bluuebunny/crossref_metadata_2025 huggingface dataset:
Changing body wall and rib defects after local application of nitrogen mustard to different mediolateral portions of rib‐forming levels of two‐day chick embryos
Authors: Sweeney Robert M. , Watterson Ray L.
Published: June 2005

Methylbis(beta‐chloroethyl)amine hydrochloride was applied for 1 minute to the slit vitelline membrane over different mediolateral portions of ribforming levels of 22‐ to 27‐somite chick embryos by uniformly prepared agar discs of uniform dimensions. Gross effects on rib patterns and external features (body wall, feather tracts, wings) were recorded after 10 to 11 days of incubation.

Rib patterns were essentially normal in most specimens with agar discs placed over the right lateral plate only; modifications of external features other than right wings were minimal under these circumstances. Placement of agar discs close to or over any portions of the somites and also over the lateral plate resulted in modifications both of rib patterns and external features. Related modifications occurred in vertebral and sternal components of ribs 3–7. Vertebral components were reduced in size, otherwise modified, or absent. Sternal components were either modified correspondingly, usually to greater degrees, or absent. Sternal components never formed in the absence of corresponding vertebral components. Similar modifications of vertebral and sternal components sometimes occurred on the left side when agar discs were applied to the right side. Modified external features (transverse grooves or depressions, body foreshortening, dorsal displacement and other modifications of breast and ventral feather tracts) appeared to be due to reduction of body musculature.

These results are compatible with the classical hypothesis that vertebral and sternal rib components and ventrolateral muscles originate exclusively from somites.
A gene producing symmelia in the mouse
Authors: Hoornbeek Frank K.
Published: June 2005

The inheritance and description of a lethal condition involving sireniform abnormalities in mice are reported. Symmelia was produced by homozygosity for an incomplete recessive gene provisionally called siren (symbol srn). Sirens were apodal, monopodal, or dipodal. with the ischia present as a vestigial structure or missing. Femora, when present, were medially placed and usually fused. Pubes and tibiae were abnormal in some cases, and fibulae usually were. Visceral defects included absent or abnormal kidneys and adrenals, and blind or undeveloped intestines.
A mechanism for closure of the secondary palate
Authors: Verrusio A. Carl
Published: June 2005

Before the palate begins to close in mouse and rat embryos the cranial base in flexed in the area of the craniopharyngeal canal. As the process of palate closure progresses there is a gradual reduction in the flexure of the cranial base until finally, when the palatine processes are horizontal, the cranial base is almost straight. Rapid growth and straightening of the cranial base might play a role in palate closure by providing the “internal shelf force.” This hypothesis can be demonstrated by means of a mechanical model. The model consists of a thin sheet of plastic cut in the shape of a sagittal view of a vertical shelf and a piece of string attached to the convex border of the model shelf to represent the cranial base (in its flexed position). When the string is pulled, and the angulation of the “cranial base” is reduced to a straight line, the distal part of the model palatine process rotates to a position perpendicular to the proximal or attached part of the shelf, in a manner similar to that of the palatine processes in the embryo.
The closure of the neural tube in the golden hamster
Authors: Marin‐padilla Miguel
Published: June 2005

The sequence of events leading to the closure of the neural tube has been investigated in hamster embryos. This consisted of: (1) approach and fusion of the neural folds at the level of the presumptive neural‐crest cells; (2) active proliferation of the neural‐crest cells at the area of fusion and formation of a distinct wedge by them; (3) fusion and closure of the surface ectoderm; (4) reduction of the number of neural‐crest wedge cells due to their active migration from it; (5) fusion of the neurectoderm beginning at the ependymal surface, progressing dorsally until the neural tube was completely closed; and (6) fusion and closure of the mesoderm between the surface ectoderm and the closed neural tube. The time required to complete this sequence of events, the amount of embryonic tissue involved in it at a given time, and the number of neural‐crest cells formed at the area of fusion varied from one region of the embryo to another. It is postulated that the mesoderm appeared to play a double role in the process of closure—a direct one late in the closure process (see 6) and an indirect one, perhaps as a buttress supporting the other cellular elements during the entire closure process.
Effect of actinomycin D and urethan on successive litters and generations of mice
Authors: DiPaolo J. A. , Elis J.
Published: June 2005

Sequential litters and generations of A/He mice were given repeated injections of actinomycin D or urethan to study effects on fertility, embryotoxicity, teratogenicity, and carcinogenicity. The drugs were given every other day throughout pregnancy. Seven weeks separated each mating and course of treatment. Both drugs had a deleterious effect on fetal development dependent on dosage and litter series. The largest dosages blocked development completely; the effect of 50 μg/kg actinomycin D lasted through the second mating period. The number of offspring relative to controls was also decreased with smaller dosages. Drug toxicity increased with successive matings. In three consecutive generations commencing with females obtained from the lowest treatment regimen a response was observed similar to that seen in offspring obtained by repeated treatment of the same females. Actinomycin D was less carcinogenic than urethan; an increase in the number of lung tumors was found only in the females used for breeding. Compared to the control group, both breeders and offspring exposed transplacentally had an increased incidence of tumors following urethan administration. Malformations occurred only after urethan treatment.
The role of sulfated mucopolysaccharides in cleft palate production
Authors: Nanda Ravindra
Published: June 2005

