bluuebunny/crossref_metadata_2025 huggingface dataset:
Toxic effects of sodium selenite on pregnant mice and modification of the effects by vitamin E or reduced glutathione
Authors: Yonemoto Junzo , Satoh Hiroshi , Himeno Seiichiro , Suzuki Tsuguyoshi
Published: June 2005

Toxic effects of sodium selenite (SS) on dams and/or conceptuses and modification of the effects by vitamin E (VE) or reduced glutathione (GSH) were investigated in pregnant mice during late gestation. Dose‐dependent fetocidal effects and fetal growth retardation were observed in mothers injected SC with SS on day 12 but not on day 16 of gestation. On day 12, abortion occurred only at a dose level of 58.8 μmol/kg SS, whereas on day 16 it occurred at two dose levels: 27.2 and 40.0 μmol/kg SS. Pregnant mice were treated with or without VE (50 mg/kg, SC, daily from day 7 to day 11) and injected with a single dose of SS (46.2 μmol/kg, SC) on day 12. VE prevented abortion and maternal death, but none of the other effects such as fetal loss, fetal growth retardation, and decrease in body weight gain of the dams. Pretreatment with GSH (0, 2, or 5 mM/kg, SC) 20 min before SS injection on day 12 exacerbated maternal death, abortion, and decrease in body weight gain of the dams. No effect were observed in the number of live offspring, and in body weight of offspring.
Comparative teratogenic effects of methyl salicylate applied orally or topically to hamsters
Authors: Overman Dennis O. , White John A.
Published: June 2005

Methyl salicylate was administered topically to pregnant hamsters at 7d9h and the teratogenic results were compared with those obtained following oral treatment with the same compound. Both treatments produced the same defect in embryos recovered at day 9: failure of fusion of the neural tube, especially in the area of the developing brain. Analysis of serum salicylate levels following both treatments produced similar curves and indicated that teratogenic levels of salicylate can reach the maternal circulation after topical exposure.
Mevalonate supplementation in pregnant rats suppresses the teratogenicity of mevinolinic acid, an inhibitor of 3‐hydroxy‐3‐methylglutaryl‐coenzyme a reductase
Authors: Minsker D. H. , MacDonald J. S. , Robertson R. T. , Bokelman D. L.
Published: June 2005

Mevinolin is a fungal metabolite, and in the hydroxyacid form, mevinolinic acid, it is an inhibitor of 3‐hydroxy‐3‐methylglutaryl‐coenzyme A (HMG‐Co A) reductase, an enzyme essential in cholesterol biosynthesis. Oral administration of 800 mg/kg/day of mevinolin to rats from days 6 through 17 of gestation produced fetal malformations of the vertebrae and ribs in 29% of the litters, and there was a treatment‐related increase in the incidence of gastroschisis. Mevinolinic acid at 60 and 90 mg/kg/day also produced fetal malformations of the vertebrae and ribs, and these teratogenic manifestations were markedly suppressed by coadministration of the product of HMG‐Co A reductase, mevalonic acid, at a dosage level of 500 mg/kg b.i.d. A diet supplemented with 0.5% or 1.0% cholesterol had no effect on the teratogenicity of mevinolinic acid. Teratology studies in rats with a dihydroxyheptanoic acid derivative of mevinolin, a compound 1/700 as potent as mevinolinic acid as an inhibitor of HMG‐Co A reductase, and dihydromevinolinic acid, an inhibitor of this enzyme comparable in activity to mevinolinic acid, indicated that the teratogenicity of these compounds was related to their relative enzyme inhibitory activity. The dihydroxyheptanoic acid derivative was not teratogenic at doses as high as 150 mg/kg b.i.d.; in contrast, when dihydromevinolinic acid was administered at 50 and 100 mg/kg/day, its potency as a teratogenic agent was comparable to that of mevinolinic acid. These studies demonstrated that inhibitors of HMG‐Co A reductase produced terata in rats and that the teratogenic effects could be antagonized by coadministration of the enzyme product, mevalonic acid.
The chronology of somites in rat embryos
Authors: Vickers T. H.
Published: June 2005

To establish their chronology in rats the somites of 902 embryos were counted. They were the products of 89 pregnancies terminated at three hourly intervals from 231 hours to 288 hours and then six hourly until 324 hours. Somites form at a virtually constant rate of one somite per 1.87 hours. This is incorporated in the regression equation

where y = number of somites, x = hours of gestation from 06.00 on the morning after overnight mating. The greatest variation in the maturity of embryos within any time‐determined sample was nine somites (= 16.8 hours) and the least was three somites (= 5.6 hours). Some uses for the data in experimental teratology are suggested.
Cephalothoracopagus syncephalus: A case report with previously unreported anatomical abnormalities and chromosomal analysis
Authors: Delprado W. J. , Baird P. J.
Published: June 2005

A case of cephalothoracopagus conjoined twins is presented. The abnormality was detected antenatally by the use of ultrasonography. A detailed anatomical description is given, including previously unreported abnormalities of the cerebrum and genito‐urinary tract. Chromosomal analysis was also performed. This showed a pericentric inversion of one chromosome 9 in the fetus. Studies performed on the mother showed pericentric inversion of both chromosome 9s. A comparison of this case with previously reported cases in the literature is then given.
Increased susceptibility to 6‐aminonicotinamide‐induced cleft lip of heterozygote Dancer mice
Authors: Trasler Daphne G. , Kemp Dorothy , Trasler Tessa A.
Published: June 2005

