bluuebunny/crossref_metadata_2025 huggingface dataset:
Dose‐response studies with genetically homogeneous lines of mice as a teratology testing and risk‐assessment procedure
Authors: Kalter Harold
Published: June 2005

Current teratology testing procedures are mainly focused on qualitative considerations and, hence, largely ignore the variability in responsiveness to exogenous agents that may exist within species. An example is given of a test using genetically homogeneous lines of animals, which shows how extensive intraspecies variability can be. Pregnant females of six strains of mice were given single doses of 12.5 to 1200 mg/kg cortisone acetate by four routes on 4 days of gestation. The frequency of cleft palate and of fetal resorption were evaluated for their dose‐response relations. The range of responses was extremely wide; in one series the malformation ED50 of the most responsive strain was about 16 times greater than that of the least responsive one. By indicating that a range of sensitivities may be possessed by species, and by approximating the limits of that range, inbred lines can reveal mild degrees of responsiveness that are frequently overlooked in using outbred stocks, and hence are of value in assessing risk.
Effect of prenatal phenytoin administration on postnatal development of the rat: A behavioral teratology study
Authors: Elmazar M. M. A. , Sullivan F. M.
Published: June 2005

Adult pregnant Wistar rats were treated with phenytoin (100 mg/kg) orally from day 7 to 19 of pregnancy, and a control group was pair‐fed during the whole treatment period. Within 24 hours after parturition, the offspring were culled to six to eight per litter and reared by fostering or cross‐fostering. The physical and behavioral development of the offspring was observed up to 90 days of age. There was a reduced survival of the offspring and a reduction in body weight which persisted to the end of the experiment, though both of these effects could be reduced by cross‐fostering. Certain neurological defects were also seen in the prenatal phenytoin group. For example, there was a delay of up to 15 days in the development of the dynamic righting reflex, a decrease in ability of offspring to stay on a rotating rod, and a decrease in ability to walk along elevated parallel rods. There seemed also to be some loss of cliff avoidance. However, there was no change in the development of crawling and walking activities at 9–21 days of age, and no important changes were observed in a head dipping test or in a conditioned avoidance test at 26–34 days. There was a significant decrease in brain weight of the treated group at age 3 days which remained significantly lower than the controls even at 90 days, but no change in the brain/body weight ratio. There was no difference in cerebellar DNA content.
Congenital malformation syndromes and elevation of amniotic fluid α1‐fetoprotein
Authors: Burck Uta , Held Karsten R. , Kitschke Hans‐J. , Carstensen Martin
Published: June 2005

Fetal malformations may introduce complications of maternal pregnancy. A polyhydramnios represents one such complication during pregnancy. We want to report five abnormal pregnancies which were marked by acute polyhydramnios and/or premature labor due to an amniotic band syndrome associated with cerebral herniation in two cases, malignant oral teratoma in one case, bilateral cystic hygromas associated with generalized fetal hydrops in one case, and multiple internal malformations in one case, α1‐fetoprotein (AFP) values between the 25th and 34th week of gestation were elevated 3.5 to 44 times the normal median value. Since all fetuses showed severe malformations incompatible with life our observations indicate the necessity to determine AFP in cases of acute polyhydramnios independent of the week of gestation. Conversely, elevated AFP levels in amniotic fluid obtained during prenatal diagnosis in the 16th week of gestation may also suggest rare fetal malformations outlined above.
Effects of vitamin A on endocardial cushion development in the mouse heart
Authors: Davis Lynn A. , Sadler T. W.
Published: June 2005

Retinoic acid (RA) (78 mg/kg) administered to ICR mice on days 9.0, 9.5, and 10.0 of pregnancy (plug day = day 1), resulted in cardiac malformations in 37.6% of the surviving fetuses, including transposition of the great arteries, ventricular septal defects, and double outlet right ventricle. Histological examination of the hearts of embryos observed 24 hours after in vivo or in vitro exposure to RA on day 9 revealed abnormalities in endocardial cushion tissue. The volume of the atrioventricular endocardial cushions was reduced in treated embryos as was the ratio of the size of the cushions to the size of the heart. The endothelial layer of the atrioventricular endocardial cushions appeared to be unaffected by the retinoic acid, however, the mesenchymal cushion cells were significantly reduced in number when compared with controls. Labeling with [3H]‐thymidine indicated that the mitotic activity of the mesenchymal cell population was significantly decreased while that of the endothelial cells was comparable to control levels. The extracellular matrix or cardiac jelly of the endocardial cushions also appeared to be affected by RA exposure, as shown by studies utilizing colloidal iron to stain GAGs, which revealed a decrease in the amount of stainable material in treated cushions. Two possible causes for the reduced thymidine index of the cushion mesenchyme are discussed, namely, a direct effect of RA on the mesenchymal cells or an indirect effect via the altered extracellular matrix of the cushion tissue.
Syncytiotrophoblast membrane vesicles: A model for examining the human placental cholinergic system
Authors: Fant Michael E. , Harbison Raymond D.
Published: June 2005