Offspring of rats treated with vitamin A, cortisone, or both drugs were studied with the aid of 35S‐sulfate to investigate whether sulfated‐mucopolysaccharides have a role in cleft palate production. Vitamin A alone or combined with cortisone produced a high frequency of cleft palate. Cortisone alone produced no cleft palates. Autoradiographic results showed that 35S‐sulfate incorporation in palatal tissue of control fetuses and those from rats treated with both drugs was almost similar, whereas isotope incorporation was several times higher than this in the vitamin A‐treated group and slightly less than this in the cortisone‐treated group. The results appear to indicate that there is no relation between disturbed sulfate mucopolysaccharide metabolism and the production of cleft palate.
The relation of the uterine vasculature to fetal growth and the intrauterine position effect in rats
Authors: Barr Mason , Brent Robert L.
Published: June 2005

Ligation of the uterine vasculature was performed on the 10th or 18th day of gestation in 114 Wistar rats. In each rat the blood vessels of one uterine horn were ligated at the level of the oviduct, midhorn, or the cervix; the opposite horn served as a control. Fetal weight and mortality data were analysed for the effect of the vascular interruption and the effect of intrauterine position. It was found that patency of the ovarian artery was not essential for normal fetal growth and that the loop‐artery configuration of the vessels to the uterine horn was not a determinant of the position effect. The time in gestation at which the ligation was performed had a decided effect on ultimate fetal weight: the later in gestation, the greater the fetal growth retardation. Various factors that could be responsible for the position effect are discussed. It is suggested that the association between fetal weight and intrauterine position is species dependent and is determined by unknown factors, not singly by hemodynamics, myometrial pressure, or time of implantation.
The embryolethal and teratogenic effects of cyclophosphamide on mouse embryos
Authors: Gebhardt D. O. E.
Published: June 2005

Pregnant mice were injected once with 10 or 20 mg/kg cyclophosphamide. A large embryolethal effect was induced by treatment on the 3rd and on the 8th and 9th days of pregnancy. Mortality was probably due to a direct effect of cyclophosphamide on the embryos. Limb malformations were induced at a later stage; therefore it appears that embryolethality and teratogenicity are separable processes. The anomalies consisted of synostoses, retardation of ossification, and poly‐ and oligodactyly. Polydactyly was induced at an earlier stage than oligodactyly.
Malformations caused in mouse embryos by a red dye contained in commercial trypan blue
Authors: Bertini Francisco , Sacerdote Fabio
Published: June 2005

A red impurity (dye C, absorption maximum 560 mμ) was separated from two commercial samples of trypan blue by dialysis against double‐distilled water and ethanol extraction. Paper and Sephadex G‐25 chromatography proved that the nondiffusable trypan blue (TBC) was made up of 85% blue dye (dye TB, absorption maximum 590 mμ) and of residual dye C (15%). Swiss mice were injected ip on day 8 of pregnancy with 2–3 mg of TBC or with dye C in an amount representing 15% of the absorbance units (at 590 mμ) of the whole dose of TBC. All were killed on day 16 of pregnancy. The conceptuses of females treated with dye TBC were 62% resorbed, and 29% of the survivors were malformed. Those of the dye C group were 4% resorbed and 17% malformed. Only one of the 73 control implants was resorbed. The mean weight of both experimental groups was significantly lower than that of controls. The malformations were, in order of frequency: omphalocele, encephalocele, exencephaly, monophthalmus and anophthalmus. The types and distribution of malformations obtained with dye C were similar to those caused by the nondiffusable dye.
Effect of actinomycin D on early axial development in chick embryos
Authors: Wolkowski Rochelle M.
Published: June 2005

A study was made of the uptake of actinomycin D, 3H‐thymidine, and 3H‐uridine in the axial regions of 11‐ to 13‐somite chick embryos cultured in vitro. Actinomycin D was taken up into all regions of embryos, with significantly more actinomycin D per cell in the axial region, including the node and unsegmented axial mesoderm (the lower axis). Demonstrable effects on RNA synthesis were restricted to tissue in the lower axial region. However, inhibition of DNA synthesis was seen in tissues of the upper axis already segmented, as well as in the lower axis. The differential response of the embryonic axis to actinomycin D is considered to be based on a greater demand for cells in the unsegmented and nodal region. Actinomycin D inhibited RNA synthesis, thereby inhibited DNA synthesis and cell division, and reduced availability of cells for growth and development. The paucity of cells in the node and unsegmented axial mesoderm restricted the formation of new somites and the laying down of new nerve cord and notochordal tissue. The upper axial region was not permanently affected.
The production of congenital malformations using tissue antisera. VII. Yolk‐sac antiserum
Authors: Brent Robert L. , Johnson Albert J. , Jensen Marcela
Published: June 2005

