bluuebunny/crossref_metadata_2025 huggingface dataset:
Thallium‐induced achondroplasia in chicken embryos and the concept of critical periods during development
Authors: Hall Brian K.
Published: June 2005

Achondroplasia was induced in chicken embryos by in ovo application of 0.6 mg/egg thallium sulfate. The critical (sensitive) period for production of achondroplasia began on day 5 of incubation and ended at the start of HH stage 35 (8.5 days). The end of the critical period was accurately timed and found to be 205–207 hours of incubation and to coincide with a 66% decrease in growth rate of the embryos. Treatment resulted in reduced tibial growth one day later, tibial angulation two clays later, and chondrocytic necrosis four days later. The last was therefore not the cause of the angulation. Tibias were taken from thallium‐treated and control donor embryos of various ages and grafted to the chorioallantoic membranes of treated and control host embryos of various ages during and outside the critical period and achondroplastic changes induced in grafted tibias exposed to thallium while on the chorioallantoic membrane. The critical period was extended into day 10 of incubation in such grafted tibias. Tibias maintained for seven days in organ culture were achondroplastic if pretreated with thallium at seven or eight days of incubation but not at ten days. Exposure of as little as 0.5 hour was sufficient to elicit micromelia when the tibias were grafted or organ cultured. Thallium therefore rapidly binds to skeletal tissues during a critical period of embryonic development but this critical period may be extended when tibias are removed from the embryo.
Cholinomimetic teratogens. V. The effect of oximes and related cholinesterase reactivators
Authors: Landauer Walter
Published: June 2005

Pyridine‐2‐aldoxime methiodide and pyridine‐2‐aldoxime methyl methane sulfonate (P2S), used as supplements to carbachol or neostigmine, greatly lowered the incidence in chicken embryos of vertebral defects and muscular hypoplasia. With 4‐pyridine aldoxime the effect of the teratogens was less reduced. Supplementation of carbachol or neostigmine with either ambenonium or toxogonin lessened the occurrence of muscular hypoplasia, but did little, if anything, to prevent malformation of the neck vertebrae. In tests with physostigmine P2S as supplement reduced or prevented cervical defects, but failed to protect the nicotinamide‐sensitive parts of the embryo.
Possible teratogenic effect of phenothiazines in human beings
Authors: Rumeau‐Rouquette C. , Goujard J. , Huel G.
Published: June 2005

A prospective survey was carried out by the French National Institute of Health and Medical Research (INSERM) in 12 University hospitals in Paris and included 12,764 women; 189 gave birth to babies with unequivocal, nonchromosomally based, malformations. There was a significant excess of malformed infants when women had taken phenothiazines during the first three months after the last menstrual period. This association did not seem due to chance or to bias and coud not be explained by the influence of the outcome of previous pregnancies. These data are to be added to results of recent surveys showing a significant increase of malformations in children exposed in utero to anticonvulsants, carbamates, benzodiazepines, tricyclic antidepressants, and amphetamines.
Teratogenic effects of retinoic acid in pigtail monkeys (Macaca nemestrina) I. General features
Authors: Fantel Alan G. , Shepard Thomas H. , Newell‐Morris Laura L. , Moffett Benjamin C.
Published: June 2005

Daily oral administration of 10 mg/kg retinoic acid to pregnant Macaca nemestrina monkeys on days 20 to 44 resulted in a high frequency of craniofacial and musculoskeletal malformations. Craniofacial defects including cleft palate and anomalies of the pinna were common as were ectrodactyly, kyphosis, and muscular‐joint contractures. Transposition of the great vessels of the heart occurred in one animal and polycystic kidney and associated urogenital anomalies in another. Shorter treatment periods with similar or higher dosages were not teratogenic and were less fetocidal. Although only relatively long treatment courses were teratogenic, the defects that resulted were morphologically similar to those induced with retinoic acid or other vitamin A compounds in other animal orders.
The influence of D‐penicillamine on the proliferation rate of cells from the upper limb bud of mouse embryos in vitro
Authors: Herken R.
Published: June 2005

D‐Penicillamine was given on the fourth day of culture of limb buds from 11‐day mouse embryos at a dose of 100 μg/ml medium and allowed to react for 24 hours. On day 5 there was found a significant decrease in the [3H] thymidine labeling index of cartilage cells and of cells of the perichondrium, whereas mesenchyme cells showed no decrease in proliferation under these conditions. The toxic effects of D‐penicillamine on prenatal skeletal development in vivo could therefore result not only from direct action on collagen but also via inhibition of proliferation of cartilage cells.
The fetal alcohol syndrome in mice: An animal model
Authors: Chernoff Gerald F.
Published: June 2005

CBA and C3H female mice were maintained on liquid diets—Metrecal plus ethanol—containing 15.35% ethanol‐derived calories. These diets, which resulted in alcohol blood levels of 73.398 mg/100 ml blood in nonpregnant females, were the sole sustenance for the females for at least 30 days before and throughout gestation. Females were killed on day 18 of gestation and offspring examined for skeletal and soft tissue anomalies. Prenatal death and maldevelopment increased with the level of alcohol intake. Deficient occiput ossification, neural anomalies, and low fetal weight occurred with low ethanol diets, and cardiac and eyelid dysmorphology with higher ethanol diets. This pattern of mal‐formations, which exhibited both a dose‐response effect and strain differences in susceptibility, indicated that chronic maternal alcoholism is embryolethal and teratogenic in mice.
Ultrastructure of the expected fusion zone in rat fetuses with diazo‐oxo‐norleucine (DON)‐induced cleft palate
Authors: Morgan P. R. , Pratt R. M.
Published: June 2005