A membrane vesicle preparation was used to examine characteristics of the human placental cholinergic system. Plasma membrane vesicles were prepared from the microvillous surface of the human placental Syncytiotrophoblast. Membranes were purified 18‐ to 20‐fold as indicated by 5′‐nucleotidase activity. Vesicle cholinesterase activity was enriched and had a substrate preference consistent with that of acetylcholinesterase (acetylcholine > acetyl‐β‐methylcholine > butyryl‐choline). Choline acetyltransferase specific activity was reduced 80%. The synthetic muscarinic ligand, [3H]‐quinuclidinyl benzilate (QNB), was used to identify two classes of muscarinic cholinergic binding sites. The dissociation constant of QNB binding was 80 pM and 30 nM for the two sites. The sites were saturable and bound 9 fmoles and 910 fmoles per mg protein for the high and low affinity sites, respectively. Specific binding was inhibited by scopolamine, atropine, carbamylcholine (CCh), and diphenhydramine, but not by non‐muscarinic ligands‐i.e. GABA, glycine, d‐amphetamine, α‐bungarotoxin and nicotine. The cholinergic agonist CCh had no effect on active AIB transport, although pharmacologic doses (1 mM) of atropine, scopolamine and lidocaine reduced Na‐gradient active transport of α‐aminoisobutyric acid (AIB). No effect on Na‐independent AIB transport was observed. Thus, these drugs apparently reduced AIB uptake through their shared local anesthetic activity and not through a central cholinergic mechanism. In contrast, CCh was able to stimulate Ca2+ uptake by the vesicles in a dose‐dependent manner paralleling its ability to inhibit QNB binding. The CCh‐stimulated Ca2+ uptake was inhibited by scopolamine, implying its mediation via cholinergic‐type binding sites. The membrane vesicle preparation therefore provides a useful model for examination of the role of the human placental cholinergic system.
The teratogenic effects of dietary cassava on the pregnant albino rat: A preliminary report
Authors: Singh Jay Datta
Published: June 2005

Cassava is a tuberous root of a shrublike plant cultivated in tropical rain forests as a staple food in South Eastern Nigeria. Reports are on record showing correlation between cassava intake and occurrence of various types of neuropathies (Money, '59; Monekosso and Wilson, '66; Osuntokun et al., '68, '69). About 0.1–2 mg of cyanide/100 gm is released from Cassava by action of hydrolase (Paula and Rangel, '46). It has been suspected by several local clinicians as a cause of congenital anomalies if consumed in excess during pregnancy. However, it remains a controversial problem and precise scientific data is lacking. This study was conducted on albino rats by giving them milled cassava powder as 50% and 80% of their diet during the first 15 days of pregnancy. Fetuses collected on day 20. from the group receiving cassava as 80% of the diet showed a low incidence of limb defects, open eye, microcephaly, and growth retardation in the rat. Interpretation of this data for the human should be made with caution.
The position effect of embryos in trisomy‐1 ‐producing mice
Authors: v. Domarus Helmut , Louton Tom
Published: June 2005

Size and weight of embryos can differ according to the location in the uterine horn. In these experiments the source of teratogenesis was within the individual trisomy‐1 embryos, producing either euploid or trisomic embryos in a given position in the uterus. We therefore used the embryo and not the litter as a statistical sampling unit. In our opinion a nested analysis of variance is the most appropriate method to assess a position effect of embryos in this model. We were unable to show a position effect on gestational days 13 and 14. There was a significant difference though, among litters. We were able to show that further investigations of trismoy‐1 embryos, in particular morphometric studies, are not complicated by a position effect. A position effect as described by several authors should be assessed for every new teratogenetic model. The methods described here provide a reasonable vehicle for similar studies.
Indicators of developmental toxicity following prenatal administration of hormonally active compounds in the rat. II. Pattern of maternal weight gain
Authors: Rands Peggy L. , Newhouse Chuck L. , Stewart Judith L. , Bradshaw William S.
Published: June 2005

Chronic prenatal exposure of rats to diethylstilbestrol, zeranol, or 3,4,3′,4′‐tetrachlorobiphenyl produced quantitative and qualitative differences in the cumulative pattern of weight gain during pregnancy. Each of the three compounds, however, exhibited unique characteristics with respect to the effect of increased dose on this response, as well as in the relationship of reduced weight gain to perinatal mortality. The weight deficit after diethylstilbestrol treatment was found to reside in the dam herself, not in any compartment of the gravid uterus. The pattern of maternal weight gain is a useful indicator of developmental toxicity permitting discrimination among structurally diverse chemical agents.
An epidemiologic study of tracheoesophageal fistula and esophageal atresia in North Carolina
Authors: Ozimek Carl D. , Grimson Roger C. , Aylsworth Arthur S.
Published: June 2005

Two hundred and eighty‐five cases of TEF/EA occurring in North Carolina from 1952–1978 were reviewed. Except for a greater incidence of low‐birth‐weight infants and hydramnios during pregnancy, the cases appeared to be representative of the population. Clustering of cases over time was statistically confirmed. The cyclic variation suggested an association with an infectious agent. The variation of reported infectious hepatitis cases during the period of this study resembled the variation of TEF/EA cases that had no other documented congenital malformations.
Development of the biochemical and morphological changes induced by administration of a β‐xyloside to chick embryos
Authors: Kanke Y. , Doller H. J. , Segen B. J. , Gibson K. D.
Published: June 2005