Heterologous antisera against rat yolk sac made in rabbits and sheep produced congenital malformation, fetal growth retardation, and embryonic death when injected into pregnant rats. Antigens present in the cellular or acellular portions of the yolk sac were capable of producing teratogenic antibodies. Fluorescence‐labeling techniques revealed that yolk‐sac antiserum contained antibodies that reacted strongly with the nonserum‐protein antigens of maternal adrenal, ovary, and kidney; fetal yolk sac; and chorioallantoic placenta. Teratogenic yolk‐sac antiserum localized in the noncellular and intracellular portions of the parietal and visceral yolk sac including Reichert's membrane. It is postulated that yolk‐sac dysfunction is produced by the localization of these antibodies in the yolk sac. The localization of yolk‐sac antiserum in the yolk sac was observed at term regardless of whether the antiserum was injected on the 11th or 20th day of gestation, although the time of injection affected the localization at term qualitatively and quantitatively. These results suggest that further studies of the functions of the yolk sac at various periods of gestation are indicated not only in rodents but in humans since the yolk sac may play a role in human teratogenesis. The unanswered questions concerning yolk‐sac function and dysfunction in rodents and the importance of the yolk sac in humans add another aspect to the problem of transferring the results of teratogenic studies in rodents to the human situation.
The distribution of cortisone‐14C in pregnant mice
Authors: Waddell William J.
Published: June 2005

The distribution of the teratogenic steroid cortisone was studied in pregnant A/J mice by whole‐body autoradiography to ascertain whether sites of localization in the pregnant females or embryos might suggest a mechanism of teratogenic action. A high concentration of radioactivity was found in maternal kidney, liver, bile, and intestinal contents and uterine cavity fluid. Maternal ovary and adrenal had much less activity but nevertheless a slightly higher activity than blood. There was no other prominent accumulation in either mothers or off spring. The concentration in the embryonic palatal buds was no higher than that in any other embryonic area, and the concentrations in embryonic tissues were less than those in maternal tissues. The remarkable accumulation in the uterine luminal fluid appeared to result from active secretion by the yolk sac. Addition of carrier cortisone or pretreatment of the pregnant mice with ouabain or mercuhydrin did not significantly alter the pattern and intensity of distribution. Pretreatment with cobaltous chloride decreased the concentration of radioactivity in the fetuses.
Symmelia in one of monozygotic twins
Authors: Davies Jack , Chazen Eric , Nance Walter E.
Published: June 2005

Postmortem dissection of a liveborn infant with symmelia who was one of a pair of monozygotic female twins revealed fusion of the preaxial halves of the hindlimbs to form a single hip joint, a femur with two medial and no lateral condyles, and knee and ankle joints that flexed backwards. The kidneys, bladder, uterus, and rectum were absent. Twenty‐three instances of twinning were found among 327 cases of symmelia reported in the medical literature. Only two pairs were definitely concordant, but whenever data were given they supported monozygosity. There appears to be more than a 100‐fold increase in the incidence of symmelia in monozygotic twin births as compared with single births. The high frequency of discordance could result from unequal expression of a cytoplasmic abnormality. Alternately, the developmental arrest of the primitive streak that leads to symmelia may also initiate the formation of a second primitive streak, thereby giving rise to twin embryos.
The effects of maternal hypercortisonism and hypervitaminosis D2 on fetal osteogenesis and ossification in rats
Authors: Ornoy A.
Published: June 2005

Pregnant rats were treated daily with intramuscular injections of 5 or 10 mg cortisone acetate dissolved in 0.5 ml normal saline, or orally with 20,000 IU vitamin D2 dissolved in 0.5 ml olive oil, or both. Controls received olive oil and normal saline, or vitamin D2. Treatment was from day 8 or 10 of gestation until the animals were killed on day 18, 20, or 22. The higher dose of cortisone shortened the diaphyses and epiphyses of long bones. Concomitant administration of vitamin D2 caused further bone shortening and hypomineralization. The main microscopic alterations in the fetal bones of cortisone‐treated rats were changes in cartilaginous intercellular substance, narrowing of the hypertrophic and calcifying cartilage cell layer, and inhibition of endochondral ossification. Bone trabeculae were very wide and irregular. The bone matrix had abnormal staining properties. Bone marrow spaces were obliterated and contained a very large number of fibroblasts, preosteoblasts, and osteoclasts. The number of osteoclasts was further increased by treatment with vitamin D2. It is presumed that cortisone passed through the placenta and affected fetal bones, causing the microscopic changes. Concomitant administration of vitamin D2 potentiated the effects of cortisone on bone, and also produced certain specific changes.
A morphological and histochemical study of thalidomide‐induced upper limb malformations in rabbit fetuses
Authors: Nudleman K. L. , Travill A. A.
Published: June 2005

The upper limbs of 21‐day‐old thalidomide‐treated rabbit fetuses were studied macroscopically, histologically, and histochemically. The deformed limbs were arthrogrypotic, twisted, or medially rotated and inverted. Often these malformations were coupled with anomalies of the thumb. One or more of the preaxial bones or their primordia were either anomalous or missing. The degree of the induced dysmelia could be recognized by the graded severity of the histology. The least severely affected limbs exhibited defects of ossification and/or chondrification, whereas more severely affected ones contained atrophic chondrocytes, undifferentiated mesenchyme, or absence of primordia. In the deformed limbs glycogen was retained in the hypertrophic and calcified chondrocytes and glycogen granules were dispersed in reduced thenar structures, but alkaline phosphatase activity was reduced or absent in the same areas. There were no detectable differences in the amount or distribution of acid mucopolysaccharides between abnormal and control limbs. However calcium deposition in the cartilaginous matrices was reduced or absent in the abnormal limbs. In limbs with reduced amounts of osseous tissue there was no evidence of histochemical aberration in the deposited bone. It would appear, therefore, that thalidomide affected mesenchymal derivatives at various stages of development; that it was associated directly or indirectly with the utilization of glycogen and the production of alkaline phosphatase; and that its influence was expressed by aberrations in the chondrification and calcification processes during later fetal development.
Embryonic abnormalities in hamsters following intrauterine injection of 6‐aminonicotinamide
Authors: Turbow M. M. , Clark W. H. , Dipaolo J. A.
Published: June 2005