The aim of this study was to determine whether the glutamine analog, 6‐diazo‐5‐oxo‐L‐norleucine (DON), which is known to inhibit cell degeneration in rat palatal processes in vitro, exerted a similar effect on cleft palatal processes in vivo. Sprague‐Dawley rats were injected intraperitoneally with 5.0 mg/kg body wt of DON on Day 15 of gestation and fetuses were removed over Days 16, 17 and 18. A high frequency (80–90%) of cleft palate was obtained. Fetal heads were removed on each of the three days and transverse sections of the palatal processes were examined by light and electron microscopy. Results showed that treatment with DON failed to inhibit degenerative changes in the palatal epithelium. The same sequence and timing of ultrastructural changes occurred in the expected fusion zone (EFZ) as have been described previously in cleft palatal processes from Meclozine‐treated and amniotic sac punctured rat fetuses; namely, autophagic cytoplasmic degeneration, loss of basal lamina and the subepithelial accumulation of macrophages all of which were most prominent in that part of the EFZ immediately next to the developing oral epithelium. The results therefore suggest that a teratogenic dose of DON does not interfere with the ultrastructurally observable changes in the EFZ.
Anencephaly in trisomy 18: Related or unrelated?
Authors: Menashi M. , Ornoy A. , Cohen M. M.
Published: June 2005

A fetus of 20 to 21 weeks of development with the trisomy 18 syndrome has been described. In addition to the phenotypic manifestations usually associated with the syndrome, i.e., low set ears, short neck, omphalocoele, flexion of fingers with the convergence of the second and fifth digits, rocker bottom feet, urinary tract anomalies and intrauterine growth retardation, the fetus also showed left diaphragmatic hernia, anencephaly and aplasia of the squamous part of occipital bone.

Since anencephaly has never been described as one of the phenotypic manifestations of trisomy 18, it is reasonable to assume that in the present fetus it is unrelated and resulted from secondary destruction of the neural tube.
Cell degeneration and recovery of the fetal mammalian brain after a chemical insult
Authors: Langman Jan , Cardell Emma Lou
Published: June 2005

In this experiment 12‐day pregnant mice were treated with 5‐fluorodeoxyuridine, an inhibitor of DNA‐synthesis, to examine the influence of the drug on the central nervous system of the embryos. More specifically the sites of cell degeneration, the type of cells affected, and the elimination of cellular debris were investigated.

Approximately two hours after treatment with FUdR, mitotic activity in the neocortex ceased and the first degenerating cells became visible in the outer zone of the neuroepithelial layer, e.g., the DNA‐synthetic zone. During the following 8 to 11 hours degenerating cells increased in number and were seen throughout the neuroepithelial layer, suggesting either that other than DNA‐synthesizing cells were affected or that degenerating cells moved from the outer zone towards the inner zone. Since all dying cells were labeled when tritiated thymidine was given shortly before FUdR treatment, it is concluded that DNA synthesizing cells have moved to the lumen despite blockage of DNA synthesis and degeneration of the nucleus. At 24 hours after treatment all degenerating cells were found in the outer region of the neuroepithelial zone, indicating that they had moved from the inner zone (near the lumen) to the outer region. Hence, the degenerating cells did not remain in the DNA‐synthetic zone, but apparently moved or were pushed from the outer to the inner zone, and vice versa.

When a search was made for cells cleaning up the debris, relatively few macrophages were seen. In addition only a few normal neuroepithelial cells could be identified as containing phagocytosed material. Many degenerating cells apparently were not phagocytosed but underwent lysis, leaving temporarily large holes in the tissue. It is thus suggested that in the embryo the large amount of cellular debris is eliminated mainly by autolysis, partially by macrophages, and also to some extent by neighboring neuroepithelial cells.

Despite the presence of many degenerating cells, a number of mitotic cells were seen 11 hours after treatment, indicating that the drug had ceased to act. During the following 24 hours the neuroepithelial zone is reconstituted, but few if any neuroblasts are formed. Hence, despite the extensive repair which follows the action of a chemical compound, a permanent shortage of neurons results.
T1Wh, a promising mouse strain with chromosomal markers for cleft palate research
Authors: Miller K. K. , Atnip R. L.
Published: June 2005

Attainment of the horizontal position by the secondary palatal shelves and fusion in relationship to morphological and chronological ages in TlWh, an albino strain of mice homozygous for a 5; 19 Robertsonian translocation, was found to be late and slow in comparison to other strains previously investigated. Spontaneous and cortisone‐induced cleft palate frequencies of 3.5% and 100% respectively, were found in this strain. Its slow and late palatal closure, high susceptibility to cortisone, obvious marker chromosomes, and good breeding performance promise to make TlWh a useful strain for cleft palate research.
Differential susceptibility of the embryo to inorganic lead during periimplantation in the mouse
Authors: Wide M. , Nilsson O.
Published: June 2005