4‐Methylumbelliferyl β‐D‐xyloside was administered to 9‐day‐old chick embryos, and the morphological and chemical changes in the embryo were followed daily. Increases in wet weight, Na and Cl content, and visible edema were detectable at 10 days and fully apparent at 11 days. Dry weight increased to the same extent in control and treated embryos for four days, but then diverged. The degree of sulfation of chondroitin sulfate was slightly less in treated than control embryos at 10 days, and reached a steady low value at 11 days. Analysis of glycosaminoglycans in skin, muscle, and aorta showed an increase in chondroitin and its sulfates in the two former tissues but not the latter. In muscle and aorta, the degree of sulfation of chondroitin sulfate was markedly reduced; but in skin the results suggested a more complex picture in which the normal metabolism of glycosaminoglycans was altered. A possible physiological role is suggested for chondroitin sulfate in embryonic soft tissues.
Fluid and glycosaminoglycan excretion by chick embryos treated with a β‐D‐xyloside
Authors: Segen B. J. , Gibson K. D.
Published: June 2005

Wet weights and glycosaminoglycan content were determined for embryo, amnion, and allantois of control chick embryos and embryos injected with 4‐methylumbelliferyl β‐D‐xyloside at nine days of age. There was an immediate increase in total uronic acid content, but not in uronic acid concentration, in the embryo. No difference could be detected either in fluid volume, nor in content or type of glycosaminoglycan, in the amnion of the two groups. The fluid content of the allantois of control eggs increased steadily between nine and 14 days, but in treated embryos the fluid content of the allantois remained low for at least a week. Less than 2 mg of uronic acid was present in allantoic fluid of control 16‐day‐old embryos, while treated embryos had accumulated more than 8 mg. More than 95% of the latter uronic acid was accounted for as chondroitin sulfate linked to methylumbelliferone and with a degree of sulfation of 50–60%. Thus β‐xyloside‐treated embryos excrete large amounts of chondroitin sulfate and very little fluid.
Potentiative interactions between caffeine and various teratogenic agents
Authors: Ritter E. J. , Scott W. J. , Wilson J. G. , Mathinos P. R. , Randall J. L.
Published: June 2005

Acetazolamide and inhibitors of DNA synthesis (hydroxyurea, 5‐fluoro‐2′‐deoxyuridine), RNA synthesis (actinomycin D), and protein synthesis (cycloheximide, emetine) were each administered to pregnant rats together with caffeine at doses where each agent alone caused minimal embryotoxicity. Caffeine co‐administered with any of the other agents induced a powerful potentiative response. It is not clear from the present experiments whether much lower caffeine dosage, as normally encountered in humans, would potentiate embryotoxicity due to other agents.
Normal and abnormal midfacial development in the cadmium‐treated hamster
Authors: Tassinari Melissa Sherman , Long Sally Y.
Published: June 2005

Clefts of the midface ranging in severity from a notched lip to complete facial disorganization were observed in the offspring of golden hamsters injected with cadmium chloride on the morning of the eighth day of gestation. Other malformations frequently observed were microphthalmia, anophthalmia, and diencephalic encephaloceles. Histologic examination of embryos on the 10th, 11th, 12th, and 13th days of gestation revealed a marked deficiency of mesenchyme in the frontonasal process, which led to a foreshortened and deformed nasal septum. These data confirm that the teratogenicity of cadmium is highly specific for the region of the anterior neural segment on the eighth day of gestation, The deficiency of mesenchyme in the frontonasal process may be the result of disruption in neural crest cell development in this region.
Effects of 2.45 GHz microwave radiation on the development of Japanese quail cerebellum
Authors: Inouye Minoru , Galvin Michael J. , McRee Donald I.
Published: June 2005

Fertilized Japanese quail eggs were continuously exposed to 2.45 GHz microwave radiation from day 1 through day 12 of incubation at a power density of 5.0 ± 0.52 mW/cm2 (mean specific absorption rate = 4.03 mW/gm). In the experiment with embryos, irradiated and control embryos were removed from eggs on day 12, 13, or 14 of incubation and the cerebella were histologically examined. In order to examine the long‐term effect of microwave radiation during embryogenesis on the cerebellum, some of the quail were allowed to hatch and were reared to eight weeks of age. Their cerebella were histologically examined, and the extent of dendritic arbores, the length of the stem of the primary dendrite, and the size of the perikaryon of Purkinje cells were measured in Gogli‐Cox impregnated sections. In the irradiated embryos, a slight developmental retardation was found in the cerebellar cortices in terms of several morphological parameters. The effects included the growth and subsequent decline of the external granular layer, the growth of the molecular layer, the cellular differentiation and the alignment of Purkinje cells, and the accumulation of granule cells beneath the Purkinje cell layer, as well as lower body and brain weights. In the eight‐week‐old quail, no significant differences were noted between irradiated and control cerebella in the morphological measurements of Purkinje cells.
Teratogens associated with congenital contractures in humans and in animals
Authors: Hall J. G. , Reed S. D.
Published: June 2005

An evaluation of over 350 patients in a study of congenital contractures of the joints (arthrogryposis) included a review of family, pregnancy, and delivery histories for teratogenic exposures. Fifteen out of the total 350 patients studied had a possible teratogenic exposure: an infectious agent (viral or bacterial), maternal drug or toxin ingestion, chronic maternal neurologic or muscular illness, or a direct physical insult such as a structural uterine anomaly. Literature was reviewed for all human and animal cases reported with congenital contractures of the joints with an associated teratogenic insult. Those findings are discussed here.
Mitotic index in mouse embryos with 6‐aminonicotinamide‐induced and inherited cleft lip
Authors: Trasler Daphne G. , Leong Susanna
Published: June 2005