Dancer heterozygotes (Dc/+) very rarely have cleft lip and show a dancing behaviour due to inner ear defects while homozygotes (Dc/Dc) have cleft lip. Males of the two genotypes Dc/+ and +/+ were mated to C3H strain and R stock females and Dc/+ males to Dc/+ females. On day 10/8 of gestation females were treated with 6‐aminonicotinamide (6AN) at either 19 mg/kg or 28.5 mg/kg followed 3 h later by a protective dose of nicotinamide. Controls were untreated. Both 6AN treatments caused a significant increase in cleft lip to between 25% and 29% for crosses of Dc/+ males to C3H and R females whereas crosses with +/+ males gave 0% cleft lip. In the controls the cleft lip frequency was: for Dc/+ × Dc/+ 14%, Dc/+ × C3H 1.4%, and for the other three crosses 0%. The four crosses given the high dose of 6AN and the +/+ × C3H and Dc/+ × R cross at the low dose showed significantly increased resorption rates to between 23% and 47% over the control rates of from 5% to 11%. The presence of the Dc gene increased the susceptibility to cleft lip caused by 6AN.
Agenesis of the penis, scrotal raphe, and anus in one of monoamniotic twins
Authors: Berry Susan A. , Johnson Dana E. , Thompson Theodore R.
Published: June 2005

Severe defects in the development of the caudal axis are rare, but lead to profound consequences for the fetus. They result from damage to multiple germ layers at a very early stage of development and vary in severity depending on the timing and degree of insult incurred. One of a set of identical male twins presented with persistence of the primitive cloaca with an absent phallus and anal atresia, but normal limb development. This combination of penile agenesis, imperforate anus, and absence of the scrotal and perineal raphae is an ominous physical finding indicative of severe renal anomalies, which in all cases have been incompatible with extrauterine survival. This constellation of findings, of which our patient is only the sixth reported example, probably results from a primary defect in caudal mesoderm migration before the fourth week of gestation. In this case, the defect may have occurred as a consequence of monochorionic monoamniotic monozygotic (MZ) twinning.
Genetic microcephaly in a pair of monozygous twins
Authors: Fried K. , Micle S. , Goldberg M. D.
Published: June 2005

A pair of monozygotic female twins with true primary microcephaly is described. The autosomal‐recessive nature of the disease is supported by the following: the twins are concordant for the disease; the parents, themselves normal, are related; the reduced skull dimensions were noted at birth; neurologic problems are absent; the karyotype is normal; the gestation and delivery were normal, without any history of influences capable of inducing microcephaly. A detailed dermatoglyphic study is given.
Sensitive stages and dose‐response analyses of palatal slit and cleft palate in C57BL/6 mice treated with a glucocorticoid
Authors: Kusanagi Takao
Published: June 2005

C57BL/6 mice were treated subcutaneously with triamcinolone acetonide in a single dose of 2.5–15.0 mg/kg once on days 6–15 of pregnancy (vaginal plug = day 0) and the palate of their fetuses was examined at term. The sensitive stages of palatal slit and cleft palate induction were studied and dose‐response relations on days 9 and 12 of pregnancy were analyzed by the log‐probit transformation method and compared. The test of significant increase in the frequencies of palatal slit and cleft palate showed that the sensitive period of palatal slit began earlier and ended later than that of cleft palate. On day 9 of pregnancy, the slope of the palatal slit response was similar to that of the cleft palate response, but the median effective dose of the former was lower than that of the latter. The slope of the palatal slit response was similar on days 9 and 12; however, the median effective dose was significantly greater on day 9. By contrast, the slope of the cleft palate response on day 12 was significantly different from that on day 9. The results of these doseresponse analyses suggest that the underlying mechanism may be the same in palatal slit induction on days 9 and 12 and in cleft palate induction on day 9; the mechanism underlying the cleft palate response on day 12 is different from that of the other three responses, and there is more than one mechanism for cleft palate induced by triamcinolone.
Direct fetal injections of diethylstilbestrol and 17β‐estradiol: A method for investigating their teratogenicity
Authors: Henry Ellen C. , Miller Richard K. , Baggs Raymond B.
Published: June 2005

The synthetic estrogen, diethylstilbestrol (DES), causes urogenital malformations in humans, primates, and rodents. This study was designed to determine whether these effects of DES are related to its estrogenicity. Therefore, DES (0.1, 1, and 10 μg) or the natural estrogen, estradiol (E2) (10 and 100 μg) was injected directly into day 19 rat fetuses. In the 6‐ to 7‐week‐old female offspring exposed to DES, a dose‐related incidence of cleft phallus, hypospadias, and incomplete coiling of oviducts was observed. The single fetal injection of E2 elicited similar urogenital malformations, but was approximately 100‐fold less potent than DES. A single subcutaneous dose of either DES (0.025, 0.25, or 2.5 mg/kg) or E2 (2.5 or 25 mg/kg) to dams on day 19 of pregnancy induced a spectrum of malformations similar to that following fetal injection. The offspring of treated dams, but not those injected directly as fetuses, had nonfunctioning ovaries (no corpora lutea) yet vaginal signs of estrous were present. It is concluded that DES can act directly in the fetus and its teratogenicity does not require maternal mediation. Since a high dose of E2 produced similar malformations when given to fetuses, it appears that excess estrogen during prenatal life is teratogenic. Thus, at least those endpoints of the teratogenicity of DES that were measured are accounted for by its estrogenic activity.
Arteriovenous malformations of the brain: A teratologic challenge
Authors: Warkany Josef , Lemire Ronald J.
Published: June 2005