The effect of intravenously administered inorganic lead on periimplantation period of embryonic development in the mouse was investigated with light microscopy. Three developmental stages were studied: the attachment of the blastocyst, the invasion of the trophoblast and the formation of the primitive streak. All three stages were affected, but the stage of invasion was found to be the most susceptible to lead as determined by decrease in frequency of animals with normal embryos.
Repair mechanism in the embryonic spinal cord after a chemical insult
Authors: Crowley Karen K. , Geelen Jan A. G. , Langman Jan
Published: June 2005

The purpose of this experiment was to determine the level of mitotic activity of the proliferative population of the central nervous system during and after treatment with 5‐FUdR (a DNA‐synthesis inhibitor) and to examine whether the high mitotic activity seen during the repair phase was used to produce neurons or neuroepithelial cells. Chick embryos were treated with 0.01 μg 5‐fluoro‐2′‐deoxyuridine in 5 μl saline on day 2.5 of incubation and fixed at various time intervals, ranging from 1 to 120 hours after treatment.

In the treated embryos the mitotic activity decreased rapidly two hours after treatment and few if any mitotic figures were seen during the following 12‐hour period. Hence, during this period few if any neuroblasts were formed. In addition, large numbers of neuroepithelial cells died as a result of the treatment, reducing the proliferative neuroepithelial population by about 50%. From 22 to 48 hours after treatment the mitotic index was almost twice that of controls, indicating that large numbers of new cells were formed to compensate for cell losses suffered during the treatment.

When the number of neuroepithelial cells in the treated embryos was counted, it decreased during the first 20 hours after treatment, but thereafter increased rapidly until it reached the control value at about 50 hours after treatment. Hence, the increased mitotic activity was used mainly to increase the depleted neuroepithelial population. The neuroblast population suffered particularly, since no neuroblasts were formed during the initial degeneration phase, and only a restricted number was formed during the repair phase when the mitotic activity was used mainly for the production of neuroepithelial cells.
Congenital anomalies of the central nervous system incidence in British Columbia, 1952‐72
Authors: Trimble Benjamin K. , Baird Patricia A.
Published: June 2005

The records of an ongoing health surveillance registry that utilizes multiple sources of ascertainment were used to study the incidence rates of congenital malformations of the central nervous system in children born in British Columbia during the period 1952‐72. No overall increase in incidence rate of these anomalies was detected over the study period and the total frequency ascertained was three per thousand births. For anencephaly, spina bifida, hydrocephaly, and other CNS anomalies, the estimated incidence rates per 1,000 births are 0.6, 0.8, 1.0 and 0.5 respectively. A greater incidence rate of neural tube closure defects was found in females than in males and this difference was most marked amongst the stillbirths. The data indicate that multiple sources of ascertainment and follow‐up of children beyond one year after birth are necessary for adequate reporting even for these sorts of defects which have generally been thought to be readily recognized at or shortly after birth.
The craniofacial skeleton in anencephalic human fetuses. I. Cranial floor
Authors: Fields Henry W. , Metzner Louis , Garol James D. , Kokich Vincent G.
Published: June 2005

Twelve anencephalic and four normal fetuses 26 to 40 weeks gestational age were compared by anatomic, radiographic and histologic methods in order to gain information concerning morphogenesis. In the anencephalics, alterations located within the body of the sphenoid bone led to a reduced cranial floor angle and a more vertical clivus. The reduced lateral extension of the lesser and greater wings of the sphenoid constricted the anterior and middle cranial fossae respectively. The posterior cranial fossa tended to have an increased transverse dimension related to the supraoccipital and exoccipital bone orientation. The increased anterior and inferior position of the lateral end of the petrous temporal ridge was positively correlated with the degree of dorsal schisis in the anencephalics. Alterations in the size, form, or duration of the neural functional matrix are suggested as the cause of changes in the cranial floor.
Effect of inorganic lead on the mouse blastocyst in vitro
Authors: Wide Mariann
Published: June 2005

In vitro culture of mouse blastocysts over the implantation period was used (1) to find out whether embryos recovered from uteri of mice given an injection of lead, which has been shown in a previous study to inhibit implantation in vivo, were capable of attachment and outgrowth when transferred to a lead free culture medium; (2) to study the effect of different amounts of inorganic lead in the culture medium on blastocyst viability and ability to attach and grow out. The levels of lead used in the medium were comparable to those found in uterine tissue of animals given an implantation inhibiting dose of lead. It was found that the preimplantation blastocyst was unaffected by the administration of lead to the mother as regards the ability to attach and grow out. It was also shown that normal blastocysts were adversely affected by the presence of lead in the culture medium. Addition of increasing amounts of inorganic lead (5, 10 and 20 μmol/l) caused a corresponding decrease in the ability of the blastocysts to attach and grow out, the highest concentration also causing abnormal appearance of the embryos within 48 hours of culture.
Hemorrhagic necrosis of the central nervous system of fetal hamsters: Litter incidence and age‐related pathological changes
Authors: Young Stuart , Keeler Richard F.
Published: June 2005