Three types of cleft lip were studied histologically before and during lip formation in mouse embryos. C57BL/6 embryos observed near term following treatment with 6‐aminonicotinamide (6AN) at gestation D9/12 (vp day = day 0) had 18% median cleft lip. Treated embryos observed at D10 and D11 showed retarded somite and nasal placode development. Sections at lip closure time showed marked reduction of medial and some reduction of lateral nasal processes, and the mitotic index was significantly reduced in the nasal area on D10 and D11 but less consistently in the neural area. 6AN‐treatment on D10/8, caused 22% lateral cleft lip. Treated embryos showed initial retardation of somite and nasal placode development that became normal by D11/14. Sections showed reduction of the medial and lateral nasal processes, and less organized denser nasal ectoderm. The mitotic index was significantly reduced in the nasal and neural areas on D10 and D11. In crosses having the major gene mutation dancer (Dc) 20% of embryos had lateral cleft lip and potential cleft lip mutant embryos showed reduced lateral and medial nasal processes. Mitotic index was not reduced in the nasal area but it was in the neural area. The CL/Fr strain, with a predisposing face shape in which 26% of the embryos have cleft lip of multifactorial origin, had a mitotic index similar to that of C57BL/6 (0% cleft lip) at lip closure time, D11/14, and prominent medial nasal processes. It is postulated that 6AN‐induced median cleft lip is due to reduced cell proliferation in and size of the medial nasal processes; 6AN‐induced lateral cleft lip to reduced cell proliferation and reduced medial and lateral nasal processes and dancer lateral cleft lip to reduction of the medial nasals.
Conjoined Twins in the United States, 1970–1977
Authors: Edmonds Larry D. , Layde Peter M.
Published: June 2005

The descriptive epidemiology of conjoined twinning in the United States was investigated using data from the Birth Defects Monitoring Program (BDMP), a nationwide congenital malformations surveillance system that monitors discharge diagnoses associated with a third of the births in the United States. This is the largest recorded series concerning conjoined twins; data were analyzed on 7,903,000 births monitored by the BDMP in the period 1970–1977. The analysis identified 81 sets of conjoined twins, for a crude incidence of 10.25 per million births. The most common types of conjoined twins were thoracoomphalopagus (28%), thoracopagus (18%), omphalopagus (10%), parasitic twins (10%), and craniopagus (6%). Conjoined twins are more common among females than males, and in nonwhites than whites. No maternal age effect was found. There was no evidence of seasonal or temporal clustering of the cases. The large number of conjoined twins who had birth defects that are not obviously linked to the conjoining (particularly neural tube defects and orofacial clefts) may provide insights into the pathogenesis of birth defects resulting from disordered embryonic migration and fusion.
Sauna and congenital defects
Authors: Saxén Lauri , Holmberg Peter C. , Nurminen Markku , Kuosma Eeva
Published: June 2005

To test a recent hypothesis on the causal relationship between sauna‐induced hyperthermia and congenital defects, 100 consecutive cases of defects of the central nervous system and 202 cases of orofacial clefts were singled out from the Finnish Registry of Malformations. The mothers and their time‐area‐matched referents were interviewed for their sauna habits. Almost every pregnant mother (98.5%) had visited the sauna regularly, and yet, the incidence of the CNS defects in Finland is among the lowest ever reported. No differences in the sauna habits were observed between the case and referent mothers. It is concluded that the relatively mild, temporal hyperthermia caused by the sauna should not be considered hazardous for the developing embryo.
Inhibition of β‐aminopropionitrile (βAPN)‐induced skeletal teratogenesis by the flavonoid β‐hydroxyethylrutosides (HR) in hamster fetuses
Authors: Joneja M. G. , Wiley M. J.
Published: June 2005

Since biochemical studies have shown that flavonoids such as β‐hydroxyethylrutosides (HR) protect against the damage to collagen induced by lathyrogens in adult rats, this compound was given to pregnant hamsters in order to determine its effects on the teratogenicity induced by β‐aminopropionitrile (βAPN). A dose of 2,500 mg/kg of βAPN alone given by gavage on day 11 produced a high frequency (69.5%) of skeletal anomalies in the offspring of hamsters. Administration of HR immediately following βAPN to pregnant animals resulted in a significantly decreased teratogenic response (P < 0.05). These data provide evidence to support the view that the primary mechanism for the βAPN‐induced skeletal dysmorphogenesis is the inhibition of cross linking during the maturation of collagen fibers.
Developmental abnormalities of the olfactory bulb: A comparative teratological and experimental study of the pig and chick embryo
Authors: Venneman W. , Van Nie C. J. , Tibboel D.
Published: June 2005

We collected newborn pigs with facial dysmorphy. In ten animals complete unilateral or bilateral hare lip was found to be associated with agenesis, aplasia, or hypoplasia of the olfactory bulbs. In order to get insight into a possible pathomorphogenetic relation between these types of clefts, malformations of the olfactory bulbs, and the role of the derivatives of the olfactory placode, the right olfactory placode was extirpated in 180 chick embryos at stage 17–18 according to Hamburger and Hamilton. Forty of the 78 surviving embryos showed shortening and deviation of the upper bill to the right, absence of the right nasal ostium, and agenesis of the right olfactory bulb. These results provide experimental evidence that the olfactory placode induces the outgrowth of the olfactory bulb. They further suggest an involvement of the olfactory placode in the normal development of the face.
Cyclopia: An anatomic and histologic study of two specimens
Authors: Kokich Vincent G. , Ngim Chun‐Han , Siebert Joseph R. , Clarren Sterling K. , Cohen M. Michael
Published: June 2005