Hamster embryos were injected intraamniotically (ia) with 6‐aminonicotinamide (6‐AN) on gestation day 7, 8, or 9 and examined near term. Control treated embryos received 5 μl of water, a needle puncture without injection, or no treatment, and had low rates of resorption and malformation. 6‐AN injected ia produced offspring with multiple defects including exencephaly, cleft palate, anophthalmia, micrognathia, and hydrocephalus. In contrast to day‐8 and ‐9 embryos, which responded to 5‐μg doses of 6‐AN, day‐7 embryos required 50–100 μg before exhibiting abnormalities.
Changes in DNA, RNA, and protein content of regions of explanted chicken embryos following insulin treatment
Authors: Hickey Eileen D. , Klein Norman W.
Published: June 2005

Chick embryos of 11–13 somites, which were cultured 48 hours on insulin‐containing medium, showed deformation of the brain and posterior trunk, and inhibited accumulation of DNA, RNA, and protein contents. These effects became more pronounced with increased insulin dose. Embryos transferred to insulin‐free medium after 2 or 3 hours' exposure to 4 U/ml insulin showed a similar morphological response as embryos continuously exposed to the same dose. Quantitation of DNA, RNA, and protein contents indicated a more severe inhibition in embryos of the continuously exposed group than in those of the briefly exposed group, although embryos of both groups were significantly inhibited relative to their controls. Region‐specific action of insulin was demonstrated in terms of the time at which each region of insulin‐treated embryos first showed reduction in DNA, RNA, or protein content. The brain was the most susceptible region to insulin action; the trunk regions responded later; and the heart and extraembryonic membranes showed no significant effect of insulin treatment. At the molecular level nucleic acid content was most influenced by insulin treatment. Reduction in DNA content of whole embryos, or of specific regions, was the first effect of insulin treatment detected. However, on continuous exposure to a low dose of insulin (0.2 U/ml) the RNA content of the brain was reduced before the DNA content.
Metabolism of β‐aminopropionitrile and its teratogenic activity in rats
Authors: Wilk A. L. , King C. T. G. , Horigan E. A. , Steffek A. J.
Published: June 2005

The administration of β‐aminopropionitrile (BAPN) to pregnant rats induced various fetal anomalies including a high percentage of cleft palate. Following oral administration BAPN was found along with its deaminatedoxidized derivative cyanoacetic acid (CAA) in embryos, placentas, and maternal tissues, serum, and urine. BAPN levels reached a maximum in tissue and serum 6 hours after treatment, were maintained for about 3 hours more, then sharply declined to negligible amounts by 24 hours. CAA levels however gradually rose and high levels were still present at 24 hours. Similar amounts of BAPN were found in tissues after its administration on either day 14. 15, or 16 of gestation; however, only on day 15 was there a positive correlation between embryonic levels of BAPN and cleft‐palate production. Thus 6 hours after BAPN treatment on day 15 embryonic levels of 106, 42, or 16 μg BAPN per g of tissue corresponded to a cleft‐palate incidence of 98, 28, or 0% respectively. Oral administration of CAA produced no cleft palate even though high embryonic levels of CAA were attained. These data indicate that BAPN itself is teratogenic and that it acts within a narrow period of time on day 15 in producing cleft palate.
Teratogenic effects of 5‐fluoro‐2′‐deoxyuridine in pregnant mice
Authors: Ohmori Kazuo
Published: June 2005

Radioactive 5‐fluoro‐2′‐deoxyuridine (FUdR) was administered to mice on day 12 of pregnancy, and the resulting radioactivity was measured in embryos, placentas, and maternal liver and spleen. The FUdR was taken up rapidly by the maternal tissues and embryos and was incorporated into nucleic acids within 1 hour of administration. In the maternal tissues the quantity of FUdR incorporated into nucleic acids within 1 hour of administration was greatly increased by increasing the applied dose. In embryos, however, only a slight increase was observed. After 0.14 mg/kg FUdR the quantity incorporated into nucleic acids reached its peak within 1 hour, and increased no further. After a dose ten times larger the quantity of FUdR incorporated into nucleic acids increased steadily in all tissues tested until nearly 8 hours after application. A greater amount of FUdR was incorporated into maternal spleen than into embryos.
Molecular differentiation of several enzymes in early human embryos
Authors: Johnson E. Marshall , Takano Kiichi , Nishimura Hideo
Published: June 2005

Homogenates of two human embryos, one each at horizons 16 and 20, were subjected to zone electrophoresis in starch and polyacrylamide gels. The gels were stained to reveal multiple molecular forms of acid and alkaline phosphatase, nonspecific esterase, and lactate, malate, and glucose‐6‐phosphate dehydrogenase. In general there were qualitative and quantitative increases in enzymatic activity with increasing gestational age. The enzymatic ontogeny observed was compared to that previously found prenatally in rats.
Variability of limb malformations induced by 5‐fluoro‐2′‐deoxycytidine in mice
Authors: Kleinebrecht J. , Degenhardt K.‐H. , Fränz J. , Schneider G.
Published: June 2005

