) or isocaloric amounts of maltose dextrin on gestation day (GD) 0 through 18. On GD 18, maternal blood samples were obtained. Fetuses were then removed and fetal brains were prepared for light microscopy. Fetal weight was reduced in the EtOH‐exposed group. The ratio of midbrain cross sectional area to cerebral aqueduct was reduced in the ethanol group, while the density of neuronal nuclear population in both the dense outer layer (DS) and sparse inner layer (SS) of the developing superior colliculus was increased. Mean nuclear volume was decreased in the SS.
Magnetic resonance microscopy of chick embryos in ovo
Authors: Effmann E. L. , Johnson G. A. , Smith B. R. , Talbott G. A. , Cofer G.
Published: June 2005

Magnetic resonance imaging (MRI) of the live 11‐day chick embryo with special radiofrequency coils and 3‐D imaging methods has produced contiguous 1.25‐mm‐thick slices with 200‐μm pixel resolution, permitting definition of cardiac chambers, cerebral ventricles, spinal cord, liver, and lungs. It was the objective of this study to image younger chick embryos in ovo with higher spatial resolution through the application of implanted radiofrequency coils. Fertilized Arbor Acre eggs were windowed at 9, 6, and 4 days. Circular coils 18 mm in diameter tuned to 85.5 MHz were suspended around the developing embryo. The eggs were sealed with tape and maintained at 37°C during the imaging procedure. MRI was performed in a 2.0‐Tesla GE system utilizing a 3‐D Fourier transform acquisition in sagittal and axial planes with a partial saturation sequence (TR = 400 ms, TE = 27 ms). Approximately 1 hour of imaging time was required to obtain 16 contiguous 600‐μm‐thick slices with 50‐μm pixel resolution. Embryos remained viable through the imaging procedure. Embryos were photographed, fixed, and cleared for correlative anatomical study. Vitelline vessels, dorsal aorta, aortic arches, cardinal veins, and cardiac chambers were identified as areas of decreased signal intensity. Cerebral ventricles and the vitreous portion of the eye have signal intensities that are less than adjacent neural, scleral, and lens tissue. Further refinements in MR instrumentation and imaging sequences promise improvements in resolution and offer the potential for sequential observations of the intact embryo.
Somatomedin inhibitors from human serum produce abnormalities in mouse embryos in culture
Authors: Balkan Wayne , Rooman Raoul P. , Hurst‐Evans Amy , Phillips Lawrence S. , Goldstein Steven , Du Caju Marc V. L. , Sadler T. W.
Published: June 2005

Two human serum fractions, one from normal individuals (Mr 1,150–1,310 daltons) and the other (Mr 800–1,100 daltons) from patients suffering with uremia (renal failure, azotemia), were added to the medium used to grow embryos in whole‐embryo culture (WEC) begining at the 3–5 (day 9) or 18–21 (day 10) somite stage. Both of these fractions possessed somatomedin (insulin‐like growth factor) inhibitory activity. Day 9 embryos exposed to either of the serum fractions for 24 hr exhibited incomplete rotation and neural tube closure defects and were smaller than control embryos (decreased total protein content). Developmental abnormalities induced in day 10 embryos following 24 hr in culture included a marked decrease in expansion of the brain regions, hypoplasia of the first two branchial arches, and decreased amounts of total protein compared to controls. The visceral yolk sacs (VYSs) of somatomedin inhibitor (SI)‐exposed conceptuses were opaque, and those from day 10 conceptuses contained significantly more protein than controls. Morphologically, the VYS endoderm cells from SI‐exposed embryos contained a much higher density of “vacuoles” than controls. These results mimic those produced by exposure of conceptuses to an SI of Mr 800–1,100 obtained from the serum of diabetic rats and suggest that similar substances and mechanisms are involved.
Teratogenic activity of lithium carbonate: An experimental update
Authors: Jurand Arthur
Published: June 2005

The teratogenic potential of lithium carbonate was re‐examined using mouse embryos as an experimental model. Externally it was found that, like many other psychoactive drugs, it exhibits a teratogenic activity that is confined to the development of the central nervous system. When administered intraperitoneally to pregnant females in doses ranging from 330 to 340 mg/kg at the very beginning of the ninth gestation day, i.e., during the critical period of the neural tube closure, it is embryotoxic, causes retardation of development, and induces the “neurotropic syndrome of malformations” comprising exencephaly, craniorachischisis, rachischisis, kinking of the spinal cord, and dilation of the fourth brain ventricle: Depending on the exact time of gestation when lithium carbonate is administered, the frequencies of exencephaly and spinal kinking after treatment 1 hour into the ninth day are compared with those after treatment 2 or 3 hours into the ninth day, incidence of exencephaly is increased at the later time and the incidence of spinal kinking is decreased.
Teratogenic effects of trichloroacetonitrile in the long‐evans rat
Authors: Smith M. K. , Randall J. L. , Tocco D. R. , York R. G. , Stober J. A. , Read E. J.
Published: June 2005