The craniofacial complex of two neonatal, human, cyclopic specimens was studied in detail. Both specimens exhibited a single ocular opening and one had a prominent proboscis positioned in the midline directly superior to the ocular aperture. No external nasal development was noted in the other specimen. The most remarkable finding was the lack of development of all skeletal derivatives of the ethmoidal cartilage (cribriform plate, perpendicular plate, superior and middle nasal conchae, medial orbital walls, and nasal septal cartilage) in both specimens. Since these bones normally form the medial, lateral, and superior walls of the nasal passage, this cavity was also absent. The two posterior halves of the maxillae were directed superiorly, medially, and with the vomer merged in the midline as a thick mass of bone. As a result the right and left alveolar portions of the maxillae were joined superiorly in the midline. With the absence of the nasal cavity, the right and left medial pterygoid plates merged medially with the palatal and pyramidal processes of the palatine bone to obstruct the junction between the oropharynx and nasopharynx (choanal atresia). The role of the skeletal parts of the ethmoid during maxillofacial growth and development is discussed.
Teratogenesis and low copper status resulting from D‐penicillamine in rats
Authors: Keen Carl L. , Mark‐Savage Pamela , Lönnerdal Bo , Hurley Lucille S.
Published: June 2005

The teratogenicity of D‐penicillamine was studied using the Sprague‐Dawley rat. Fetuses from rats fed diets containing 0.83% D‐penicillamine during pregnancy had a high incidence of malformations. Maternal and fetal tissue copper levels were significantly lower in the D‐penicillamine group than in controls, suggesting that the teratogenicity of the drug may be due in part to the induction of copper deficiency by its chelating properties.
Effects of environmentally differential rearing upon maze performance in prenatally irradiated microcephalic rats
Authors: Seo Misako L. , Inouye Minoru , Kiyono Sigehiro , Shibagaki Masamitsu
Published: June 2005

Pregnant rats received 100 rads of X‐irradiation on day 17 of gestation. Control pregnant rats were sham‐irradiated on the same gestation day. The male offspring were reared under environmentally enriched, standard colony, and impoverished conditions for 30 days after weaning. Then the Hebb–Williams maze test was carried out. All the prenatally X‐irradiated rats were microcephalic: their mean cerebral wet weight was 15.5% less than controls. The effect of X‐irradiation was not significant in error scores and running times, whereas the effect of environment was significant in these items; initial and total error scores and running times were decreased in enriched groups compared to impoverished groups in controls as well as in X‐irradiated animals.
Teratogenic effects of lithium in mice
Authors: Smithberg Morris , Dixit Padmakar K.
Published: June 2005

The question of the teratogenicity of lithium carbonate was tested in two inbred strains of mice that are susceptible to teratogens. Strains 129 and A/J mice were treated with varying dosages of lithium carbonate on day 8, 9, or 10, and strain A/J mice were sequentially treated on days 11, 12, and 13 of gestation. Another group of mice of strain 129 were given lithium carbonate in drinking water throughout pregnancy. Levels of lithium were determined in mouse serum (and in brain) of mothers and their offspring with the purpose of comparing equivalent values in mice and in man. A baseline dosage of 0.8 mg of lithium carbonate was chosen, since this dose produced a serum lithium level of 0.8 meq/L, which is comparable to values of patients treated for manic‐depressive illness. This baseline dosage or 2 and 4 times this amount did not prove teratogenic in strain 129 mice. However, 5.0 mg (200 mg/kg), which is one‐half the LD50 value, caused 41% malformations. The baseline dosage did not cause malformations in strain A/J when given on day 11, 12, or 13 of gestation. Lithium carbonate given in the drinking water to strain 129 mice throughout pregnancy at a concentration that produces serum levels in mice consistent with human values was deleterious. The data suggest that whole or part of total litters were eliminated. The few survivors were apparently normal. Our results suggest that 6 times the therapeutic serum lithium level in humans is teratogenic in mice, as tested by acute experiments. Chronic treatment with a quantity of lithium that produces a serum level equivalent to that of human values is toxic to whole or part of the litters of mice.
A study of fetal growth retardation in teratological tests: Relationship between body weight and ossification of the skeleton in rat fetuses
Authors: Ariyuki Fumio , Ishihara Haruo , Higaki Koh , Yasuda Mineo
Published: June 2005