Malformations of limb elements produced in C57BL/10 mice by various dosages of 5‐fluoro‐2′‐deoxycytidine given at day IX or XI were analyzed. This investigation was restricted to the analysis of aplasia, synostosis, synchondrosis, and inhibition of calcification. Teratological patterns were described in detail. Day‐IX treatment induced patterns of ulnar, radial, ulnarradial, and tibial aplasias. Day‐XI treatment produced groups of defects with common characteristics, but no clear teratological patterns. Synostoses, synchondroses, and inhibition of calcification predominated. Dose‐response relations occurred after treatment at both stages.
Distribution and metabolism of triamcinolone acetonide in inbred mice with different cleft palate sensitivities
Authors: Zimmerman Ernest F. , Bowen Donna
Published: June 2005

The distribution and metabolism of labeled triamcinolone acetonide was compared in A/J, C3H, and CBA inbred mice. 3H‐Triamcinolone acetonide (5 mg/kg) administered at day 11.5 of gestation caused 100% cleft palate in A/J, 40% in C3H, and 0% in CBA. A half to 3 h later CBA maternal tissue (skeletal muscle) contained 60% as much radioactivity as did A/J and C3H tissue. CBA mice metabolized the drug faster than A/Js and C3Hs, although levels of unmetabolized drug and metabolites in livers of the three strains were not significantly different. As a consequence of the increased maternal metabolism of the drug in CBAs the level of unmetabolized drug in CBA embryos was 60% of that in A/J and C3H embryos. It is concluded that the cleft palate resistance of CBA embryos derives from the increased maternal metabolism of administered teratogen. However, the greater resistance of C3H than A/J is probably not due to increased metabolism, nor to altered distribution of drug.
Accessory lobe of the liver in Gunn‐derived rats
Authors: Machado Emilio A. , Lozzio Bismarck B.
Published: June 2005

Congenital accessory lobe of the liver in rats is described. The defect may be an inherited one, and if so may involve a recessive gene with low penetrance or may be polygenic. No affected individual produced offspring. The accessory lobe consisted of a round intrathoracic mass with vascular connections to the cava or suprahepatic veins. Microscopically, there was disarray of the normal architecture, blood stasis, and severe chronic congestion, which often led to rupture of the dilated vessels and formation of large hemorrhagic areas.
Independent effects of fluorouracil and two mutant genes in mouse embryos
Authors: Dagg C. P.
Published: June 2005

Previous experiments demonstrated that fluorouracil, injected into female mice at day 10 of gestation, reinforced the effects of two limb‐deforming mutant genes, luxoid (lu) and luxate (lx). In the present investigations, male mice heterozygous for lu or lx were mated to + / + females who were injected with fluorouracil at day 11 or 12 of gestation. Some offspring from these matings were mated to + / + mice to determine their genotypes (+ / +, + /lu, or + /lx). Preaxially hyperphalangous hind feet, characteristic of untreated + /lu, and + /lx mice, were found only in the mutation‐bearing offspring. There were no correlations between genotypes and the abnormalities (kinked tail, white belly patch, and small fabella medialis) produced by fluorouracil. It was concluded that under these experimental conditions there were no significant interactions between the teratogen and the mutant genes at 11 and 12 days of development.
The localization of vitamin A in the pregnant rat by means of fluorescence microscopy
Authors: Geelen J. A. G.
Published: June 2005

Pregnant Wistar rats were administered 50,000 IU of vitamin A palmitate orally on each of the 7th, 8th, and 9th days of gestation. Fluorescence microscopy of serial sections of 10th‐, 11th‐, and 12th day embryos revealed a fading, bright green color indicative of vitamin A. The fluorescence was located in the decidua capsularis, decidua basilaris, Reichert's membrane, parietal yolk‐sac epithelium, giant cells, and uterine musculature but not in the visceral yolk‐sac epithelium or embryo. The thyroid, adrenal, and kidney of experimental pregnant females showed an increase of vitamin A fluorescence.
Sagittal growth trends of the craniofacial complex during formation of the secondary palate in mice
Authors: Hart James C. , Smiley Gary R. , Dixon Andrew D.
Published: June 2005

Normal C57BL and A/J mice and A/Js with spontaneous bilateral cleft lip and palate were obtained at 13–16 days of gestation and the heads were prepared for serial sectioning in the sagittal plane. The midsagittal sections were photographically enlarged and measurements made to assess the amount and rate of growth. The C57BL fetuses outgrew the A/Js. in all parameters. A mandibular growth spurt was not observed, but an increase in mandibular growth relative to that of the maxilla was found. Maxillary growth was less in malformed A/Js but the mandible was not micrognathic. The cranial base angle was not significantly different in normal and malformed A/J fetuses, but the vertical dimension was significantly greater in the former than the latter at days 15 and 16. The increase in the angle made by the mandible and the posterior cranial base before and during palatal closure appeared to have the greatest influence on the vertical dimension.
The in vivo biosynthesis of DNA, RNA, and proteins by mouse embryos after a teratogenic dose of cyclophosphamide
Authors: Short Robert D. , Rao K. S. , Gibson James E.
Published: June 2005