The occurrence, anatomic distribution, and character of lesions of spontaneous hemorrhagic necrosis (SHN) are reported in each hamster fetus of/two affected litters examined on the fifteenth day of gestation and in selected individuals of other affected litters on the twelfth, thirteenth, and fourteenth days of gestation. The pathologic process seems primarily to affect the capillary vasculature of the central nervous system and shows a predilection for rapidly growing and differentiating regions of the fetal forebrain, thalamus, and brain stem. Lesions demonstrable in members of affected litters of susceptible stocks are of a progressive character, increasing both in severity and topographic extent with increasing fetal age and growth. Spontaneous patterns of regression and recurrence of SHN disease in susceptible stocks may reflect variable physiologic factors in the intrauterine environment.
Congenital deformities produced in hamsters by potato sprouts
Authors: Keeler Richard F. , Young Stuart , Brown Dennis , Stallknecht Gilbert F. , Douglas Dexter
Published: June 2005

Dried ground potato sprout preparations from seven varieties produced congenital deformities in one strain of hamsters. Incidence of affected litters varied from 8 to 25%, depending on potato variety. Certain steroidal solanum and veratrum alkaloids produced similar defects. Neither peel nor tuber material was teratogenic from one of the potato varieties with highly teratogenic sprouts.
Effects of salicylamide and protein restriction on the skeletal development of the rat fetus
Authors: Knight Enid , Roe Daphne A.
Published: June 2005

Salicylamide has previously been shown to be teratogenic to the rat. Aims of the present study were to examine separate effects and interactions of salicylamide administration and protein restriction on development of the rat fetus. In experiments using Holtzman rats, the percentage of fetal resorptions was significantly increased by drug treatment and by protein restriction. Malformations were seen in fetuses from dams given the drug from the fifth to eleventh days of gestation; the incidence of these malformations being independent of the diet. Factors affecting appearance of ossification centers included drug dosage, placental and fetal weight and litter size. Protein restriction had no significant effect on the development of centers of ossification.

It is concluded that salicylamide, as well as protein restriction, produces adverse effects on pregnancy outcome in the rat.
Limb development in mouse embryos. II. Reduction defects, cytotoxicity and inhibition of DNA synthesis produced by cytosine arabinoside
Authors: Kochhar D. M. , Penner John D. , McDay Jane A.
Published: June 2005

Various morphological and biochemical parameters were used to study the mode of interference by cytosine arabinoside (Ara‐C) in critical phases of embryonic limb development. Inhibition of embryonic DNA synthesis occurred immediately after injection of Ara‐C into the mother. The inhibition was dose‐dependent and was substantial even after the nonteratogenic dose (2 mg/kg) of Ara‐C. The pattern of limb bone deficiencies in Ara‐C treated fetuses was specific for each developmental stage at which the treatment was given; the site of affect moved distalwards along the limb as the development advanced. The teratogenic dose was cytotoxic to mesenchymal cells with a high proliferation rate but did not affect others such as the future cartilage cells in which the rate of proliferation was lower. The existence of this differential susceptibility at each stage of development, together with information about the pattern of bone defects at the same stage, permitted us not only to define with some precision the cellular basis of origin of limb defects but also to infer the relative level of cell differentiation pertaining to each successive stage.

Deoxycytidine, if injected simultaneously with and at doses eight times larger than Ara‐C, afforded virtually complete protection against teratogenic effects. Deoxycytidine also prevented cell death in the limbs of Ara‐C treated embryos. However, a dramatic increase in the frequency of polydactyly was found in the protected fetuses. The fact that the frequency of ectrodactyly in the protected fetuses decreased in inverse proportion to the frequency of polydactyly strengthened the notion that there may be a common cellular basis underlying these two types of digital defects.

Striking changes were found in the structure of AER at 24 hours after Ara‐C treatment; it was abnormally thickened into a gland‐like structure and its inner edge facing the mesenchyme was thrown into several folds. This may constitute a response to impairment in the underlying mesenchyme with which AER has long been considered to have an interdependent relationship.
Investigation of the effect of hydroxyurea on the cell cycle and the development of necrosis in the embryonic CNS of mice
Authors: Herken R. , Merker H.‐J. , Krowke R.
Published: June 2005

On day 10 of gestation pregnant mice (strain NMRI) were given an intravenous injection of 500 mg/kg Hydroxyurea (HU). Simultaneously either 5 μCi/g or 10 μCi/g 3H‐thymidine (3H‐Tdr; specific activity 5 Ci/mmol) was administered to the animals. At various times after treatment embryos were removed, sectioned and prepared for autoradiography, light microscopy and electron microscopy. Two hours after administration of HU condensations of the chromatin structure could be detected electron microscopically in some cells. Thirty minutes later the nucleolus became smaller and denser, the cytoplasm shrank, and the cell organelles moved closer together. Three hours after application of the drug break‐down of the involved cells set in. As in the autora‐diograms about 98% of the counted necroses were labelled, and since labelled thymidine is almost exclusively incorporated during the S‐phase, it can be stated that HU influences only metabolic processes which take place during the S‐phase. From the morphological findings it can be concluded that in the case of the S‐phase‐specific metabolic pathway, which is influenced by HU, we are primarily dealing with DNA synthesis.
Biochemical aspects of the interactions of the teratogens 5‐fluorouracil and 5‐fluorodeoxyuridine with normal nucleic acid precursors in mice selected for low and high expression of Strong's luxoid gene
Authors: Forsthoefel Paulinus F. , Blend Michael J. , Snow June W.
Published: June 2005

Pregnant female mice selected for plus‐ and minus‐modifying genes of the limb‐skeleton effects of Strong's luxoid gene (1st) were injected ip on day 10 of gestation with 20 mg/kg of 14C‐labeled 5‐fluorouracil (FU) or 5‐fluorodeoxyuridine (FUdR) with or without added equimolecular amounts of unlabeled uracil (U) or thymidine (TD). At 1, 2, or 4 hours after injections, the treated mice were killed and their plasma, livers, embryos, and extraembryonic tissues removed. TCA‐soluble, RNA, DNA, and protein fractions were separated from the tissue samples and the radioactivity of each fraction determined.