The normal development of preterm rat fetuses (day 19.0 to day 21.0) was investigated with respect to body weight and ossification of the sacrococcygeal vertebrae, supraoccipital bone, sternebrae, and proximal phalanges in the forepaw. Normal standard growth curves were established for these indexes in rat fetuses. A method was devised for the analysis of the relationship between low body weight and retarded ossification induced by teratogenic agents. In normal fetuses, mean body weight and number of ossified sacrococcygeal vertebrae and the ossification stage of the supraoccipital bone increased approximately linearly with advancing fetal age. The number of ossified sternebrae and proximal phalanges in the forepaw increased curvilinearly with advancing fetal age. By use of the standard curves, fetal growth retardation observed in teratological experiments may be expressed as retardation in relation to the standard in hours. The characteristic pattern of growth retardation induced by an agent may be evaluated by comparison of the degree of retardation expressed in a common “hour” scale among various growth indexes. This method was applied to experimental data of fetal growth retardation induced by maternal fasting. The degree of retardation was found to differ among growth indexes; body weight and ossification of the sacrococcygeal vertebrae were the most severely retarded; ossification of the supraoccipital bone and the sternebrae was moderately retarded; ossification of the proximal phalanges in the forepaw was least retarded.
Blood flow during pregnancy in the rat: I. Flow patterns to maternal organs
Authors: Buelke‐Sam J. , Nelson C. J. , Byrd R. A. , Holson J. F.
Published: June 2005

Normal blood flow patterns to several maternal organs were characterized in individual CD rats, nonpregnant (NP) or on day 6, 7, 8, 10, 11, 12, 13, 16, 18, or 20 of gestation using the radioactive microsphere technique. Weights and flow values were determined for several uterine tissue samples as well as maternal organs. No significant changes were found in blood flow to the stomach, spleen, and urinary bladder of these animals. There also were no remarkable changes as pregnancy progressed in blood flow to the lungs, suggesting that no marked arterial‐venous shunting occurs in maternal placental tissues over gestation. Slight but consistent decreases in absolute (ml/min) and relative (ml/min/g tissue) blood flow to the brain were noted, and percent cardiac output (CO) was significantly decreased on all days of gestation except day 7. Complex changes were observed in blood flow to the kidneys, liver, adrenals, and heart. Absolute flow to the kidneys and liver reached maximum values on day 11, although percent CO delivered to both organs was consistently reduced throughout gestation. Absolute flow to the heart and adrenals peaked on day 13 and days 11–12, respectively. Absolute flow to the ovaries increased nearly 5‐fold from the NP state (0.36 ± 0.11) to day 20 of pregnancy (1.61 ± 0.33). Interlitter differences in ovarian blood flow during midgestation were found to be a result of differences in litter size and distribution of embryo/fetuses between the two uterine horns. The fact that the majority of changes observed in maternal organ flow coincide with placental development, rapid augmentation of total uterine flow, and/or maternal hormonal changes suggests that these patterns may be important indicators of the dynamic physiology of pregnancy.
Teratogenicity in vitro of 2‐acetylaminofluorene: Role of biotransformation in the rat
Authors: Faustman‐Watts E. , Greenaway J. C. , Namkung M. J. , Fantel A. G. , Juchau M. R.
Published: June 2005

2‐Acetylaminofluorene (AAF), a highly effective mutagen and carcinogen, was tested as a direct‐acting teratogen in an embryo culture system. Concentrations of up to 75 μg/ml (336 μM) of AAF produced no detectable malformations and only minimal decreases in viability and growth of rat embryos explanted on day 10 (11th day of gestation; the day after fertilization was designated as day 0). Inclusion of a microsomal monooxygenase system (prepared from rat liver) in the culture medium, however, resulted in marked changes in viability and growth. All explanted embryos exposed to concentrations of AAF above 60 μg/ml (269 μM) plus the microsomal monooxygenase system exhibited readily observable malformations as well as significant decreases in size and macromolecular content. Two metabolites, N‐hydroxy‐2‐acetylaminofluorene (N‐OH‐AAF) and N‐acetoxy‐2‐acetylaminofluorene (AAAF), each produced malformations in the absence of a monooxygenase system. At concentrations of 25 μg/ml (105 and 88 μM) approximately 50% of the embryos exposed to these metabolites were malformed. The predominant malformations associated with the metabolites were ventrolateral protrusions and hypoplasia of the prosencephalic region, whereas AAF plus the monooxygenase system produced an interruption of neural tube closure. This suggested the possibility that other metabolites may participate in the AAF‐induced malformation syndrome. The addition of the monooxygenase system to cultures containing N‐OH‐AAF or AAAF increased the frequency of malformations without increasing lethality or decreasing growth.
Ionic effects on strain differences in hepatic cytosolic glucocorticoid receptor levels in mice
Authors: Harper Kenneth J. , Erickson Robert P.
Published: June 2005

Ionic conditions were varied during homogenization of adult livers and during incubation of hepatic cytosol with glucocorticoid, and the effects on the detection of differences between inbred strains of mice for receptor levels were studied. When homogenized directly in 0.01 M Tris or homogenized in distilled water and then buffered to either 0.05 M Tris or 0.01 M potassium phosphate, A/J glucocorticoid receptor levels were greater than those of B10.A. However, when homogenized directly in 0.05 M Tris or buffered to 0.05 M potassium phosphate after homogenization in distilled water, A/J and B10.A had similar receptor levels. When buffered to 0.01 M Tris after homogenization in distilled water, A/J receptor levels were greater than those of B10.A but not significantly so. In Tris buffers, glucocorticoid receptor levels were higher when livers were homogenized directly in buffer than when liver homogenates were buffered after homogenization. This concentration effect is apparently due to the more rapid decay of glucocorticoid receptor in the lower molarity buffer. A reducing agent, thioglycerol, did not appear to affect either the rate of decay of the receptors or the measured level of receptor for B10.A and A/J. C57BL/6J receptor levels were measured in Tris buffers and had a similar relationship to A/J as did B10.A.
Another specific effect of prenatal acetazolamide exposure in the mouse
Authors: Beck Sidney L.
Published: June 2005

Subcutaneous injection of pregnant mice on day 8 of gestation with 1,000 mg/kg or 200 mg/kg of an aqueous solution of the sodium salt of acetazolamide, divided into three equal treatments at 8‐hour intervals, in two series of experiments performed 8 months apart on separately purchased random bred CD‐1 animals, resulted in the occurrence of a novel variant of the frontal bones of the skull when animals exposed in utero were examined at 62 ± 2 days postnatal.

