bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of gestational sex steroid exposure on limb development and endochondral ossification in the pregnant C57BI/6J mouse: I. Medroxyprogesterone acetate
Authors: Carbone J. P. , Figurska K. , Buck S. , Brent R. L. 
Published: June 2005

AbstractAlthough data supporting the teratogenic potential of intrauterine progestin exposure is lacking, concern persists among some individuals within the scientific community that these drugs have the potential for nongenital teratogenesis, especially with regard to limb reduction defects. Our laboratory has been interested in the ontogeny of steroid receptors in the developing embryo and in the role of steroid‐receptor interactions in limb development, particularly the process of endochondral ossification. Since limb reduction defects can be produced from abnormal processes that are operative during organogenesis or during midgestation (vascular disruption) we have designed an animal study whereby embryos were exposed to sex steroids throughout organogenesis and fetal development. The present study assesses the effects of medroxyprogesterone acetate (MPA) on intrauterine endochrondral bone development specifically, as well as overall embryo‐fetal development. Primagravid C57B1/6J mice were treated via subdermal pellets which deliver MPA at dosages of 5.0, 50.0, and 500.0 mg/kg/day on gestational days 7 through 19. These doses were 25‐, 250‐, and 2,500‐fold higher on a mg/kg basis than the human dose equivalent (HDE). No increases in nongenital malformations were noted at any evaluated MPA dosage level. At 25 × the HDE, MPA did not influence endochondral bone development as evidenced by a lack of significant effects on assessed bone growth parameters. In the 250‐ and 2,500‐fold HDE dosage groups, MPA was shown to exert an embryotoxic effect inducing 48 and 100% resorptions respectively. Mean embryo weights/litter were significantly reduced by MPA exposure at 250 × the HDE. Intrauterine exposure to 250 × the MPA HDE induced reductions in humeral and femoral diaphyseal length in proportion to a reduction in overall growth. The data demonstrate that MPA, administered at dosages of up to several orders of magnitude in excess of the HDE and which permitted embryo survival, did not induce increases in the frequency of nongenital teratogenesis at any dose or gestational stage. Importantly, limb reduction defects were not noted even in instances where the dosage of MPA induced an inhibition of endochondral bone growth.
Effects of secondary bile acids on the intrauterine development in rats
Authors: Zimber Amazia , Zusman Igor 
Published: June 2005

AbstractThe effects of secondary bile acids (lithocholic—LCA, and deoxycholic—DCA) on the in vivo development of rat embryos and fetuses were studied. Daily intraperitoneal injections of 2 ml of 1 mM LCA and of 5 mM DCA during days 6 till 15 of pregnancy resulted in an increase of resorptions among 20 day‐old fetuses to 22.8% and 9.9%, respectively, vs. 6.2% in controls. Similar injections on days 12 to 19 resulted in an increase of resorptions to 10.3% after treatment with LCA and to 36% after treatment with DCA. Percent of retarded embryos was similar for both bile acids: 7.7 and 8.7% after injections on days 6–15 and 12.3–12.5% after injections on days 12–19 of gestation. This was accompanied by a significant increase in the wet weight of the placenta of living embryos. Intraamniotic injections of 2 μl of 1 mM LCA into 10 day‐old embryos resulted in 18.5% resorptions (vs. 7.5% in controls), 9.2% malformations, and 3.1% growth retardations observed on day 12 of pregnancy. The rate of resorptions following this treatment increased on day 20 of pregnancy to 71% vs. 16% in controls. No differences were found in the wet weight of 20 day‐old living fetuses or their livers and placentas between experimental and control groups following i.p. or intraamniotic injections. In addition, single intrauterine instillation of 0.2 ml of 1 mM LCA 10–14 days before mating with normal isogeneic males resulted in 9% of malformations among 12 day‐old embryos while malformations were absent in the saline‐injected controls. The deleterious effects of secondary bile acids to the embryos were accompanied by damage to the visceral yolk sac. These findings may be significant in relation to the complications previously associated with cholestasis of pregnancy in humans.
Developmental toxicity of temafloxacin hydrochloride in the long‐tailed macaque (Macaca fascicularis)
Authors: Tarantal A. F. , Lehrer S. B. , Lasley B. L. , Hendrickx A. G. 
Published: June 2005