Label was incorporated into the RNA of all materials but only into the DNA of embryos. The addition of U to FU and of TD to FUdR increased the retention of FU in the TCA‐soluble fraction and the incorporation of FU into RNA. The radioactivity of the TCA‐soluble fraction declined rapidly over the entire 4‐hour sampling period, while the level of incorporation of FU into RNA of embryos and extraembryonic tissues showed large increases. No effects of 1st or of its modifiers on the biochemical parameters investigated were found.

These results provide some understanding of the biochemical pathways for the teratogenicity of FU and FUdR and the effects of added U and TD.
The effect of hypervitaminosis A on rat palatal development
Authors: Lorente Carol A. , Miller Sanford A.
Published: June 2005

Retinoic acid or retinyl acetate was administered to pregnant rats in doses sufficient to induce a 90% incidence of cleft palate. In another study, a delay in the reorientation of the palatal shelves was observed to be longer with the more potent teratogen, retinoic acid. On day 16 of gestation, 24 hours after final dosage with vitamin A, the synthesis of DNA and protein was studied in fetal carcass, mandible, and palate, and that of sulfated mucopolysaccharides (S‐MPS) and glycoproteins (GP) in fetal head, mandible, and palate. Increases in DNA synthesis in fetal palate and in GP synthesis in fetal palate were found; thus, the mechanism of action of vitamin A in inducing cleft palates in rats may be caused by interference with the normal biochemical synthetic pattern of the palatal shelves.
Teratogenic potential of ethanol in mice, rats and rabbits
Authors: Schwetz B. A. , Smith F. A. , Staples R. E.
Published: June 2005

Pregnant CF‐1 mice, Sprague‐Dawley rats and New Zealand white rabbits were given 15% ethanol in their drinking water during the period of major organogenesis, from day 6 through 15 of gestation in mice and rats and days 6 through 18 of gestation in rabbits. Maximum blood alcohol levels, measured in non‐pregnant animals, were about 200 mg percent in mice and 25–50 mg percent in rats and rabbits. Maternal toxicity in the form of decreased liquid intake and decreased maternal body weight occurred in all species during the experimental period. A significant increase in the incidence of external or soft tissue alterations was not observed in the alcohol‐exposed groups of any species, but a significant increase in minor skeletal variants was observed in mice and rats. These were probably due to retarded fetal growth rather than to a specific effect of the ethanol. Teratogenic effects were not observed in any of the three species.
Folate antagonism following teratogenic exposure to diphenylhydantoin
Authors: Netzloff Michael L. , Streiff Richard R. , Frias Jaime L. , Rennert Owen M.
Published: June 2005

Previous studies have reported indirect evidence for the mediation of folate antagonism in the induction of malformations by diphenylhydantoin. We have demonstrated that a teratogenic regimen of folate‐deficiency and antagonism using 9‐methyl PGA in the rat produces significantly decreased rates of oxygen consumption in the maldeveloping embryos. The present study reports similar reductions in oxygen uptake by mouse embryos from mothers treated with teratogenic doses of diphenylhydantoin, and documents a significant depression of the actual folate levels in such embryos. The differences are less significant with lower doses of diphenylhydantoin, and do not occur with a nonteratogenic dose.
An aberrant nucleus in the telencephalon following administration of ENU during neuroembryogenesis
Authors: Hallas Brian H. , Das Gopal D.
Published: June 2005

Administration of ENU to rats during embryonic development caused the emergence of aberrant nuclei in the dorsal telencephalon. They were located in the corpus callosum, and were composed of pyramidal and stellate neurons. This suggested that the aberrant nuclei arose out of the neurons of cerebral cortex that had failed to migrate during embryogenesis. The aberrant nuclei were found predominantly in the animals receiving ENU on day 18 or earlier of gestation.
A potential mechanism in medroxyprogesterone acetate teratogenesis
Authors: Kimmel G. L. , Hartwell B. S. , Andrew F. D.
Published: June 2005

Medroxyprogesterone acetate (MPA) has been shown to be teratogenic in rabbits but not in rats or mice (Andrew and Staples, 1977). Since normal steroid action appears to be mediated, in large part, through interaction with specific steroid receptors, we postulated that the species difference in teratogenicity might be due to a difference in the interaction of MPA with target cells. A primary event in steroid‐cell interaction is the binding of a steroid to intracellular receptors. Studies were initiated to measure the specific nature of MPA binding to glucocorticoid and progestin receptors in appropriate rat and rabbit target tissues. The competition of MPA with 3H‐dexamethasone binding in liver cytosol (glucocorticoid receptor) and with 3H‐progesterone binding in uterine cytosol (progesterone receptor) was determined. In rabbit liver cytosol MPA was as effective at competing for specific dexamethasone binding as the natural glucocorticoids and considerably more effective than the nonspecific steroids. In rat liver cytosol; MPA was only 10% as effective as the natural glucocorticoids, and the competition could not be distinguished from that of nonspecific steroids. A similar species difference was not seen in uterine cytosol MPA competed with progesterone in a similar fashion in both rat and rabbit. These data demonstrate a distinct species difference in the competitive nature of MPA for the glucocorticoid receptor but not for the progestin receptor. The results suggest that MPA, or possibly a metabolite, may be teratogenic in rabbits by binding with specific glucocorticoid receptors to inhibit or alter normal steroidal function in embryo‐fetal development.
Genetic independence of the embryonic reactivity difference to cortisone‐ and 6‐aminonicotinamide‐induced cleft palate in the mouse
Authors: Biddle F. G. , Fraser F. C.
Published: June 2005