Congenital arteriovenous malformations of the brain are lesions which are well‐known to neurologists and neurosurgeons but are puzzling to teratologists because they occur sporadically and are unassociated with congenital malformations outside the central nervous system. They are recommended to teratologists as a field of etiologic and pathogenetic research.
Neck web and congenital heart defects: A pathogenic association in 45 X‐O Turner syndrome?
Authors: Clark Edward B.
Published: June 2005

This study explores the association between neck web and congenital heart disease in patients with Turner syndrome. Of 193 cases with documented 45 X‐O karyotype, 106 (55%) had a web neck and 87 (45%) had a normal neck. The incidence of congenital heart disease was significantly different between these two groups, occurring in 30% of those with web neck and 9% of those with normal neck (χ2 = 12.82, P<.0005). The difference was most striking in coarctation of the aorta for which the prevalence was 25% with web neck and 3% with normal neck (χ2 = 17.65, P<.0001). The association between web neck and congenital heart disease suggests a pathogenic relationship exists between the two. The following hypothesis is proposed to explain the association. Increased lymphatic pressure associated with jugular lymphatic sac obstruction distends the thoracic ducts, which compress the ascending aorta altering intracardiac blood flow. Redirection of intracardiac blood flow produces coarctation of the aorta and other defects in the spectrum of left heart obstruction. This proposed mechanism is an example of a teratogenic event remote from the heart, which alters cardiovascular morphology.
Effects of ethanol on the primitive streak stage mouse embryo
Authors: Nakatsuji Norio , Johnson Kurt E.
Published: June 2005

Recent studies of mouse models have suggested that malformations associated with the fetal alcohol syndrome (FAS) are caused by the effects of ethanol on early embryos during gastrulation and neurulation. A study of Xenopus laevis embryos showed that exposure of gastrula stage amphibian embryos to ethanol inhibits migration of the mesodermal cells, causes formation of small neural plates, and subsequently causes hypoplastic craniofacial malformations in tadpoles. We now report effects of ethanol on the primitive streak stage mouse embryos. An ethanol solution (25%) was injected intraperitonealy twice into mice of 6.5–7.0 days of pregnancy at a dose of 0.015 ml/gm of body weight. Histological and morphometric examinations of 7.5‐day embryos, 20 hr after the second injection, showed that the epiblast layer was disorganized and shrunk with formation of many blebs. In addition, formation of the mesodermal cell layer was retarded in the ethanol‐treated embryos, suggesting that exposure of gastrula stage embryos to ethanol causes similar abnormalities in mouse and Xenopus embryos. These results suggest that the inhibition of the morphogenetic movements during gastrulation may be the primary effect of ethanol in causing major craniofacial malformations of FAS.
Estrogenic activity of zearalenone and zearalanol in the neonatal rat uterus
Authors: Sheehan Daniel M. , Branham William S. , Medlock Kevin L. , Shanmugasundaram E. R. B.
Published: June 2005

Fusarium sp. contaminated feedstuffs elicit adverse estrogenic effects in several commercially important animal species via the mycotoxin zearalenone. An estrogenically active synthetic derivative, zearalanol, is used as an anabolic agent in cattle. Since estrogens can irreversibly alter target tissue development, we investigated the estrogenic activity of these compounds in the neonatal rat uterus. Both induced dose‐dependent premature uterine growth when injected daily on postnatal days 1–5 (ED50 = 1.3 mg/kg BW). Nuclear estrogen receptor levels dramatically increased 1 hour after either a single injection on day 5 or after five daily injections. In 5‐day‐old animals, the translocated nuclear receptor was characterized as a single class of binding sites with a dissociation constant (KD) for estradiol (E2) of 1 nM. At 15 days, zearalanol‐treated animals showed greater uterine nuclear receptor retention than zearalenone‐treated animals. In 5‐day‐old animals, single mycotoxin doses induced five fold elevations of ornithine decarboxylase (ODC) at 6 hours. Unlike the growth response, ODC dose‐response studies showed zearalanol to be about 20‐fold more effective than zearalenone. Time course studies revealed that a low dose of zearalenone, but not of zearalanol, resulted in a shift in peak activity from 6 to 8 hours. These data suggest that metabolism of zearalenone may be important in short‐term pharmacodynamics. In a competitive binding assay, neither compound competed [3H]E2 from the E2 binding site on alphafetoprotein. We conclude that the uterine growth response and ODC induction demonstrate the neonatal estrogenic action of these mycotoxins, apparently mediated via the estrogen receptor. The greater effectiveness of zearalanol in inducing ODC may be related to nuclear retention and/or zearalenone metabolism.
Maternal toxicity—a possible factor in fetal malformations in mice
Authors: Khera K. S.
Published: June 2005