AbstractThe potential developmental toxicity of temafloxacin hydrochloride was studied in the long‐tailed macaque (Macaca fascicularis). Ten animals in each of the three drug‐treated groups (25, 50, and 100 mg/kg) were administered temafloxacin via nasogastric intubation during gestational days (GD) 20–50. A control group of ten animals received vehicle only. The dams were monitored daily for adverse physical signs and maternal blood samples were collected for analyses of serum progesterone (P), 17β‐estradiol (E2), and chorionic gonadotropin (CG). In addition, the conceptus was monitored periodically by ultrasound during gestation to confirm growth and viability. Increased maternal toxicity (weight loss, anorexia, emesis) and embryolethality were observed at 100 mg/kg, and a no‐observable‐adverse‐effect‐level (NOAEL) of 50 mg/kg was established. The incidence of prenatal mortality was as follows: Control = 1/10 (10%); 25 mg/kg = 1/10 (10%); 50 mg/kg = 2/10 (20%); and 100 mg/kg = 5/10 (50%). Analysis of P, E2, and CG indicated no significant effect of treatment. In addition, no significant differences were observed in embryonic/fetal growth and development when compared to historical controls. No gross structural changes were observed in fetuses exposed to 50 or 100 mg/kg, although one fetus exposed to 25 mg/kg exhibited microphthalmia. This anomaly was considered spontaneous and, therefore, unrelated to treatment.
Developmental alterations in offspring of female rats orally intoxicated by aluminum lactate at different gestation periods
Authors: Muller Guy , Bernuzzi Viviane , Desor Didier , Hutin Marie‐France , Burnel Daniel , Lehr Paul R. 
Published: June 2005

AbstractPregnant rats were treated orally with aluminum lactate (400 mg Al/kg/day) during three periods of gestation to determine the treatment's influence on mortality, weight gain, neuromotor maturation, and learning abilities of their pups. No effect of treatment on litter size, mortality rate, and weight gain of pups was detected. In the negative geotaxis test, the scores of pups from females treated during the second and third weeks of gestation were diminished. In the locomotor coordination and the operant conditioning tests, significant differences in the comparison of controls vs. the three treated groups were found, indicating long‐term effects of early intoxication upon the central nervous system.
Descriptive epidemiology of selected malformations of the aorta, Atlanta, 1970–1983
Authors: Martin Mary Louise , Adams Melissa M. , Mortensen Mary L. 
Published: June 2005

AbstractTo augment available population‐based epidemiologic data for obstructive malformations of the aorta, we studied the descriptive epidemiology of coarctation, hypoplasia, and interruption of the aortic arch in Atlanta from 1970 through 1983. The study used data from the Metropolitan Atlanta Congenital Defects Program, a population‐based birth defects registry. One hundred seventy infants were identified as having either interruption of the aortic arch (18), coarctation (131), or hypoplasia (21) of the aorta. The prevalence per 10,000 live births was as follows: interruption of the aortic arch, 0.50; coarctation, 3.62; and hypoplasia of the aorta, 0.58. Despite the differences in rates, the descriptive epidemiology for the three malformations was similar. None of the malformations was associated with gender or maternal age. Birth prevalence for whites was higher than that for other races; the increase, however, was statistically significant only for coarctation. Birth prevalence of these malformations increased during the period of observation, with the greatest increase (threefold) seen with interruption of the aortic arch. The rates for all malformation groups also showed a strong inverse association with birthweight.
Teratogenic effects of maternal biotin deficiency on mouse embryos examined at midgestation
Authors: Watanabe Toshiaki , Endo Akira 
Published: June 2005

AbstractPregnant mice were fed a basal diet that not only did not contain biotin, but also contained the spray‐dried egg white including avidin that caused the biotin deficiency. The effects of maternal biotin deficiency on craniofacial and limb development in embryos were examined at two stages of midgestation. On day 12.6 of gestation, male and female embryos weighed less and digit development was retarded in the biotin‐deficient group. On day 15.6 of gestation (dg), the embryos also weighed less and external malformations, such as micrognathia (94.8%), micromelia (41.4%), and exencephaly (11.4%), were observed. The inhibition of palatal and digit formation by biotin deficiency at midgestation is responsible for later formation of cleft palate and micromelia. On dg 12.6 the liver biotin level of biotin‐deficient dams was reduced to 20% of control values. Interestingly, the biotin content of the whole embryonic body was about ninefold greater than liver biotin levels in their dams.
An anatomic comparison of cebocephaly and ethmocephaly
Authors: Souza James P. , Siebert Joseph R. , Beckwith J. Bruce 
Published: June 2005

