bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of metabolic factors in the diabetic state on the in vitro development of preimplantation mouse embryos
Authors: Zusman Igor , Yaffe Perhiya , Ornoy Asher 
Published: June 2005

AbstractThe effects of insulin, glucagon, β‐hydroxybutyrate, and acetoacetate on the in vitro development of preimplantation mouse embryos were studied. In controls, 24% of blastocysts failed to develop successfully when grown for 72 h in Eagle's medium supplemented with 10% fetal calf serum. Insulin at concentrations of 1.0 and 2.0 IU/ml of culture medium interfered with development in 62–63% of the blastocysts. Preimplantation embryos showed a threshold pattern in their reaction to glucagon: its addition in concentrations of 0.0015 mM (5 μg/ml) did not significantly inhibit blastocyst development, while concentrations of 0.003 mM (10 μg/ml) inhibited 70% of blastocysts. The embryotoxic effects of ketone bodies were manifested only in relatively high doses. β‐hydroxybutyrate was embryotoxic at concentrations greater than 5 mg/ml, and its effects were dose dependent: 48 mM (6 mg/ml) inhibited 45% of blastocysts, while 80 mM (10 mg/ml) arrested 87% of embryos from further development. Acetoacetate at concentrations of 0.1 mM (10 μg/ml) inhibited the development of 50% of the blastocysts, and its effects were not dose dependent: concentrations of 1 mM (100 μg/ml) inhibited development in 63% of the embryos. The combination of the diabetic metabolic factors in relatively low concentrations was highly embryotoxic, especially when accompanied by hyperglycemia.
Craniofacial dysmorphogenesis following hypervitaminosis A in mice
Authors: Kay Elizabeth D. 
Published: June 2005

AbstractMalformations of the temporomandibular joint (TMJ), zygomatic arch, middle ear ossicles, and mandibular musculature following hyper‐vitaminosis A were described in fetal mice. Pregnant mice (Mus musculus) were each given a 0.2‐ml solution of corn oil containing 10,000 IU of retinol palmitate by gavage on day 8.7. Thirty‐eight fetal heads were collected and hemisected. The left hemiheads were serially sectioned, stained, and examined histologically. Right halves were cleared and double‐stained with alizarin red and alcian blue. The craniofacial morphologies of the test mice were found to vary from normal to maximally involved (feature unidentifiable) even among littermates. Both inter‐ and intralitter variation were discussed. Errors in chondrogenesis were determined to have produced the variety of dysmorphologies observed. Changes in Meckel's cartilage affected both the TMJ and ossicles; the presence of ectopic cartilages affected the zygomatic arch; and the musculature was affected secondary to skeletal system changes. Several modes of vitamin A interference leading to craniofacial dysmorphogenesis have been proposed in the literature. It was determined that proposals implicating altered cellular differentiation were the most compatible with the in vivo data recorded here and elsewhere.
Embryotoxicity of sex steroidal hormone combinations in nonhuman primates: I. Norethisterone acetate + ethinylestradiol and progesterone + estradiol benzoate (Macaca mulatta, Macaca fascicularis, and Papio cynocephalus)
Authors: Hendrickx A. G. , Korte R. , Leuschner F. , Neumann B. W. , Prahalada S. , Poggel A. , Binkerd P. E. , Günzel P. 
Published: June 2005

AbstractTwo sex steroid hormone combinations which have been used clinically as tests for detection of early pregnancy were examined for embryotoxic effects in macaques and baboons. Norethisterone acetate and ethinyl estradiol (NEA + EE) were orally administered to rhesus and cynomolgus monkeys and baboons at dosages ranging from one to 1,000 times the human dose equivalent (HDE) during days 20–50 of pregnancy. Progesterone and estradiol benzoate (P + EB) were delivered by two to six intramuscular injections to rhesus and cynomolgus monkeys between gestational days 20 and 35 at 0.1–25 × HDE. Fetuses were examined following cesarean section at 100 ± 2 days (NEA + EE) or at term (P + EB). The results showed increased embryolethality over controls at 100–1,000 × HDE (NEA + EE) and at 10 and 25 × HDE (P + EB). Besides growth retardation, isolated cases of minor nongenital malformations were observed only in cynomolgus monkeys following treatment with both hormone combinations mainly at embryolethal dose levels and were considered spontaneous in nature. Virilization of female cynomolgus fetuses following NEA + EE treatment was manifested as two cases of clitoral enlargement in the 300 × HDE group and two cases of increased anogenital distance with reduced vaginal opening in the 1,000 × HDE group. The highest dose of NEA + EE was also maternally toxic, as two maternal deaths occurred at the end of the treatment period. One dead female cynomolgus fetus exposed to P + EB (10 × HDE) also exhibited masculinized external genitalia. The results support epidemiologic and laboratory data which indicate that sex steroid exposure during early pregnancy does not induce nongenital teratogenicity.
Shakespeare, genetics, malformations, and the Wars of the Roses: Hereditary themes in Henry VI and Richard III
Authors: Hook Ernest B. 
Published: June 2005

AbstractThe four plays in the Henry VI‐Richard III sequence well illustrate Shakespeare's recognition of hereditary influences upon the human condition. The inheritance of physical characteristics as manifest particularly by resemblance between fathers and sons is noted frequently. The absence of such resemblance is cited occasionally as evidence of illegitimacy. Personality traits are also viewed as inherited, although less consistently and there are important exceptions. Physical and mental traits when not derived from parents are ascribed to “nature” in the sense in which the term is often used today. Such traits are seen as being congenital or inborn even if not obviously “hereditary.” Important exceptions to this are provided by the characters of the two lead characters in the play sequence. The weak‐willed Henry VI is markedly different from his father, grandfather, and son who were all valiant, warlike, and brave. Shakespeare never explains this abrupt difference among generations. And the source of the evil character of Richard III is somewhat ambiguous. It seems most likely that in the first three plays of the sequence Shakespeare intended Richard's villainousness to be perceived as innate, caused by the same forces of nature that produced Richard's deformities (which are not further explained). But when Shakespeare wrote Richard III and gave more conscious consideration to what was now his central character he invoked an “environmentalist” explanation. Richard now is presented, albeit somewhat inconsistently, as evil in response to social ostracism because of his ugly deformities. This rather modern interpretation of the social origins of the personality of the deformed is particularly striking because it goes beyond anything in Shakespeare's historical sources, although Francis Bacon, a con‐temporary of Shakespeare, also recognized the effect of social forces upon the personality of the deformed.
Teratogenicity and developmental toxicity of valproic acid in rats
Authors: Vorhees Charles V. 
Published: June 2005

AbstractThe 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

AbstractThis 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

AbstractSprague‐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

AbstractThirty‐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

AbstractThe 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

AbstractIn 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

AbstractThe 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

AbstractParents' 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

AbstractThe 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

AbstractLosulazine 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

Abstract△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

AbstractIn 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.