The assumption that major fetal malformations are indicative of a chemical's teratogenic potential was not supported by a literature review of teratology studies conducted in mice. In these studies, dose levels of test agents that manifested maternal toxicity as suggested by reduction in dam's body weight, clinical signs of toxicity, or deaths, also invariably caused reduction in fetal body weight, increased resorptions, and rarely fetal deaths. In several such studies, conducted with maternotoxic doses of structurally unrelated test agents, a consistent pattern of fetal defects was discovered. These defects included exencephaly, open eyes, hemivertebrae, fused arches or centra of lumbar or thoracic vertebrae, fused, missing or supernumerary ribs, and fused or scrambled sternebrae. These defects were absent at drug dosages that were distinctly nontoxic for the mother. In a few studies conducted at two or more maternally toxic doses, the degree and severity of maternal toxicity showed a positive correlation with the incidence and severity of above fetal defects. It is hypothesized that maternal toxicity, on its own, may have an etiologic role in these fetal defects.
Teratogenic effects of avidin‐induced biotin deficiency in mice
Authors: Watanabe Toshiaki , Endo Akira
Published: June 2005

Teratogenic effects of maternal biotin deficiency were examined at different levels of severity by adding three levels of avidin (10, 20, or 40 mg/kg) in the basal diet. There was a considerable increase of fetuses with multiple congenital malformations (micrognathia, cleft palate, and micromelia) with increasing amounts of avidin. The dose‐response relationship was observable in the incidence of each malformation as well. The body weight of live fetuses was also significantly reduced. However, the dams did not exhibit any typical signs of biotin deficiency, such as loss of hair, dermatitis, or nervous irritability. These results suggest that biotin is important for early embryonic development in the mouse.
Reproductive and genetic effects of continuous prenatal irrediation in the pig
Authors: Erickson B. H. , Martin P. G.
Published: June 2005

The stem germ cells of the prenatal pig are highly vulnerable to the cytotoxic effects of ionizing irradiation. This study was conducted to determine whether sensitivity to killing was also marked by a sensitivity to mutation and how prenatal depletion of the germ‐cell population affects reproductive performance. Germ‐cell populations were reduced by continuously irradiating sows at dose rates of either 0.25 or 1.0 rad/day for the first 108 days of gestation. The prenatally irradiated boars were tested for sperm‐producing ability, sperm abnormalities, dominanat lethality, reciprocal translocations, and fertility. Prenatally irradiated females were allowed to bear and nurture one litter, then tested for dominant lethality in a second litter; germ cell survival and follicular development were assessed in their serially sectioned ovaries. Sperm production was not significantly affected in the 0.25‐rad boars, but boars irradiated with 1.0 rad per day produced sperm at only 17% of the control level. Incidence of defective sperm was 4.9% and 11.1% in the 0.25 and 1.0 groups, respectively. Four of the 1.0‐rad boars were infertile, but prenatal irradiation apparently caused neither dominant lethality nor reciprocal translocations in fertile males. Number of oocytes was reduced to 66 ± 7% of control in the 0.25‐rad gilts, but reproductive performance was unaffected and no dominant lethality was observed. Only 7 ± 1% of the oocytes survived in the 1.0‐rad group. Reproductive performance was normal for the first litter, but four of the 23 sows tested were infertile at the second litter and a significant incidence of dominant lethality was observed. Whether this was a direct irradiation effect or the consequence of severe oocyte depletion is discussed. Diminished reproductive capacity rather than mutation appears to be the major consequence of continuous prenatal irradiation in the pig.
An anatomical study of human otocephaly
Authors: Lawrence Daniel L. , Bersu Edward T.
Published: June 2005

This study describes the gross anatomic variations observed in a 32‐week male fetus diagnosed as having otocephaly. Special attention was given to the muscular, peripheral nervous, and vascular systems of the entire body. External features included approximation of the ears on the front of the neck, underdevelopment of the lower jaw, and a small oral cavity. The mandible, maxillae, and zygomatic bones were smaller than normal and appeared shifted in a ventrocaudal direction. The middle ear ossicles were fused and abnormally positioned. The tongue was positioned abnormally and malformed. The muscles of mastication were fused in the midline and formed the floor of the oral cavity. The variations were similar to the spectrum of abnormalities reported in two cases in the literature. Because of this finding, it is possible that the causative events leading to these deviations were similar in the three cases. Possible mechanisms are considered which could lead to the observed malformations seen in these cases. There were also several muscle and nerve anomalies outside of the head region.
Cerebral dysraphia (future anencephaly) in a human twin embryo at stage 13
Authors: Müller Fabiola , O'Rahilly Ronan
Published: June 2005

Cerebral dysraphia was studied histologically and by graphic reconstruction in a twin at stage 13, and comparisons were made with the normal (discordant) twin. The normal, bidirectional closure of the rostral neuropore was investigated in several embryos, from which it was concluded that the situs neuroporicus is represented by the future commissural plate rather than by the (adult) lamina terminalis. In the abnormal twin the neural tube was open over part of the midbrain and forebrain, although the situs neuroporicus was closed. The experimental production of anencephaly by Giroud and co‐workers was reviewed, and comparisons between embryonic staging systems in the rat, mouse, and human were made. Three corresponding phases are found in the human: (1) cerebral dysraphia, occurring before or during Carnegie stage 11 (approximately 23–25 days); (2) exposure of a highly developing and well‐differentiated brain during the remainder of the embryonic period; and (3) degeneration of the exposed brain throughout the fetal period, resulting in anencephaly. Hence the abnormal twin described here is believed to represent a precursor of typical anencephaly, and is the earliest example of purely cerebral dysraphia so far recorded.
Acetazolamide teratogenesis: Association of maternal respiratory acidosis and ectrodactyly in C57BL/6J mice
Authors: Weaver Timothy E. , Scott William J.
Published: June 2005