AbstractCebocephaly (hypotelorism, single‐nostril nose) and ethmocephaly (hypotelorism, interorbital proboscis) lie in the middle of the spectrum of craniofacial changes associated with holoprosencephaly. Because these defects and thorogh anatomic studies of them are rare, knowledge concerning morphologic as well as pathogenetic relationships is lacking. We report the autopsy findings and anatomic features of the dried skull of a 31 week fetus with cebocephaly and the craniofacial dissection of a 36 week fetus with ethmocephaly. Both manifested dysplastic changes of the ethmoid bone and anterior portion of the sphenoid bone, with concomitant hypotelorism and defects of the medial orbital walls. Through these latter defects, the eyes were joined in the ethmocephalic fetus (synophthalmia). Other changes of bone (single optic foramen, approximated maxillae, choanal atresia, thickened palate) and soft tissue (eccentric or fused extraocular muscles, single optic nerve) in both fetuses resembled those reported in other cases of cebocephaly and ethmocephaly, as well as cyclopia. In the 19th century, both cebocephaly and ethamocephaly were classified as two‐orbit variants of cyclopia, a view supported by the present study.
Route‐dependent pharmacokinetics, distribution, and placental permeability of organic and inorganic selenium in hamsters
Authors: Willhite Calvin C. , Ferm Vergil H. , Zeise Lauren 
Published: June 2005

AbstractInorganic selenium (Se) salts (selenite and selenate oxyanions) and the organic selenoamino acids (selenomethionine and seleniferous grains) are teratogenic and embryolethal in domestic and wild birds. Selenium bioaccumulation has been held responsible for reproductive failure among waterfowl at the Kesterson Reservoir (California), the Ouray and Stewart Lake Wildlife Refuges (Utah), and the Carson Sink (Nevada). Anecdotal field and controlled laboratory reports have implicated Se exposure in mammalian embryotoxicity (including human), but developmental toxicity studies in hamsters failed to demonstrate an adverse response, except at maternally toxic doses (Ferm et al., Reprod. Toxicol., in press). Uptake, distribution, and elimination of Se after a single bolus equimolar dose (60 μmol/kg) of selenate or selenomethionine by oral or intravenous administration were compared using day 8 pregnant hamsters. Intravenous selenate was eliminated ten times more rapidly from maternal plasma than oral selenate, but concentrated in liver, kidney, and placenta to the same degree. Intravenous (iv) L‐selenomethionine achieved lower maximum circulating total [Se], but it was eliminated more slowly than iv selenate. Larger areas under the plasma and peripheral tissue [Se]:time curve (AUC) after oral or parenteral selenomethionine than after equimolar selenate were consistent with previous studies in rodents and in humans. Embryonic [Se] plateaued at 3 nmol/g after selenate, but embryonic [Se] after selenomethionine continued to accumulate (80 nmol/g) as gestation progressed. The lack of a teratogenic response in hamsters at doses of either selenate or selenomethionine less than those associated with maternal intoxication cannot be attributed to lack of Se accumulation in early embryonic and placental tissue.
Renal agenesis and dysgenesis: Are they increasing?
Authors: Stroup Nancy E. , Edmonds Larry , O'Brien Thomas R. 
Published: June 2005

AbstractData from the Birth Defects Monitoring Program (BDMP) of the Centers for Disease Control (CDC) suggest that the birth prevalence of renal agenesis and dysgenesis combined is increasing. Medical records were reviewed for 1,404 of 1,669 (84%) infants in the BDMP with renal agenesis or dysgenesis noted on the newborn discharge summary to assess whether the observed trend reflects a true increase in one or both conditions or if it reflects changes in diagnostic, coding, or surveillance practices over time. For 1970–1982, the average rate per 100,000 live births and stillbirths was 3.5 for autopsy‐confirmed bilateral renal agenesis and 1.7 for autopsy‐confirmed bilateral renal dysgenesis. The birth prevalence of autopsy‐confirmed bilateral renal agenesis fluctuated within this time period, peaking in 1975, while the rate of autopsy‐confirmed bilateral renal dysgenesis increased steadily by 0.2 cases/100,000 births per year (P<0.001) with small peaks in 1976 and 1979. Unilateral renal agenesis or dysgenesis accounted for 17% of the confirmed cases, but most were detected by autopsy among infants who died shortly after birth rather than by diagnostic procedures such as ultrasound. Diagnostic information in the medical record suggested that the increase in the birth prevalence of renal agenesis and dysgenesis combined in the BDMF is due primary to the increasing prevalence of renal dysgenesis. Since medical records did not include sufficient information on risk factors, detailed analytic studies are needed to identify maternal risk factors that might account for the apparent increase in renal dysgenesis over time.
Exposure of the pregnant rat to warfarin and vitamin K1: An animal model of intraventricular hemorrhage in the fetus
Authors: Howe Andrew M. , Webster Williams S. 
Published: June 2005