Trichloroacetonitrile (TCAN) is among a number of contaminants found in drinking water produced by reactions of chlorine with background organic material. Long‐Evans rats were intubated with TCAN (0, 1, 7.5, 15, 35, 55 mg/kg) in a tricaprylin vehicle on gestation days 6–18. The highest dose tested (55 mg/kg) was lethal in 21% of the dams and produced 100% resorptions in two‐thirds of the survivors. Only one maternal death was seen at the next‐lower dose; however, fetal weight and viability were decreased in a dose‐related manner. The percentage of embryolethality was 13.9% at the lowest dose and 78.4% at the high dose, with resorption of entire litters seen at 7.5 mg/kg and above. At all doses, cardiovascular (interventricular septal defect, levocardia, common carotid, and right‐sided aortic arch and ductus arteriosus) and urogenital (hypoplastic, missing, misplaced and fused kidneys, and hypoplastic uterine horns) malformations were seen in the offspring. Frequency of these malformations was dose related, ranging from 8% to 35% at the 1.0‐ and 35‐mg/kg doses, respectively. The incidence of total soft tissue malformations was statistically significant at 15 and 35 mg/kg. There were no significant treatment‐related changes in the incidence of skeletal malformations. The no‐effect dose was established by statistical analysis to be 1.0 mg/kg/day.
Effects of perinatal exposure to a synthetic estrogen and progestin on mammary tumorigenesis in mice
Authors: Lopez Joanne , Ogren Linda , Verjan Roberta , Talamantes Frank
Published: June 2005

The effects of perinatal exposure to synthetic estrogens and progestins on mammary tumorigenesis were studied in female C3H/HeN/MTV + mice. Mice were treated neonatally with 0.001 μg/day diethylstilbestrol (DES), with 15 μg/day 17α‐hydroxyprogesterone caproate (HPC), or with oil on days 1–5 of life (birth = day 1). As adults, neonatally hormone‐treated mice received long‐term treatment with a synthetic estrogen and progestin combination or vehicle. Animals were palpated weekly for mammary gland tumors. The effect of treatment on the probability of tumor development was examined. Neonatal treatment with a low dose of DES increased the probability of mammary‐gland tumor formation, whereas neonatal treatment with HPC had a slightly protective effect on tumorigenesis. Subsequent treatment of adult mice with synthetic steroids did not affect mammary gland tumorigenesis in neonatally DES‐treated or oil‐treated animals. There was a significant interaction between the effect of neonatal HPC treatment and subsequent steroid treatment on mammary tumorigenesis but examination of the data indicated that this interaction was due to the protective effect of HPC in the absence of subsequent exposure to synthetic steroids and the probability of tumor appearance in mice treated with both HPC and synthetic steroids as adults did not differ from that of neonatally oil‐treated controls.
Medroxyprogesterone acetate therapy in early pregnancy has no apparent fetal effects
Authors: Yovich John L. , Turner Simon R. , Draper Rogan
Published: June 2005

Medroxyprogesterone acetate (MPA; Provera) was given orally to 449 women from the 5th to 7th week of pregnancy until at least the 18th week. Data are recorded from two treatment groups (recurrent abortion and threatened abortion) and are compared to a matched series. A total of 1,016 pregnancies are included in the study, and all patients were recruited from a subfertile population conceiving from a range of infertility treatments. Early pregnancy wastage was high throughout the groups and was significantly elevated (43%; P <.001) in those women who had vaginal bleeding in early pregnancy. The study focuses on the question of potential teratogenicity of progestagens administered in the first trimester. There were 15/366 (4.1%) infants with congenital abnormalities in the MPA‐treated group and 15/428 in the untreated group (3.5%). The difference was not significant, and MPA is considered to have no embryopathic risk, nor is it likely to retain an abnormal fetus that might otherwise abort. It appears that MPA is a safe drug to use in pregnancy although the question of efficacy has not been addressed in this report. Considering other recent negative epidemiologic studies with regard to teratogenicity, we add to the conclusion that MPA cannot be demonstrated to have a measurable teratogenic risk and certainly does not present a risk for congenital heart disease and limb reduction defects.
Ventricular blood pressure and cardiac output changes in epinephrine‐ and metoprolol‐treated chick embryos
Authors: Rajala Gregory M. , Kolesari Gary L. , Kuhlmann Randall S. , Schnitzler Henry J.
Published: June 2005