Exposure of C57BL/6J mice to CO2 during a critical period of gestation results in predominatly right‐sided, postaxial, forelimb ectrodactyly in the offspring. The incidence and severity of CO2–induced limb malformations has been shown to be dependent on the concentration of inspired CO2, the developmental age of the embryo at exposure and the duration of CO2 exposure. Offspring of acetazolamide‐treated C57BL/6J mice also display this highly specific form of ectrodactyly (Green et al., '73). Since the drug has been shown to elevate tissue CO2 tension (Mithoefer and Davis, '58), the teratogenic effect of acetazolamide may be related to induction of a hypercapnic embryonic environment.
Fetal alcohol syndrome in the ferret (Mustela putorius)
Authors: McLain Daniel E. , Roe Daphne A.
Published: June 2005

Gastric intubation of 1.5 g ethanol/kg maternal body weight produced a significant teratogenic response in ferrets (Mustela putorius) treated once daily from gestational days 15 through 35. This response was evident by a rise in the frequency of fetuses with one or more malformations (21%), and by a rise in the frequency of litters with one or more malformed fetuses (50%). Palatoschisis and greater relative intermedial canthi distance observed in this study are diagnostic features of the fetal alcohol syndrome (FAS). Although mean (±SEM) peak blood alcohol levels of 207 ± 9 mg/dl did not affect other reproductive parameters, high doses of alcohol (3.0 g/kg) resulted in the inability of treated females to consume adequate food or water, in the complete resorption of litters, and in significant maternal mortality (88%). Fetal deaths occurred prior to gestation day 17 in the high‐dose alcohol group. Based on objective evaluation of differences among ethanol‐treated, pair‐fed sucrosetreated, and untreated ad libitum diet controls, the ferret would seem a valuable alternative animal species for future studies of FAS.
Interactions of salicylate, dietary zinc, and genetic strain in teratogenesis in rats
Authors: Hackman Robert M. , Hurley Lucille S.
Published: June 2005

The influence of dietary zinc concentration on salicylate teratogenesis was studied in Wistar and Sprague‐Dawley rats. Females were fed purified diets containing 0.4, 4.5, 9, 100, or 1,000 μg zinc/gm diet, or a stock diet (Purina Rat Chow) from day zero to day 21 of gestation, when they were killed and the fetuses were examined. On day 9, rats were given saline or 250, 500, or 750 mg sodium salicylate/kg body weight by gavage. Increasing drug dose caused increased frequency of malformed or resorbed fetuses, while increasing dietary zinc reduced the teratogenic effects of salicylate, but in different patterns in the two strains. The teratogenic effect of zinc deficiency also varied by strain. Statistical analysis showed that the frequency of malformed fetuses was significantly affected by levels of dietary zinc or salicylate dose, and interactions of zinc × salicylate and genetic strain × zinc. Frequency of resorption was affected by strain, zinc, salicylate, and interations of strain × salicylate, zinc × salicylate, and strain × zinc × salicylate. Frequency of resorption was affected by strain, zinc, salicylate, and interactions of strain × salicylate, zinc × salicylate, and strain × zinc × salicylate. Frequency of abnormal sites (malformed or resorbed) was affected by strain, zinc, salicylate, and interactions of strain × salicylate, zinc × salicylate, and strain × zinc × salicylate. The results suggest that marginal zinc deficiency in certain pregnant women might increase the possibility of salicylate teratogenicity.
Reproduction and fetal development in rats exposed to nitrous oxide
Authors: Mazze Richard I. , Wilson Anne I. , Rice Susan A. , Baden Jeffrey M.
Published: June 2005

The effects of 24 hours of nitrous oxide exposure on reproductive indices and fetal development were examined in Sprague‐Dawley rats. Four different experiments employing four concentrations of nitrous oxide—0.75%, 7.5%, 25% and 75%—established that the threshold of toxicity was greater than 25%. At 75% nitrous oxide there was a significant increase in early and late resorptions, and a consistent teratogenic effect (e.g., runts, occular malformations, limb deformities). Neither the stress of shipping dams while pregnant nor the witholding of food during nitrous oxide exposure resulted in additional adverse effects. Exposure to 25% nitrous oxide was associated with increased deoxyuridine suppression values; however, adverse reproductive effects were not seen at this nitrous oxide concentration. The results of this and other studies which have examined the reproductive and teratogenic effects of nitrous oxide do not contraindicate its use in operating rooms nor, when necessary, as an anesthetic for pregnant surgical patients.
Ethanol teratogenicity in mice: An electron microscopic study
Authors: Bannigan John , Cottell David
Published: June 2005