The A/J strain of mice is more reactive than C57BL/6J to both cortisone‐ and 6‐aminonicotinamide‐induced cleft palate. A breeding study was set up to determine the genetic control of the differences in embryonic reactivity between the two strains to the two teratogens. In this paper the test for possible association between the two response traits is presented. In the second‐backcross generation of embryos where segregation of the two traits could be studied no association was found. Therefore, any embryonic genes making major contributions to differences in reactivity between the two strains are not the same for the two teratogens.
Influence of drinking water–tap versus purified–on embryo and fetal development in mice
Authors: Staples R. E. , Worthy W. C. , Marks T. A.
Published: June 2005

Pregnant CD‐1 mice drank either chlorinated tap water obtained at NIEHS from the City of Durham, North Carolina municipal water supply or this same water passed in sequence through an organic removal cartridge and a demineralizer, followed by glass distillation. No significant overall differences in the reproductive status of pregnant mice were noted wnen the two groups were compared. Similarly, no significant overall influence on the incidence of malformed fetuses could be traced to the purity of drinking water. Month by month comparisons indicated that there were three statistically significant differences; all of which indicated improved performance for the mice that drank tap water. When the results for both groups were combined and a month by month comparison was made there was a significant difference in the pregnancy rate for February (68%) as compared with an overall pregnancy rate of 80% and a 79‐93% spread for the other months, but the decrease was due to the low incidence of pregnancy in the group that drank the purified water.
Cytogenetics of extragonadal tumors
Authors: Kaplan Cynthia G. , Askin Frederic B. , Benirschke Kurt
Published: June 2005

Tissue from six human extragonadal teratomas was obtained for cytogenetic study. These included two gluteal lesions in infant females, and one each of thyroid, mediastinal, sacral and gastric teratomas in males. Tissue culture characteristics indicated tumor growth. All tumors, except the mediastinal lesion showed the presumed karyotype of its host, XX or XY. The mediastinal mass was tetraploid XXYY and contained an X chromatin body and double Y bodies.

Our data support the concept that extragonadal teratomas in males and females arise mitotically from diploid cells and are more similar to identical twins. No heterosexual (XX) tumors were seen in males which would be expected in parthenogenetic tumors. The sex chromatin positive tumors seen in earlier studies may have resulted from polvploidy. Thus, male and female extragonadal teratomas have a different origin from the postmeiotic ovarian teratomas.
Influence of various levels of hypervitaminosis A and zinc deficiency on teratogenesis and DNA synthesis in the rat
Authors: Eckhert Curtis D. , Hurley Lucille S.
Published: June 2005

Administration of excess vitamin A during gestation results in gross malformations of the fetus. It has been proposed that the mechanism of action of vitamin A in producing malformations is through a reduction in DNA synthesis and altered cellular differentiation. A similar mechanism has been suggested for the teratogenic effect of zinc deficiency. The simultaneous treatment of pregnant rats with excess vitamin A (3,000 or 30,000 IU/day) and low dietary zinc (0.4 or 9 ppm) resulted in a high incidence of fetal malformations from each treatment with no discernible interaction. Both treatments resulted in brain deformities, but zinc deficiency caused a higher incidence of lung and tail malformations and a general reduction in the uptake of 3H‐thymidine into embryonic DNA. The administration of excess vitamin A resulted in a higher incidence of fetal eye and palate anomalies than did zinc deficiency but had no effect on DNA synthesis. The lack of interaction between the treatments with regard to fetal malformations, the differences in the types of organs which were affected by the two treatments, and the reduction in DNA synthesis by zinc deficiency but not by vitamin A excess suggest that these conditions alter development through different mechanisms.
Teratologic evaluation of synthetic Δ9‐tetrahydrocannabinol in rabbits
Authors: Sofia R. Duane , Strasbaugh Julianna E. , Banerjee Bhola N.
Published: June 2005

Synthetic Δ9‐tetrahydrocannabinol (THC) was dissolved in undiluted propylene glycol and administered in daily subcutaneous doses of 15.0, 30.0 or 60.0 mg/kg to pregnant New Zealand white rabbits on days 7–19 of gestation. Maternal food consumption and weight gain were markedly reduced at all dose levels. Embryotoxicity and embryocidal effects were observed in the form of reduced litter weight and number of viable fetuses, respectively, in offspring from pregnant mothers treated with THC. However, on the basis of extensive external, visceral and skeletal examination of all fetuses it may be concluded that THC is not teratogenic in the New Zealand white strain rabbit following subcutaneous administration of doses as high as 60.0 mg/kg/day during the critical period of organogenesis (days 7–19 of gestation). On the other hand, an oral dose of thalidomide (200.0 mg/kg/day), the positive control used in this study, was both embryocidal and teratogenic.
Is there a fetal gasoline syndrome?
Authors: Hunter Alasdair G. W. , Thompson Diane , Evans Jane A.
Published: June 2005