The effects of a teratogenic dose (5 μg) of epinephrine on mean ventricular blood pressure (MVBP) and cardiac output (CO) at one and two hours after treating stage 24 chick embryos were investigated. Previous work demonstrated that a differential response in terms of cardiac rhythm during the first hour after epinephrine treatment was related to pathogenesis of two contrasting types of aortic arch malformations. Absence of one or more aortic arches occurred more frequently in embryos which developed a characteristic dysrhythmia, while persistence of the left fourth aortic arch (PL4AA) occurred more frequently in nondysrhythmic embryos. In this study, dysrhythmic epinephrine‐treated embryos exhibited reductions in both MVBP and CO at one hour after treatment when compared to control values. Nondysrhythmic epinephrine‐treated embryos exhibited elevated MVBP and no change in CO at one hour after treatment. MVBP and CO in recovered dysrhythmic and nondysrhythmic embryos were similar to control values at two hours following epinephrine treatment. MVBP and CO measurements were obtained from embryos which were pretreated with metoprolol and then subsequently treated with epinephrine. Metoprolol is a beta1‐adrenoreceptor antagonist which was previously shown to block the teratogenic effects of epinephrine and other catecholamines with beta1‐adrenoreceptor agonist properties. Pretreating embryos with metoprolol in this study reduced the dysrhythmogenic potential of epinephrine and also blocked the MVBP and CO changes observed in embryos treated with epinephrine alone. We conclude that pathogenesis of 1) abnormally absent aortic arches is related to dysrhythmogenesis, reduced MVBP, and reduced CO, and 2) an abnormally persistent left fourth aortic arch is related to elevated MVBP in the epinephrine model.
Morphometric analysis of Macaca nemestrina exposed to ethanol during gestation
Authors: Sheller Barbara , Clarren Sterling K. , Astley Susan J. , Sampson Paul D.
Published: June 2005

This study was part of a multidisciplinary investigation of the effects of gestational ethanol exposure in nonhuman primates. Thirty‐one pregnant Macaca nemestrina were exposed to weekly ethanol doses of 0.0, 0.3, 0.6, 1.2, 1.8, 2.5, 3.3, or 4.1 g/kg maternal weight. Dose cohorts 0.0 through 1.8 were exposed to the initial ethanol dose within 10 days postconception. Dose cohorts 2.5 through 4.1 received their initial dose after the fifth week of gestation. Morphometric analyses performed on cranial radiographs showed that animals exposed to high doses of gestational ethanol had, on average, slightly smaller, distorted crania than control animals. A dysmorphic, flat face characteristic of fetal alcohol syndrome was recognized in one animal of the 1.8 g/kg cohort. The animal that received the highest doses of gestational ethanol was microcephalic. Similar malformations were not seen with low ethanol exposures or in controls. These data suggest a pattern of cranial distortion that may be recognizable and characteristic of ethanol teratogenesis.
Effects of prenatal X‐irradiation on the 14th–18th days of gestation on postnatal growth and development in the rat
Authors: Jensh Ronald P. , Brent Robert L.
Published: June 2005

Thirty‐nine pregnant adult Wistar strain rats were randomly assigned to one of three exposure groups: 0, 0.75, or 1.50 Gy X‐radiation total exposure. Animals were exposed from the 14th to the 18th days of gestation at 0, 0.15, or 0.30 Gy per day. At term, 15 rats were killed and morphologic analyses were completed. Twenty‐four rats were allowed to deliver their offspring. On the first day of postnatal life, litters were reduced to a maximum of eight pups per litter, with equal numbers of male and female offspring wherever possible. A total of 187 pups were observed for the age of acquisition of five reflexes (air righting, surface righting, visual placing, negative geotaxis, auditory startle) and the appearance of four physiologic markers (pinna detachment, eye opening, vaginal opening, testes descent). There was significant dose‐related weight reduction in term fetuses and offspring throughout the 86‐day postnatal period. Postnatal growth rate (g gained/day) was unaffected. Adult offspring brain and gonadal weight and organ weight:body weight ratios were reduced. Using the PAC50 methodology, dose‐related alterations occurred in the acquisition of several reflexes. All physiologic markers exhibited a dose‐related delay in appearance. These results indicate that fractionated exposure to X‐radiation during the fetal period in the rat results in dose‐dependent alterations in postnatal growth and physiologic development. These studies are important for our understanding of the long‐range effects of prenatal exposure to ionizing radiation late in gestation.
Morphology and embryological interpretation of a congenital occipito‐atlanto‐axial malformation in a dog
Authors: Watson Alastair G. , de Lahunta Alexander , Evans Howard E.
Published: June 2005

A clinical, radiological, and morphological study of a congenital occipito‐atlanto‐axial malformation in a 13‐week‐old male Saint Bernard dog that became suddenly tetraplegic at 8 weeks is described. The dog was recumbent, had generalized muscle atrophy, but was alert and responsive. Pain was elicited when the head‐neck junction and the cervical vertebrae were palpated, and a bony abnormality was palpated at the occiput and atlas. Clinical signs of upper motor neuron and general proprioceptive deficits in all four limbs were compatible with a focal lesion in the cervical spinal cord. Plain radiographs of the head and neck revealed malformation of the occipital bones, atlas, and axis, unilateral atlanto‐occipital fusion, and atlanto‐axial sub‐luxation. At necropsy the right half of the atlantal neural arch was fused to the right exoccipital bone. On the axis, the dens was small, malformed, and deviated to the left; the transverse processes were enlarged; and the spinous process was small with a cleft caudally. The spinal cord was severely compressed at the level of the atlanto‐axial articulation, and histological examination revealed extensive loss of neuronal cell bodies, axons, myelin, and the central canal. Reactive astrogliosis was also extensive. After a discussion of normal and abnormal development of the vertebral column and its joints, it was concluded that a failure of normal joint development at about 30 days of gestation in the dog could lead to congenital occipito‐atlanto‐axial malformation.