In this study, the neuroepithelium (NE) cells of the mouse embryo were examined with the electron microscope at various intervals after maternal injection of 0.03 ml/g body weight 25% (v/v) ethanol on day 9 of gestation (plug day = day 1), by the intraperitoneal route. Within 1 hour of treatment, the mitochondria of the NE cells became greatly swollen but could recover. Recovery occurred in two phases: a rapid one during the second hour after treatment, followed by a more gradual one that lasted until 12 hours after treatment. About 5 hours after treatment, dying and fragmenting cells were seen in the NE of all embryos examined. The debris from this necrosis was phagocytosed by neighbouring healthy cells. Also at 5 hours after treatment there was an apparent expansion of the intercellular space of the NE and an enlargement of the apical pseudopodial processes of the NE cells. The latter two changes may have been the result of failure of energy‐dependent cell fluid homeostasis consequent to mitochondrial dysfunction. All of these changes were reversed by 15 hours after treatment. Although all embryos examined had abnormalities of the NE, including cell necrosis, at 24 hours after treatment only 28% had failed to complete neural tube formation. Hence, either the degree of ethanol‐induced damage varies between embryos in the same litter, or the sensitive period is so restricted that variations in stage of development within a litter can account for the lack of concordance between the presence of cellular damage and the subsequent occurrence of a neural tube defect.
Diflunisal‐induced maternal anemia as a cause of teratogenicity in rabbits
Authors: Clark Robert L. , Robertson Richard T. , Minsker David H. , Cohen Sheila M. , Tocco Dominick J. , Allen Henry L. , James Mary L. , Bokelman Delwin L.
Published: June 2005

Diflunisal [5‐(2,4‐difluorophenyl)‐salicylic acid] is a new analgesic antiinflammatory drug that, when administered orally to rabbits at 40 and 60 mg/kg/day, caused terata, most commonly axial skeletal defects. These same dosage levels also caused a severe maternal hemolytic anemia following a dramatic decrease in erythrocyte ATP levels. The teratogenicity, anemia, and depletion of ATP were unique to the rabbit among species examined. To test the possible causality between the teratogenic effects and anemia induced by diflunisal, a single dose of 180 mg/kg diflunisal was administered to rabbits on gestation day 5. This treatment produced an anemia that persisted through gestation day 15 in addition to causing the characteristic axial skeletal defects. Since diflunisal was cleared from maternal blood before gestation day 9, the critical day for induction of similar axial skeletal defects by hypoxia, the skeletal malformations probably resulted from maternal hypoxia secondary to anemia and not from a direct and specific effect of the drug on the embryo. In addition, we observed that the diflunisal level in the embryo was less than 5% of the peak maternal blood level probably as a result of high plasma protein binding of diflunisal in the maternal blood (>98%). This relatively low placental transfer may explain the lack of diflunisal teratogenicity in rats and mice compared to aspirin which crosses the placenta more readily. These studies demonstrate that a species that exhibits unusually severe drug‐specific maternotoxicity is probably an unsuitable model for the prediction of the teratogenic potential of that drug in humans.
D‐penicillamine‐induced cleft palate in mice
Authors: Myint Ba
Published: June 2005

The teratogenic potential of the lathyrogen, D‐penicillamine (DP), was assessed in pregnant mice, especially with respect to its ability to produce cleft palate. The dosage and the duration of treatment as they relate to the induction of cleft palate were also studied. Two different doses of DP were administered orally for either 5 or 4 consecutive days during the critical period of palatal closure. D‐penicillamine (DP) at a dose level which does not have any apparent maternal toxic effects produced cleft palate in the offspring, and this teratogenic effect depended more upon the duration of treatment than the dosage administered. Inhibitory effects on the formation of bone matrix were observed at the base of the palatal shelf. It is suggested that DP is potentially an osteolathyrogenic agent. The mechanism of induction of cleft palate in DP‐treated mice was explored by histological studies using light microscopy. Delayed elevation of the palatal shelves was observed and is considered to be the cause of the induction of cleft palate. No other external malformations could be detected in DP‐treated fetuses.
Cardiovascular birth defects and antenatal exposure to female sex hormones: A reevalution of some base data
Authors: Wiseman R. A. , Dodds‐Smith I. C.
Published: June 2005

A re‐evaluation of the base data as reported by Heinonen et al. from the Drug Epidemiology Unit of the Boston Collaborative Perinatal Project (CPP) was undertaken in order to examine particularly three matters which were not fully considered in the publication. These were, first, the timing of administration of sex hormones during the index pregnancy, which is relevant to determining whether any statistical association reported between sex hormone exposure and malformations could be causal; second, the incidence of serious maternal vaginal bleeding in early pregnancy, which could be an indication of threatened abortion, which in turn in associated with an increased malformation rate, and in addition is an indication for sex hormone administration; and third, the incidence of malformations or other adverse outcome in previous pregnancies, which, if present, might play a material role in the risk of malformation in the index pregnancy. Examination of the records of the 19 cases described by Heinonen et al. as hormone‐exposed/cardiac‐malformed revealed that no preparation containing hormone was administered in two patients, that five cases were given hormones too late in the index pregnancy to have any effect on cardiac organogenesis (which by general consensus begins on day 19 and ends at the latest on day 50 of gestation), that two cases were given hormones too early and two cases had Down's Syndrome. Thus eight children were exposed to hormones during the critical period of cardiac organogenesis, out of 17 actual hormone takers (47%). The description of vaginal bleeding did not allow any conclusions regarding differential rates of threatened abortion. It was found that the incidence of major malformations was 17% in the index group and 4% in the non‐malformed group. This suggests that the hormone‐exposed patients who gave rise to children with cardiac malformations were a highly selected group. The re‐evaluation therefore reveals that the incidence of exposure to sex hormones during the critical period of cardiac organogenesis was not significantly different statistically in those women whose children had cardiac lesions as compared to those without such lesions. It is suggested that the result of this re‐evaluation should direct the attention of epidemiologists to the quality of their base data. Re‐examination of the base data of the Boston CPP does not support their reported association between the exposure to female sex hormones during pregnancy and the occurrence of cardiac malformations.
Cartilage‐staining technique for the examination of unskinned fetal rat specimens previously processed with alizarin red S
Authors: Boardman J. P. , Mitala J. J. , Carrano R. A. , Iuliucci J. D.
Published: June 2005