AbstractPregnant Sprague‐Dawley rats were given daily oral doses of sodium warfarin (100 mg/kg) and concurrant intramuscular injections of vitamin K1 (10 mg/kg). This dosing regimen did not have any apparent deleterious effect on the dams and did not affect the fetuses when administered from day 1 to day 12 of pregnancy. However, similar treatment from day 9 to day 20 caused hemorrhage in the fetuses examined on day 21 of gestation. There were no hemorrhages in the control fetuses from dams receiving vitamin K1 only. The lowest effective dose of warfarin, in conjunction with daily doses of vitamin K1, was 3 mg/kg. This dose caused hemorrhage in 28% of fetuses; the incidence of affected fetuses was not further increased by doses of warfarin up to 100 mg/kg. Hemorrhages affected the fetal brain, face, eyes, and ear and occasionally the limbs. Brain hemorrhages were frequently intraventricular and caused various degrees of hydrocephaly. Bony defects were not a feature of prenatal exposure to warfarin.These results show that prenatal exposure of the rat to warfarin and vitamin K duplicates the hemorrhagic abnormalities and pathology associated with prenatal exposure to warfarin in the human. It did not induce bony or facial defects probably because the vitamin K‐dependent components of bone development occur postnatally in the rat. This model should allow detailed determination of the role of vitamin K‐dependent proteins in development.
Immunological factors responsible for pathogenetic cell degeneration in pregnancy
Authors: van der Zee D. C. , de Heer E. , Mentink M. M. T. , Vermeij‐Keers C. 
Published: June 2005

AbstractThe placenta has an important role as an immunological barrier during pregnancy. When the placental barrier is disrupted, maternoembryonic transfusion takes place. Several clinical reports relate congenital malformations or abortion to intrauterine bleeding or transplacental transfusion. In an earlier experiment, pathogenetic cell degeneration was induced using an in vitro whole rat embryo culture. Transplacental transfusion was simulated by intracardiac injection of an allogeneic rat‐antirat serum directed against the blood group antigens. The present study examines the morphological and immunological effects on the development of rat embryos 9 to 10 days old (stages 8–10 somites) of the separate administration of primary allogeneic antisera, obtained 10–17 days after immunization, and secondary allogeneic antisera, obtained after booster immunization on day 45–52. Rat‐antirat alloantibodies were directed against the blood group antigens. Transplacental transfusion was simulated by the embryonic intracardiac microinjection of approximately 0.5 μl serum enriched with either primary or secondary obtained allogeneic antibodies. After 48 hours' incubation, the embryos were examined microscopically, and it appeared that the secondary antisera, which had hemolytic activity, was more potent (P<0.005) in the induction of pathogenetic cell degeneration. It is well known that IgG antibodies display hemolytic activity. This finding was confirmed by direct immunofluorescence performed on rat embryos 2, 4, and 6 hours after injection, where incubation with rabbit‐antirat anti‐IgG antibodies gave a strong reaction. The hypothesis discussed is whether or not pathogenetic cell degeneration subsequent to transplacental transfusion of maternal antibodies can be initiated by similar immunological events.
Maternal vitamin A supplementation in relation to selected birth defects
Authors: Werler Martha M. , Lammer Edward J. , Rosenberg Lynn , Mitchell Allen A. 
Published: June 2005