In its greatest manifestation this variation consisted of a 2–3 mm posteriad extension of the dorsomedial portion of the posterior margin of both bones, although all degrees of asymmetry and variations in the extent of involvement of the posterior margin of the bones were seen. This frontal extension variant was seen in 30.9 ± 4.7% and 53.1 ± 5.0% of the 97 and 98 specimens in the highdose groups, and in 8.1 ± 2.7% and 14.6 ± 3.7% of the 99 and 89 low‐dose specimens in the two series. It was not seen in untreated groups, or to any significant extent in vehicle‐treated groups, or in a treatment regime involving exposure during days 9–11 of gestation. It was also not seen in 2,110 specimens from four other series of experiments reported in detail involving the teratogens, trypan blue (two series), 5‐bromodeoxyuridine, or 2,4,5‐T, or in approximately 1,000 specimens from comparable experiments with a variety of pesticides (Maneb, Captan, Trifluralin, Decamethrin) or Thalidomide.

In contrast, a morphologically analogous variant, accessory parietal, in which a suture in the anterodorsal surface of the parietal bones running posteromedial and seemingly delimiting a separate bone, is seen in all series. Although it looks as though frontal extension could be an accessory parietal fused with the frontal bone, observation of the specimens does not strongly support that relationship. Even if that were the case, it happens only in day‐8 acetazolamide exposure.

From the rather extensive series of observations performed, it would appear that frontal extension is a specific response to in utero exposure to acetazolamide during the day 8 of gestation.
Peripheral nerves do not play a trophic role in limb skeletal morphogenesis
Authors: Strecker Teresa R. , Stephens Trent D.
Published: June 2005

Research was undertaken to test the hypothesis that thalidomide‐induced limb defects resulted from damage to the neural crest or peripheral nerves and that normal limb development depends upon either the quality (level specific) or quantity of peripheral nerves. Barriers which were placed into early chick embryos to block brachial plexus‐level neural crest cells from reaching the limb resulted in normal limb skeletons. These data agree with previous work in suggesting that skeletal morphology is independent of innervation.
Maternal exposure to exogenous sex hormones in relation to birth weight of offspring
Authors: Polednak Anthony P. , Janerich Dwight T. , Glebatis Donna M.
Published: June 2005

Birth weight was analyzed among singleton live births (N = 665) in Upstate New York in 1974 to women who used oral contraceptives (OC) in comparison to live births to women who used no contraceptives (N = 716), within 11 months prior to last menstrual period (LMP). In addition, birth weight was examined among live births to women who received hormone support therapy (N = 97) and hormone pregnancy tests (N = 75) during pregnancy. There was no evidence for a reduction in mean birth weight, or an increase in frequency of lower weights, among births to OC users, including those who stopped using OC within 2 months of LMP. Generally similar findings held within three maternal age groups (<25, 25–29, and 30–39 years). There was no evidence for a reduction in birth weight among offspring of women who received hormone pregnancy tests. Mean birth weight was relatively low among male and female births to women who received hormone therapy for “threatened abortion,” but this may reflect the selection of women for such treatment rather than an effect of exogenous hormones on fetal growth.
Pharmacology of dextroamphetamine‐induced cardiovascular malformations in the chick embryo
Authors: Cameron Ray H. , Kolesari Gary L. , Kalbfleisch John H.
Published: June 2005

We have observed dextroamphetamine sulfate to cause cardiovascular malformations in the 4‐day‐old chick embryo. Essentially all malformations were of the heart and great vessels. About one‐half of these were the abnormal persistence of the left fourth aortic arch. Ventricular septal defects comprised the vast majority of the other malformations. Since d‐amphetamine has both a direct and, more importantly, an indirect mode of alpha and beta adrenergic stimulation, three drugs were used to try to inhibit malformation production: alpha‐methyl‐p‐tyrosine (AMT), a catecholamine synthesis inhibitor; metoprolol, a beta1 blocker; and phentolamine, an alpha blocker. When given with d‐amphetamine, all three drugs significantly reduced the malformation rate resulting from d‐amphetamine alone. We speculate that the embryonic chick is capable of responding to the alpha and/or beta properties of dextroamphetamine sulfate. These properties may be causally related to the malformations observed.
Comparative distribution and metabolism of triamcinolone acetonide and cortisol in the rat embryomaternal unit
Authors: Rowland J. M. , Althaus Z. R. , Slikker W. , Hendrickx A. G.
Published: June 2005