Pregnant Swiss‐Webster mice received 20 mg/kg cyclophosphamide ip on day 11 of gestation and 100–125 μCi/kg 14C‐labeled thymidine, orotic acid, uridine, or leucine at various times afterwards. DNA synthesis in embryos, as measured by 14C‐thymidine incorporation, was significantly reduced at 12 h but not 3, 6, 24, 48, or 72 h after treatment, and embryonic DNA was reduced at 12, 24, 48, and 72 h. 14C‐thymidine incorporation and DNA content were also reduced in placentas and maternal livers after a delay of at least 6 h. Embryonic protein synthesis, as measured by 14C‐leucine incorporation, was significantly reduced at 72 and 96 h after treatment. Embryonic RNA synthesis or content was not significantly affected. It was concluded that a teratogenic dose of cyclophosphamide quantitatively affects the synthesis of DNA and protein in the mouse embryo. The temporal aspects of the changes indicated that the effects on DNA synthesis may be the cause of induced developmental defects but effects on protein synthesis appear to be the result rather than the cause of the defects.
Early and late effects of in vitro exposure of preimplantation mouse embryos to trypan blue
Authors: Fisher D. L. , Smithberg M.
Published: June 2005

Preimplantation 129/SvSl mouse embryos obtained by induced superovulation and cultured from the 4‐cell to blastocyst stage were exposed to various concentrations of trypan blue for 48 h or to the LD50 (0.16%) and LD99 (0.35%) concentrations for various lengths of time. At least 2 ½ h exposure to the latter concentrations was required before significant reduction in blastulation rates (80% in controls) occurred. Embryos that blastulated after 48 h of culture were transplanted to adult nulliparous 2‐day‐pseudopregnant 129/SvSl females and fetuses were examined 15 days later. Approximately 70% of implanting control blastocysts developed into fetuses. Significantly fewer fetuses developed after 48 h preimplantation exposure to concentrations of 0.08 % or more of trypan blue. The percentage of resorptions increased with exposure to increasing concentrations of trypan blue during the preimplantation period. The only abnormality found in treated fetuses was subdermal hematoma.
Experimental first‐trimester amniocentesis in nonhuman primates
Authors: Poswillo D.
Published: June 2005

The effects of amniocentesis prior to palate closure were investigated in Macaca irus embryos. Nine embryos were used as operated controls, being obtained by hysterotomy on consecutive days from 39 to 47 of development; nine animals composed the experimental group, in which amniocentesis was carried out via a laparotomy approach from day 39 to 47, and the fluid used for cytological investigations; nine unoperated pregnant animals, chosen at random from consecutive births in the colony, provided a further control group. Radiographs of experimental fetuses at regular intervals after amniocentesis revealed one instance of postural moulding which assumed a normal position within 2 months. Histological examination of the operated control embryos confirmed that experimental amniocentesis covered the 9 days immediately preceding palate closure. All nine of the animals in the amniocentesis group were delivered by Cesarean section at term, and found free of gross abnormalities. From birth until 6 months these were compared with the normal controls. Birth weights and sizes fell within the normal range, and at 6 months there were no features to distinguish between the experimental and control groups in any aspect of growth or development.
The influence of the fetal genome on trypan blue‐induced cardiovascular defects
Authors: Fox Marjorie H.
Published: June 2005

The mean litter incidence of genetically determined, congenital patencies of the interventricular cardiac septum was found to differ significantly and consistently in control neonates produced by matings within and between two Long‐Evans lines of rats (O/O>C/O>O/C>C/C). When dams carrying siblings of control neonates were injected with a standardized dose of trypan blue on day 8 of pregnancy, there occurred significant increases in the incidence of cardiovascular malformations in litters of all genotypes. Although neither the magnitude of the increases nor the severity of the induced malformations was directly correlated with line or sibship differentials with respect to the incidence of spontaneous septal, patencies some unidentified aspect of the fetal genome significantly influenced the nature of the induced defects. Both O/O and hybrid litters were characterized by a high incidence of severe transposition syndromes, consistently associated with highly specific, unilateral cephalic malformations or extensive spina bifida. The incidence of comparable associated head and heart malformations was significantly lower in C/C litters, in many of which the dye exposure merely increased the incidence of isolated interventricular septal patencies over that found in control siblings or induced noncardiovascular malformations at the caudal end of the body axis. In general, the collective data afford little support for the concept that a familial or subline predisposition towards spontaneously occurring cardiac malformation renders the fetal cardiovascular system particularly susceptible to the teratogenic activity of trypan blue.
Hydrocortisone‐induced cleft palate in hamsters
Authors: Shah Ravindra M. , Chaudhry A. P.
Published: June 2005

Single im doses of 25–30 mg hydrocortisone on day 11 of gestation produced 100% cleft palate in hamsters without undue fetal resorption; 75 mg produced a significantly larger resorption rate. The cleft palates varied in morphology, some being complete and others incomplete; the latter were relatively more common with smaller doses. The fetal birth weight of experimental offspring was greatly decreased.
Teratogenic effects of intrauterine injection of acetazolamide and amiloride in hamsters
Authors: Storch T. G. , Layton W. M.
Published: June 2005