A novel staining technique has been devised that permits a cartilage examination of unskinned fetal rats that have been previously processed for skeletal examination with alizarin red S. The procedure consists of rinsing alizarin red S‐stained specimens in distilled water and placing the specimens in a 3% acetic acid solution. A transfer of the stain from bone to adjacent cartilage occurs, producing purple‐stained cartilaginous structures that can be differentiated from still‐discernible bone structures.
Effects of lead and hyperthermia on prenatal brain growth of guinea pigs
Authors: Edwards M. J. , Beatson Jenny
Published: June 2005

The effects of lead at blood levels of 100 μg/100ml or less on the brains of young animals have not been clearly defined, and little is known of its effects and interactions with other agents on prenatal brain development. This study examined the effects of subclinical doses of lead acetate given to pregnant guinea pigs on the development of the embryo brain. At 9 A.M. on day 20 or 21 of pregnancy, guinea pigs were given 6, 12.5, or 25 mg/kg body weight of 0.5% lead acetate in distilled water by intraperitoneal injection. Some of the animals at each dose rate were also exposed to hyperthermia at 11 A.M. on the day of injection and the following day. Another group was exposed to hyperthermia without lead treatment. A saline‐treated control group was used for comparison. Mean levels of lead in blood 1 hour after dosing ranged between 65 and 128 μg/100 ml and at 24 and 72 hours between 65 and 96 μg/100 ml. Brain weights of newborn guinea pigs in the 12.5‐ and 25‐mg lead acetate group were significantly reduced compared with control values. Body weights of all groups receiving lead were not significantly differently different from those of controls. There was no indication of interaction between hyperthermia and lead acetate in doses of 6 or 12.5 mg/kg. At 25 mg/kg plus hyperthermia, there appeared to be a strong synergistic response, with an incidence of 88% micrencephaly compared with 5% in the group given 25 mg/kg without hyperthermia and 46% in the hyperthermia without lead group. The results indicate that subclinical levels of lead can retard prenatal brain growth, and this effect is potentiated by hyperthermia.
Moderate prenatal carbon monoxide exposure produces persistent, and apparently permanent, memory deficits in rats
Authors: Mactutus Charles F. , Fechter Laurence D.
Published: June 2005

The effects of moderate (150 ± 2 ppm) prenatal carbon monoxide (CO) exposure (maternal HbCO concentrations of 15.6 ± 1.1%) on learning and memory were assessed in young and aged adult rats using a two‐way active avoidance paradigm. In experiment 1, the prenatal CO‐exposed rats at 120 days of age acquired a conditioned avoidance response equally well as control animals in a 100‐trial session. However, following a 24‐hr interval the CO‐exposed rats failed to demonstrate significant retention of the task as indicated by the absence of significant improvement in performance over the previous day; control subjects did show significant retention. In experiment 2, in which 120‐day‐old animals received 50 training trials per day until a criterion of ten consecutive avoidance responses was met, the prenatal CO‐exposed subjects again acquired the task as well as control animals. When tested for retention 28 days later, a significant memory impairment was again observed in terms of trials required to reattain the avoidance criterion as well as in total percent avoidance responding. In neither experiment did an analysis of initial or average latency to escape the footshock stimulus reveal any significant alterations. These latter results suggest that the observed performance impairment reflected a memory deficit and not a disruption of sensory, motor, or motivational factors. In experiment 3, prenatal CO‐exposed rats approximately 1 year of age (300–360 days of age) showed impairment relative to air‐exposed controls in both the original learning and retention of the two‐way avoidance response. Again, however, there was no evidence for alterations in performance factors per se. Collectively these data indicate that while young adult rats prenatally exposed to 150 ppm CO demonstrate an associative deficit restricted to memory impairment, aged adults similarly exposed during the prenatal period display a more pronounced deficit similar to that recently reported for animals tested as juveniles. The importance of parametric manipulations in uncovering long‐term toxicity is also discussed.
Embryolethality in rats caused by retinoic acid
Authors: Vickers T. H.
Published: June 2005

Retinoic acid (25 mg/kg) administered by gavage to rats at 216 hours of gestation killed almost all conceptuses by 288 hours and all by full term. The embryolethal dose50 was 12.3 mg/kg. Embryos died from damage to the allantois leading to agenesis or hypogenesis of the chorioallantoic placenta. Suppression of cell division in, disturbed fluid entry into, and impaired normal vascularization of the allantois underlay the abnormality, the predominant element depending principally on when exposure occurred. Hydremia (Br. J. Exp. Pathol., 57:525–541, '76) affected over 50% of the sacs. Relating data from the literature to resorption patterns suggested that 25 mg/kg of retinoic acid raised a lethotoxic level (approximately 2 μg/ml) of retinoate in the plasma for about 5 hours. This, together with asynchronous development, was used to help explain why groups of embryos responded to the teratogen for 18 hours longer than single embryos and why exposure 18 hours before the allantois on average appears, killed some young. Comparison showed that retinoic acid was 4.8 times as embryolethal as retinol. Otherwise, each behaved qualitatively similarly, suggesting that either retinol acts through retinoic acid or via a common path entered independently by each. Placental agenesis is well documented in Soviet literature. It is almost unknown in Western teratology even though it is probably the most important cause of embryonal death following teratogenic procedures around the time of placentation.
Alcohol enhancement of marihuana‐induced fetotoxicity
Authors: Abel Ernest L.
Published: June 2005