Two children from a small Amerindian community presented with profound retardation, initial hypotonia progressing to hypertonia, scaphocephaly, a prominent occiput, poor postnatal head growth, and additional minor anomalies. Abuse of gasoline by inhalation was a widespread problem in the community, and gasoline inhalation during the pregnancy could be documented in both of the pregnancies. We are raising the question as to whether inhalation of gasoline during pregnancy may be teratogenic in humans.
Interference of lead with implantation in the mouse: A study of the surface ultrastructure of blastocysts and endometrium
Authors: Wide Mariann , Nilsson B. O.
Published: June 2005

Implantation chambers, trophoblast and uterine luminal surfaces were examined on days 5 and 6 of pregnancy by electron microscopy in mice with implantation failure due to an intravenous injection of 75 ppm of lead chloride on day 4. Attachment of the trophoblast cells to the surface of the endometrium and closure of the uterine lumina had failed to occur. Uterine epithelial cells in implantation chambers and along the lumina were covered with abundant microvilli. This appearance is similar to that seen in mice in experimental delay of implantation before the oestrogen‐induced attachment of the blastocyst has occurred. It may therefore be assumed that lead has in some way interfered with the activity of ovarian steroid hormones on the endometrium. No significant changes were observed in surface ultrastructure of the blastocysts from the lead‐treated and control groups.
Role of vitamin E in the etiology of spontaneous hemorrhagic necrosis of the central nervous system of fetal hamsters
Authors: Keeler Richard F. , Young Stuart
Published: June 2005

The intraperitoneal inoculation of pregnant hamsters with vitamin E during the first half of gestation reduced the severity or eliminated the occurrence of grossly observable effects of spontaneous hemorrhagic necrosis (SHN) of the central nervous system in their offspring and improved the pre‐weaning viability of their litters. The addition of corn oil (16%) or linoleic acid (8%) to a ration associated with the occurrence of SHN in fetal hamsters enhanced the incidence and severity of the disease, and these effects were moderated by inoculation of the dams with vitamin E.

Experimental data indicated that, among multifactorial contributions to the cause of SHN in hamsters, vitamin E availability and levels of dietary polyunsaturated fatty acid played a significant and interrelated role.
Differences in maternal age‐specific rates of down syndrome between Jews of European origin and of north African or Asian origin
Authors: Hook Ernest B. , Harlap Susan
Published: June 2005

Rates of Down syndrome in livebirths in West Jerusalem in 1964‐1975 were studied in relation to the mother's continent of birth or, if she was born in Israel, to the maternal grandfather's continent of birth. In women of European origin the crude livebirth rate of Down syndrome was 1.3 per 1,000 livebirths. This crude rate and the maternal age‐specific rates in this group were very close to those observed in a Swedish study and two studies of white livebirths in the United States. For West Jerusalem women of North African or Asian origin the crude rate was about 2.4 per 1,000 livebirths, and at all maternal ages except the youngest their rates were higher than for women of European origin. The summary adjusted relative risk for a Down syndrome livebirth for all those of North African or Asian origin, compared to those for women of European origin, was about 1.56. If attention is restricted to mothers born outside of Israel, the adjusted relative risk for mothers born in Europe, the Americas or English speaking countries of the British commonwealth compared to those born in North Africa or Asia was 1.97, consistent with a two‐fold difference in the likelihood of a Down syndrome livebirth between these two groups. To our knowledge this is the first report of ethnic differences in maternal age specific rates of Down syndrome that cannot be plausibly explained by differences in ascertainment.
The interaction of cadmium‐binding proteins (Cd‐bp) and progesterone in cadmium‐induced tissue and embryo toxicity
Authors: Wolkowski‐Tyl Rochelle , Preston Susan F.
Published: June 2005

Previous work indicates that a dimer of Cd‐thionein (Cd‐bp‐D, 19,000 MW) is involved in the hereditary resistance to Cd‐embryotoxicity seen in the inbred NAW/Pr (NAW) mouse strain. Cd‐bp‐D is not detected in virgin females after Cd exposure and is detected only after the first 24 hours of exposure to Cd in an inbred strain (C57BL/10ChPr) susceptible to Cd‐induced em‐bryotoxicity (Wolkowski, 1974; Wolkowski‐Tyl, 1978). Since progesterone (P) is critical for maintenance of pregnancy in mice, we have studied the possible relationship between this hormone and Cd‐bp‐D production. As a model system, we examined effects of Cd treatment on Cd‐bp synthesis in NAW males. It was anticipated that this model could provide information bearing not only on the relationship between P and Cd‐bp‐D production, but also on that between Cd‐bp‐D and Cd toxicity, since a single sc injection of CdCl2 causes typical testicu‐lar hemorrhagic necrosis in NAW males, and these animals make only metallothionein and not Cd‐bp‐D. NAW males were, therefore, given P (0.1 g/Kg bw) and then exposed to Cd. Sephadex gel chromatography (G‐200) of liver cytosol from animals killed 24 hours later detected only Cd‐bp‐D. Testes of these males did not show hemorrhagic necrosis. Since the adrenals of male mammals release P in response to stress, NAW males were stressed by repeated sesame oil or propylene glycol injections (5 ml/Kg bw), or the adrenal was stimulated directly with injections of ACTH (100 IU/Kg bw) for seven days prior to Cd exposure. All methods tested which significantly elevated serum P levels (as confirmed by radioimmunoassay), also resulted in production of Cd‐bp‐D and absence of testicular hemorrhage in Cd‐treated NAW males. Suppression of P release by injection of dexamethazone or corticosterone or by adrenalectomy resulted in testicular hemorrhage and production of only metallothionein after Cd exposure. The relevance of the interaction between P, Cd‐bp‐D and protection against Cd‐induced toxicity seen in the model system was supported by analysis of serum P levels in pregnant females; elevated levels were seen in resistant NAW dams on day 10 of gestation and significantly lower levels seen in dams from a Cd‐sensitive strain.
Teratogenic potential of dichlorvos given by inhalation and gavage to mice and rabbits
Authors: Schwetz B. A. , Ioset H. D. , Leong B. K. J. , Staples R. E.
Published: June 2005