AbstractHigh doses of vitamin A cause birth defects in animals. Concern over vitamin A teratogenicity in humans has been prompted by reports of teratogenic effects of the vitamin A analogue, isotretinoin. The pattern of defects observed among isotretinoin‐ and vitamin A‐exposed infants and animals suggests a possible mechanism involving cranial neural crest cell activity. Data from a case‐control study were used to assess maternal use of vitamin A supplements alone and vitamin A‐containing multivitamin supplements in relation to the occurrence of certain birth defects involving structures derived, at least in part, from cranial neural crest cells. Cases were 2,658 infants with such defects (primarily craniofacial and cardiac malformations). Controls were 2,609 infants with other malformations. Vitamin A supplementation was defined as daily use for at least 7 days of retinol alone or with vitamin D, or of fish oils. Information on vitamin A dose and nutrition was not available. The mothers of six controls used vitamin A supplements in each of the first three lunar months of pregnancy in comparison to the mothers of 15, 14, and 10 cases in lunar months 1, 2, and 3, respectively. Relative risk estimates and 95% confidence intervals were 2.5(1.0–6.2) for lunar month 1, 2.3(0.9–5.8) for lunar month 2, and 1.6(0.6–4.5) for lunar month 3. These findings should be considered tentative because no dose information was available, small numbers of cases and controls were exposed to vitamin A supplements, and relative risk estimates were not statistically significant. Separate analyses of the more common intake of multivitamins which contain vitamin A, including “prenatal” vitamins, found relative risks of these defects for daily use approximated unity and 95% confidence intervals excluded even small increases in risk.
Eliciting principles of hazard identification from experts
Authors: Jelovsek Frederick R. , Mattison Donald R. , Young John F. 
Published: June 2005

AbstractNational experts in the field of developmental toxicology were interviewed in order to elicit the principles, or rules‐of‐thumb, they use in determining if a compound or agent is likely to be a developmental hazard during pregnancy. Several levels of individual and cumulative consensus activity were carried out that resulted in consensus in 71 rules and partial consensus in an additional 24 rules of 145 rules initially elicited. Rules could be divided generically into those affecting the expert's confidence in a piece of scientific evidence and those determining the weight of importance of that evidence in deciding about hazard identification. Topically, the rules also divided into those about the general nature or characteristics of a compound, animal studies testing for an effect of the compound, and human reports about the presence or absence of developmental effects associated with the compound. Several conclusions about the methodology include the following: (1) expert systems must be based on the knowledge of more than one expert; (2) considerable human effort is expended in evaluating the certainty of scientific evidence before combining the evidence for problem solving; (3) how experts use evidence of different degrees of uncertainty in their decisions is a major area that is yet to be determined and that may greatly affect subsequent efforts in artificial intelligence; and (4) knowledge elicitation by interview has limitations but is a workable methodology for medical decision making.
Biochemical basis for D,L,‐beta‐hydroxybutyrate‐induced teratogenesis
Authors: Shum L. , Sadler T. W. 
Published: June 2005

AbstractPrevious investigations have demonstrated that a potential mechanism for D,L,‐beta‐hydroxybutyrate (BOHB)‐induced teratogenesis in neurulating mouse embryos (5–6 somite stage) after 24 hours of exposure in vitro is mediated by an inhibition of the pentose phosphate pathway (PPP) (Hunter, et al. '87). Employing conceptuses of an earlier stage (2–3 somite stage), the biochemistry of BOHB‐induced abnormalities was examined further by exposing embryos to 32 mM BOHB for 24 hour and comparing results with controls with respect to the rate of metabolism via the PPP, de novo pyrimidine biosynthesis (PB), and BOHB utilization. Moreover, the capability of these BOHB‐exposed embryos to recover from such an insult was also assessed by transferring them to fresh control medium and allowing them to grow for an additional 36 hours. Both controls and BOHB‐exposed embryos showed a progressive increase in rate of BOHB utilization between days 9 and 11.5 of gestation in vitro. Exposure to the ketone body produced a 100% rate of neural tube defects and a 25.2% decrease in total embryonic protein content. In contrast to results obtained at the 5–6 somite stage, no inhibition of the PPP in whole conceptuses, embryos, or visceral yolk sacs was observed in the group exposed to BOHB at the 2–3 somite stage. Furthermore, a 7.5 mM D‐ribose supplement, an intermediate in the PPP, was unable to rescue the younger embryos from BOHB‐induced abnormalities and growth retardation. On the other hand, BOHB produced a 34.3% decrease in pyrimidine biosynthesis in the 2–3 somite embryos, but not in the visceral yolk sac. In addition, embryos recovered biochemically after being transferred to control medium, demonstrating a 25.5% overshoot in pyrimidine biosynthesis. Therefore, the mechanism of BOHB‐induced teratogenesis appears to differ depending on the stage of embryonic development at the time of initial exposure.