In two separate studies marihuana and alcohol were administered, either separately or in combination, to pregnant mice or rats. Control animals were given vehicle only or were nontreated. Marihuana‐, alcohol‐, and vehicle‐treated animals were pair‐fed and pair watered with animals given marihuana plus alcohol, to control for drug‐related undernutrition. The combination of marihuana and alcohol caused a 100% fetomortality in mice and a 73% fetomortality in rats, whereas neither marihuana nor alcohol alone had any effects on fetomortality that differed significantly from vehicle treatment. These studies suggest a potential danger to pregnancy resulting from the combined use of two commonly used drugs that is far greater than that associated with use of either drug alone.
The induction of microphthalmia, encephalocele, and other head defects following hyperthermia during the gastrulation process in the rat
Authors: Webster William S. , Germain Mary‐Ann , Edwards Marshall J.
Published: June 2005

The aim of this study was to ascertain whether there is a period during early embryonic development of the rat that is particularly sensitive to hyperthermia. Pregnant Sprague‐Dawley rats were partially immersed in a water bath at 43.5°C until their core temperatures, monitored by a rectal thermistor probe, were elevated to 43.5°C. The procedure was repeated 6 hours later. The regimen of two heatings was performed over a range of development from early gastrulation (8 days 18 hours) to about the 12 somite stage (10 days 18 hours). The rats were killed on days 17–19 and the fetuses were examined. Each group contained a minimum of five litters. The main teratogenic effect of the hyperthermia was the induction of one or more head defects, notably microphthalmia, encephalocele (either a single, large, parietal encephalocele or multiple small protuberances), and maxillary hypoplasia. Microphthalmia was the most common defect with approximately 90% of surviving fetuses having small eyes when heating occurred between 9 days 6 hours and 10 days 0 hours (9.06 and 10.00). Encephaloceles were induced by heating between 9.00 and 10.00 with a peak sensitivity between 9.12 and 9.18 when 57% of surviving fetuses were affected. Maxillary hypoplasia resulted from heating between 9.06 and 10.06 with up to 20% of surviving fetuses being affected. Control rats were exposed to the same experimental procedure in a water bath at 38°C on 9.12 and 9.18, the gestational time most sensitive to hyperthermia induced malformations. There were no abnormal fetuses in the controls. The critical period identified spans 9 days 6 hours to 10 days 0 hours gestational age. In developmental terms this includes a large proportion of the gastrulation process.
Congenital tracheal stenosis in lambs induced by maternal ingestion of Veratrum californicum
Authors: Keeler Richard F. , Young Stuart , Smart Ross
Published: June 2005

Seven of nine lambs born to six ewes gavaged with Veratum californicum root and rhizome material on days 31, 32 and 33 of gestation died from asphyxia within 5 minutes after birth. Five of the seven were autopsied and found to have severe stenosis of the trachea. None of the 12 lambs born to seven control ewes had tracheal stenosis. The defect was characterized by lateral flattening of the trachea throughout its entire length. Cartilaginous tracheal rings were reduced in number, nonuniform in size and shape, irregularly spaced, and with abnormal orientation. The rings were thinner than those of control tracheas, and had zones of chondrogenesis on outer and inner surfaces which were of equal width, rather than of unequal width as in controls. The smaller size and relatively noncurved shape of the cartilaginous rings of the stenotic trachea resulted in a nondistended lumen.
Zinc deficiency in pregnant Long‐Evans hooded rats: Teratogenicity and tissue trace elements
Authors: Rogers John M. , Keen Carl L. , Hurley Lucille S.
Published: June 2005

The Long‐Evans hooded rat is widely used in experimental teratology. This study determines the teratogenicity of maternal Zn deficiency in the Long‐Evans hooded rat, and examines the effects of Zn deficiency on Zn, Fe, and Cu concentrations in maternal and fetal tissues. Dams were fed an egg white‐based diet containing 100 μg/g Zn for 1 week prior to mating. At mating rats were fed diets with 0.5, 4.5, 9.0, or 100 μg/g Zn ad lib, or 100 μg/g Zn pairfed to 0.5 μg/g Zn dams. Laparotomies were performed on day 21 of gestation. Live fetuses and resorptions were counted. Fetuses were weighed and examined for external malformations. Some fetuses were used for Zn, Fe, and Cudeterminations, others for internal or skeletal examination. Zn, Fe, and Cu levels were determined in maternal liver, kidney, and plasma. The 0.5 μg/g Zn dams lost weight during pregnancy; 27% of implantation sites were resorbed, 91.7% of live fetuses were malformed, and fetal weight was low. There were no malformed fetuses in the 4.5 μg/g Zn or 9.0 μg/g Zn groups; litter weights were low in the 4.5 μg/g Zn group. Tissue Zn was correlated with dietary Zn. Increased Fe concentration occurred in all maternal and fetal tissues in the 0.5 μg/g Zn group. The teratogenicity of Zn deficiency in the Long‐Evans rat appears similar to that previously reported in the Sprague‐Dawley strain.