To learn if acetazolamide acts at an intrauterine site when it produces limb deformities in the hamster, acetazolamide was injected into one horn of the pregnant uterus and an inactive analogue into the opposite horn. Significantly more forelimb malformations occurred in the acetazolamide‐injected horns, but hindlimb malformations occurred with equal frequency in both horns. These results suggest that acetazolamide acts at an intrauterine site when it produces forelimb malformations, but may not do so when it produces hindlimb malformations. In other experiments, acetazolamide was given intraperitoneally, and a dose of amiloride, too small to affect the acetazolamide‐induced extrauterine potassium alterations, was also injected into one uterine horn and a control solution into the opposite. Significantly fewer forelimb malformations occurred in the amiloride‐injected horns, suggesting that amiloride can act at an intrauterine site to reduce the incidence of forelimb malformations without affecting the extrauterine potassium changes.
Relationship of temporal patterns of cell death and development to malformations in the rat limb. Possible mechanisms of teratogenesis with inhibitors of DNA synthesis
Authors: Ritter E. J. , Scott W. J. , Wilson J. G.
Published: June 2005

Cytosine arabinoside palmitate (ara‐CP) is a sustained‐action form of the DNA‐synthesis‐inhibitor cytosine arabinoside (ara‐C). When given at day 12 of rat gestation ara‐CP caused moderate but prolonged depression of DNA synthesis, killed embryonic cells after 2–3 days, and led to severe limb and other defects and extreme growth retardation. The results were compared with those obtained in earlier studies with hydroxyurea and with ara‐C, both of which also caused depression of DNA synthesis, cell death, and limb defects, but at different times in relation to treatment. There was a relation between the time of maximal cell death in the limbs after treatment and the specific limb malformations seen at day 20. The relation of cell death to teratogenesis seen with these chemical agents is similar to that previously reported for X irradiation.
Induction of a cytoplasmic factor increasing resistance to the teratogenic effect of 6‐aminonicotinamide in mice
Authors: Pollard D. R. , Fraser F. C.
Published: June 2005

It was previously shown that maternal treatment with 6‐aminonicotinamide (6‐AN) produces a higher frequency of cleft palate (CP) in A/J than C57BL/6J mice. C57BL mice are more resistant to 6‐AN when fed a high niacin diet (Purina Lab Chow) than a low niacin diet (Purina Breeder Chow). This component of the strain difference appears to be cytoplasmically transmitted. The present study showed that when C57BL mice were transferred from the low niacin to the high niacin diet for 1 h before 6‐AN treatment the CP frequency dropped to the value in offspring of females raised on the high niacin diet and remained at this low level when the time on this diet before treatment was increased to as much as 1 month. In A mice the response was not as immediate as in C57BLs, and as the time the females were on the high niacin diet before treatment was increased the CP frequency rose again. It is suggested that niacin in the diet functions as an inducer for an enzyme system controlled by a cytoplasmic factor that increases the resistance of the organism to the CP‐producing effect of 6‐AN.
The further epidemiological differentiation of cleft lip and palate: A population study of clefts in King County, Washington, 1956–1965
Authors: Emanuel Irvin , Culvers Bruce H. , Erickson J. David , Guthrie Ben , Schuldberg David
Published: June 2005

A retrospective epidemiological study of cleft lip and palate in King County, Washington, between 1956 and 1965 is reported. Multiple sources of ascertainment were employed, and particular attention was given to obtaining information concerning other associated malformations. Occurrences of cleft lip (CL), cleft lip and palate (CL + P), and cleft palate (CP) were analyzed by sepa rate categories, depending on the presence or absence of associated major or minor malformations. The results strongly indicated that clefts with associated malformations are different epidemiological entities from pure clefts. Sex‐ratio reversals occurred for some categories with associated malformations. In contrast to the usual male excess of CL ± P, there was a female excess of CL ± P with major associated malformations. In contrast to the usual female excess of CP, 49% of children with CP with associated malformations were male. No maternal‐age effect was observed for any “pure” cleft category, but significant “U‐shaped” maternal‐age distributions were seen for CL + P with associated major malformations, CP with associated major malformations, and CP with all associated malformations. Increased frequency of low birth weight and infant mortality were confined to categories with associated malformations. No significant birth order, season, secular change, or time–space clustering effects were observed. The incidence rate for all clefts was 1.84/1000 live births.
Further data on the slit‐lid mutant in mice and the effect of cortisone and doca on its development
Authors: Stein Kathryn F. , Kettyle Cynthia Nichols
Published: June 2005

The development of a mutant with eyelids open at birth that appeared in our laboratory was described previously (Stein et al., '67). It differed from similar mutants described in the literature and was called slit‐lids. Later Ricardo and Miller ('67) reported that complementarity tests between our mutant and another, called lid‐gap, indicated they were identical or allelic. They found that cortisone injected prenatally reduced the frequency of the lid‐gap phenotype (also reported by Watney and Miller, '64), but not of the slit‐lid mutants supplied by us. In our hands, however, cortisone did correct the defect in a large proportion of the slit‐lid progeny of injected pregnant females (Stein and Nichols, '68). Further experiments, reported here, confirmed our earlier results, and data from both series are combined in this paper. Injections of a mineralocorticoid, deoxycorticosterone, magnified the defects characterizing the untreated slit‐lid mutant. Histological data have been reviewed and supplemented for comparison with those of Harris and Fraser ('68) who reported no evidence in lid‐gap of the excessive vacuolation of the lens described by us in our mutant, but noted evidence of injurious adhesion of eyelids to cornea. In both respects the slit‐lid mutant appears to differ from lip‐gap.
Dilatation of the urinary tract in fetal rabbits following postcesarean incubation
Authors: Springman Frank R. , Roell Michael G. , Doerr Bruce I.
Published: June 2005