Dichlorvos (2,2‐dichlorovinyl dimethyl phosphate) is an important organophosphate insecticide and anthelmintic with widespread use. The purpose of this study was to evaluate the teratogenic potential of dichlorvos given orally at the maximum tolerated dose to mice (60 mg/kg/day) and rabbits (5 Mg/kg/day) and by inhalation in both species at a concentration of 4μg/l seven hours daily. Dichlorvos was not found to be teratogenic in either species bv either route of administration.
The survival and implantation of mouse blastocysts at varying degrees of reduced atmospheric pressure
Authors: Blackburn R. O. , Clegg E. J.
Published: June 2005

Pregnant mice were exposed to reduced atmospheric pressures ranging from 630 to 390 mm Hg during the pre‐implantation and implantation periods and the numbers of embryos surviving 85 hours post coitum compared with those in litter‐mate controls. Even at a pressure of 630 mm Hg (  1,550 mm Hg) there was a significant fall in numbers of normal blastocysts and rise in abnormal forms before implantation, and implantation sites were reduced in number. The numbers of abnormal forms increased and implantation sites decreased at lower pressures, suggesting strongly that the hypoxia of reduced atmospheric pressure was responsible for the abnormalities observed.

The pre‐implantation period appears to be one during which the fertilised ovum is at particular risk, both of hypoxic damage and of failure to implant. Implantation may afford a degree of protection against hypoxia.
Teratogenic effects of external egg applications of methyl mercury in the mallard, Anas platyrhynchos
Authors: Hoffman David J. , Moore John M.
Published: June 2005

The embryotoxic potential of external applications of methyl mercury on mallard eggs was investigated to assess the possible impact of mercury transferred from the plumage of effluent‐contaminated aquatic birds to their eggs. Eggs were treated on day 3 of development with microliter applications of methyl mercury that was dissolved with ethyl acetate into an aliphatic hydrocarbon vehicle. Mercury analysis by atomic absorption indicated that almost half of the mercury applied entered the eggs past the shell membranes within several days of treatment. Most mortality occurred within this period at doses of 9 μg of mercury per egg or higher. Decreased embryonic growth resulted with similar doses. A significant incidence of malformations occurred at a dose of 1 μg per egg. These malformations were mainly minor skeletal aberrations and incomplete ossification. With higher doses of mercury, defects included gross external ones such as micromelia, gastroschisis, and eye and brain defects. Application of the aliphatic hydrocarbon vehicle did not result in any of these defects.
Diazepam‐induced cleft palate in the Mouse: The role of endogenous maternal corticosterone
Authors: Barlow S. M. , Knight A. F. , Sullivan F. M.
Published: June 2005

The aims of the experiments were to investigate the effects of diazepam treatment on day 14 of pregnancy in the mouse on endogenous maternal plasma corticosterone levels and induction of cleft palate (CP) in the offspring, and to evaluate any interaction between diazepam and stress‐induced or corticosterone‐induced CP. Sub‐teratogenic doses of diazepam (10 mg/kg orally, given t ice 12h apart) had no significant effect on the induction of CP by 24h maternal food deprivation. Similarly, neither sub‐teratogenic doses (10 or 50 mg/kg, given twice) nor teratogenic doses (100 mg/kg, given twice) of diazepam had any significant effect on the induction of CP by exogenous corticosterone given at low (2.5 mg) or high (10 mg) doses. However, diazepam alone (10‐400 mg/kg) raised endogenous plasma corticosterone levels in a dose‐related way. Mice given teratogenic doses of diazepam, 100 or 200 mg/kg, causing 3‐6% CP, sustained elevated endogenous corticosterone levels for at least 6h after dosing, in comparison with sub‐teratogenic doses of diazepam or vehicle controls. In a comparison of mice given 400 mg/kg diazepam, causing 20% CP, with mice given 2.5 mg corticosterone, causing 25% CP, the mean endogenous corticosterone level was lower in the diazepam group at 1h but higher at 6h after dosing than that of the exogenous corticosterone group. These results suggest that diazepam may cause CP in the mouse by raising endogenous maternal corticosterone levels. The stress of fasting and immobilisation resulting from the heavy sedation caused by teratogenic doses of diazepam may contribute to the elevations in endogenous corticosterone levels.