Triamcinolone acetonide (TAC) is teratogenic in rats while cortisol has been reported as not teratogenic. The objective of this investigation was to determine whether this difference in teratogenicity could be due to a difference in the metabolism and distribution of the parent compound in the embryomaternal unit. 3H‐TAC and 14C‐cortisol were administered intramuscularly to pregnant rats on day 12 of gestation. These dams were killed at each of the following time points after injection: 0.5, 1, 3, 6 and 24 hr. Maternal plasma and embryos were analyzed by high performance liquid chromatography (HPLC) and liquid scintillation counting. The plasma concentration of parent TAC was significantly greater than that for parent cortisol at all time points. The plasma elimination half‐life for TAC, 86 min, was also calculated to be significantly longer than that for cortisol, 8 min. Furthermore, the percentage of total plasma radioactivity representing HPLC resolved TAC was much higher than that representing cortisol at all time points. The concentration of TAC in the embryos was significantly greater than for cortisol at all time points. The elimination half‐life for unchanged TAC in the embryos was 142 min compared to 22 min for cortisol. The percentage of total radioactivity in the embryos representing unchanged TAC was similar to that found in maternal plasma while the percentage of total radioactivity representing unchanged cortisol was much lower than that found in maternal plasma. These findings support the hypothesis that differences in the distribution and metabolism of the parent compound are a critical factor in determining the teratogenicity of that compond.
Mirex‐induced fetal cataracts: Lens growth, histology and cation balance, and relationship to edema
Authors: Rogers John M. , Grabowski Casimer T.
Published: June 2005

The effects of mirex on growth, histology, and K+ and Na+ concentrations of the fetal lens are examined. Pregnant Long‐Evans rats were intubated with 6 mg/kg/day mirex in peanut oil on days 8–15 of gestation. Control dams received pure peanut oil. Fetuses were removed on days 18–21 and rated for extent of lens opacification and degree of edema. Lenses were removed, weighed, and assayed for K+ and Na+. Selected eyes were examined histologically. Cataracts were found in 49.6% of live treated fetuses on day 20, and the incidence and severity of cataracts were both correlated with the degree of fetal edema. Lens weights were reduced in treated litters whether or not cataracts occurred, but the reduction in cataractous lenses was greater. Sodium tended to be elevated and K+ reduced in lenses from treated fetuses, and the K+/Na+ ratio was significantly reduced in all treated groups. Histologically, treated lenses had swollen fibers on day 18 and areas of apparent cell breakdown by day 20. The swollen lens fibers, reduced K+/Na+ ratios and the correlation with edema suggest that fetal cataraots induced by mirex may be due to lens fiber cell breakdown subsequent to osmotic swelling.
Gross anatomical studies of a newborn with the Meckel syndrome
Authors: Pettersen James C.
Published: June 2005

A male infant with the Meckel syndrome was studied anatomically. The findings were compared with those from eight trisomy‐13 cases to determine whether or not the superficial similarities between the two syndromes were matched by similarities in the internal variations. Emphasis was on the head and limbs.

In the head, major differences were found in the nasal bones, mandible, and tongue. In the limbs, the skeletal variations were more severe in the Meckel syndrome infant, but he lacked the muscle variations diagnostic of trisomy 13.
Effects of the cytostatic drug cis‐platinum on the developing neocortex of the mouse
Authors: Köpf‐Maier Petra , Merker Hans‐Joachim
Published: June 2005

The effects of the new cytostatic drug cis‐diamminedichloro‐platinum(II) (cis‐platinum) on the developing neocortex of NMRI mouse embryos or fetuses were investigated using light‐ and electron‐microscopic methods. Single doses of 20 mg cis‐platinum/kg were applied intraperitoneally on day 10, 11,…, or 16 of gestation. After treatment on day 10 or 11—i.e., during the phase of organogenesis—no morphological alterations could be detected in the neuroepithelium. However, after treatment on day 12 or later, the mitotic activity was markedly reduced and a great number of cells had become necrotic within 12–24 h after application of the drug. At the ultrastructural level, the development of necroses began with a condensation of the chromatin, culminating in the formation of large condensation plaques and shrinkage and fragmentation of the cytoplasm. The observed necroses can be classified according to Schweichel and Merker as type I necroses. It is argued that the apparent teratogenic inefficiency of cis‐platinum on days 10 and 11 of murine pregnancy is caused by the inability of cis‐platinum to pass the placental barrier at this stage of pregnancy.
Phencyclidine exposure and the developing mouse: Behavioral teratological implications
Authors: Nicholas J. Michael , Schreiber Eric C.
Published: June 2005

The effects of perinatal exposure to phencyclidine (PCP) on the reflex development of the offspring of mothers given PCP during gestation and/or lactation were determined. ICR Swiss mice received daily injections of either PCP (5, 10, 20 mg/kg, PO) or saline during gestation and/or lactation. Thus, four groups of animals were studied; those exposed only prenatally, postnatally, both pre‐ and postnatally, or control. After birth, these offspring were observed daily until weaning for the appearance of certain reflexes, using a modification of the Fox battery. There was a delay in the disappearance of the cross extensor reflex and delayed appearance of reflexes, such as walking, crawling, vibrissal placement and vibrissal stroking in the offspring of PCP‐treated mothers. Treated animals also showed slower righting times than control animals. Growth rate was decreased in PCP‐exposed animals beginning at 3 days of age and continuing through 15 days of age. These results indicate that PCP exposure during gestation or nursing adversely affects the development of behavioral reflexes in mice and suggest that regular observation of reflex ontogeny in neonates may be a sensitive indicator of behavioral teratology.