According to the revised guidelines of 1966 of the Food and Drug Administration for reproductie studies in rabbits, Cesarean‐delivered fetuses might be incubated for 24 h as a test of survival. The present experiment indicated that this procedure, followed by fixation of fetuses in Benin's solution, results in apparent dilatation of the urinary tract. Most of the incubated fetuses showed distended bladders (71%) with occasional dilatation of ureters (9.3%) and renal pelves (8.5%) as compared to none in the nonincubated fetuses. An awareness of these induced changes in the urinary tract is important for the investigator, who may construe the observations as a teratogenic effect of a test compound.
Investigations into the teratogenic potential of imperfect potatoes
Authors: Poswillo D. E. , Sopher D. , Mitchell S. J. , Coxon D. T. , Curtis R. F. , Price K. R.
Published: June 2005

To examine the hypothesis that spina bifida and anencephaly are related to the consumption of “blighted” potatoes, feeding trials were conducted in Wistar rats and marrnosets (Callithrix jacchus). Both species were fed “blighted” potato concentrate during early pregnancy. No abnormalities were observed in fetal rats, but cranial osseous defects were found in 4 of 11 fetal marmosets. Further trials were conducted in which concentrates of normal potato, tubers rejected by graders in the food industry; and potatoes infected with Erwinia carotovora were fed to pregnant marmosets under similar conditions. No gross abnormalities were found, but behavioral deficits were observed in 6 of 12 marmosets whose mothers had consumed “industry reject” concentrate. The level of glycoalkaloids was found to be high both in this material and in the original “blighted” potato concentrate. High levels of terpenoids did not appear to be associated with abnormality. Mercury levels were found to be within normal limits. Tests of all samples for cytochalasin activity showed it to be present only in the “blighted” Kerr's Pink concentrate. Analysis of Chloroform extracts of all test concentrates revealed some correlation between the “blighted” Kerr's Pink and the “industry reject” samples. A substance common only to these two groups was found, but its nature remains unidentified. The observation of behavioral defects highlights the need for parameters to test for teratogenic substances in food that may affect the differentiation or maturation of the cerebral cortex; such factors may have great social and political significance.
Are potatoes teratogenic for experimental animals?
Authors: Swinyard Chester A. , Chaube Shakuntala
Published: June 2005

This study was designed to test in experimental animals the hypothesis (Renwick, 1972) that human spina bifida and anencephalus are causally related to maternal consumption of blighted potatoes. Gavaging of pregnant rats with blighted potatoes on days 5–11 or daily ip injections of solanine or glycoalkaloids (5–10 mg/kg) extracted from B5141‐6 potatoes, given on days 5–12 or 7–17 of gestation, resuited in minor skeletal and renal tract abnormalities, but failed to produce neural‐tube defects. Daily injections (days 5–12) of 20 and 40 mg/kg of the glycoalkaloid caused 100% fetal and maternal mortality, respectively. Daily ip injections of 5 mg/kg of solanine into New Zealand White rabbits on days 0–8 of gestation produced abortion in one‐third of the treated animals, 23% resorptions, but no teratogenesis. Single yolk‐sac injections of 5–20 mg/kg of solanine into 20–22 h incubated white Leghorn eggs produced 63–90% mortality within 72 h without significant teratogenesis. Diced B5141‐6 potatoes containing an average of 260 mg of solanine per kg of tuber fed ad libitum to time‐mated rhesus monkeys for a period of 25 days postcopulation produced no maternal toxicity; on the other hand single injections of 40 mg/kg of the glycoalkaloid extract and two injections of 20 mg/kg of solanine killed adults within 48 h of treatment. At autopsy nasal, oral, and periorbital hemorrhage was present; there was accumulation of serosanguinous pleural and peritoneal fluids and mild hepatic and splenic congestion. Examples of human toxicity and mortality from consuming potatoes with a high solanine content are reviewed.
In vivo and in vitro studies of the cytogenetic effects of Cannabis sativa in rats and men
Authors: Martin Patricia A. , Thorburn Marigold J. , Bryant Sybil A.
Published: June 2005

The cytogenetic effects of Cannabis sativa were studied in (a) embryonic rat fibroblasts and rat and human leucocytes exposed to 40–200 μg/ml of cannabis resin in vitro for 6–72 h, (b) embryonic rat cells and leucocytes from pregnant rats exposed to a teratogenic dosage of cannabis resin in vivo, and (c) leucocyte cultures from male Jamaican chronic cannabis smokers. The in vitro experiments showed depression of mitotic rate with increasing doses of cannabis resin. In both in vitro and in vivo studies the experimental groups showed no increase in the percentage of numerical or structural chromosome aberrations. It appears that the reported teratogenic effects of cannabis are not due to chromosome damage though they may be due to mitotic inhibition.
Cleft palate lateral synechia syndrome without the lateral synechia (CP ± LS syndrome)
Authors: Preus M. , Fraser F. C. , Fuhrmann W.
Published: June 2005

A syndrome with cleft palate and unusual facies is described in which cleft palate with or without lateral synechia is associated with a beaked nose, short philtrum, maxillary hypoplasia, downturned mouth with a “pouty” lower lip, broad cheeks, and a short or retroplaced chin. Evidence from a previously reported family suggests autosomal dominant inheritance with variable expressivity. Study of further cases will be needed to determine the range of expression of the syndrome.