bluuebunny/crossref_metadata_2025 huggingface dataset:
Studies on metabolism and identification of the causative agent in aspirin teratogenesis in rats
Authors: Kimmel Carole A. , Wilson James G. , Schumacher Herbert J.
Published: June 2005

Pregnant Wistar rats treated orally at day 9, 10, or 11 with 250, 500, 750, or 1000 mg/kg aspirin showed a teratogenic dose‐response relation at each treatment time, but a decreased overall embryonic susceptibility as treatment was applied later in gestation. The types of abnormalities produced generally correlated with the state of development at the time of treatment. Treatment of animals at day 9 with 510 mg/kg benzole acid and 2 hours later with 250 or 500 mg/kg aspirin caused a significant increase in percentage of malformations above effects observed after 250 or 500 mg/kg aspirin alone. Determination of free salicylate in embryos and maternal serum after treatment at day 11 with sodium salicylate with or without benzoic acid pretreatment indicated that benzoic acid significantly increased the concentration of salicylate in both embryos and serum 6 and 12 hours after salicylate treatment and throughout the observed period. Thin‐layer chromatography of tissues from these animals revealed only salicylic acid in both embryos and maternal serum, thus implicating salicylic acid as the causative agent in aspirin teratogenesis.
Teratogenic action of acetazolamide in golden hamsters
Authors: Layton W. M.
Published: June 2005

The carbonic‐anhydrase inhibitor acetazolamide was teratogenic for golden hamsters when given in single intraperitoneal doses of from 300‐1200 mg/kg on the 9th day of pregnancy. Most deformities were of the postaxial part of the forelimb. There was a well‐defined dose‐response relation with an ED50 of 695 mg/kg. A sensitive period was demonstrated from 192–210 hours after mating with a peak at 204 hours. The production of this deformity was not associated with a significant embryonic mortality. Acetazolamide is quite specific in that in addition to hand deformities only a few foot deformities and rare cases of exencephaly were produced. In contrast to rats, where acetazolamide‐induced deformities are almost exclusively of the postaxial portion of the right forelimb, the deformity in hamsters occurred in either forelimb, although when a single hindfoot was malformed it was always the left one. The demonstrated sensitive period is during the time of limbbud formation, and the first external signs of deformity were seen as a flattening of the postaxial margins of the limb bud 24 hours after drug administration. The mechanism of action of acetazolamide is not clear since the teratogenic dose probably exceeds the amount needed for complete inhibition of carbonic‐anhydrase activity. The dose needed is also much greater than that used for human therapy, so it does not appear that this drug is a teratogenic hazard for human beings.
Teratogenic effects of methamphetamine in mice and rabbits
Authors: Kasirsky Gilbert , Tansy Martin F.
Published: June 2005

Pregnant CFI mice and New Zealand White rabbits were given methamphetamine hydrochloride intravenously during days 9–15 and 12–30 of gestation, respectively. Offspring of mice given 5.0 mg/kg on days 9–15 of gestation had less than 2% anomalies. When 10.0 mg/kg were given on days 9–15, a 13.6% incidence of anomalies was observed. Offspring of rabbits receiving 1.5 mg/kg of methamphetamine on days 12–15, 15–20, and 12–30 of gestation showed an incidence of fetal anomalies of 12, 4, and 15.5% respectively. Offspring sired by treated males showed no significant weight change and had no increased anomaly rate.
Effects of fasting and insulin on skeletal development in rats
Authors: Hannah Richard S. , Moore Keith L.
Published: June 2005

Acute hypoglycemia was produced in pregnant Holtzman rats, by fasting or fasting plus insulin injections. Rats were fasted for 48 hours beginning on days 7, 9, or 11 of gestation. Examinations of day‐21 fetuses showed that greatest susceptibility to the effects of fasting occurred during gestation days 9 and 10. The effects noted were retarded ossification of the axial skeleton and increased frequency of supernumerary ribs, duplicated vertebral centra, and asynchronous ossification of vertebral centra. Insulin administered during the fasting state produced no further decrease in the ossification rate, but the frequency of supernumerary ribs and duplicated vertebral centra was increased.
Lupin alkaloids from teratogenic and nonteratogenic lupins. II. Identification of the major alkaloids by tandem gas chromatography‐mass spectrometry in plants producing crooked calf disease
Authors: Keeler Richard F.
Published: June 2005

The major alkaloids of lupin plants producing crooked calf disease were identified by tandem gas chromatography‐mass spectrometry and infrared analysis. The gas chromatography peak invariably present in teratogenic plants proved to be anagyrine. A minor but irregular contaminant of the peak was α‐isolupanine. Other alkaloids present but apparently not associated with crooked calf disease were lupanine and two others that were probably epimethoxylupanine and 5,6‐dehydrolupanine.
Teratogenic activity of 2‐amino‐1,3,4‐thiadiazole hydrochloride in Wistar rats and the protection afforded by nicotinamide
Authors: Beaudoin Allan R.
Published: June 2005

Pregnant Wistar rats were each injected once ip with various doses of 2‐amino‐l,3,4‐thiadiazole hydrochloride (ATDA) at days 1–16 of gestation (sperm day = day 0). The optimal teratogenic dose was determined to be 100 mg/kg and this dose was employed throughout the experiment. At autopsy at day 20 resorptions and malformations were found in all litters from treated females. Two periods of increased embryonic susceptibility to the lethal effects of ATDA were observed. The first at day 5 (100% resorbed) and the second at days 9 and 10 (71.5 and 92.5% resorbed). Periods of increased sensitivity to the teratogenic action of ATDA were at days 9 through 13, when the incidence of abnormal fetuses produced exceeded 90%. The major malformations were anophthalmia, microphthalmia, hydrocephalus, short tail, taillessness, ectrodactyly, syndactyly, and cleft palate. Other malformations occurred occasionally. The malformations were related to the developmental stage at the time of treatment. Supplemental treatment with nicotinamide at days 5, 11, 12, and 13 markedly diminished the teratogenic and lethal effects of ATDA, and at day 11 the administration of nicotinamide completely abolished its teratogenic activity. ATDA probably acts by interfering with NAD‐dependent enzyme reactions.
Alkaline phosphatase activity in fetal hind limbs of the mouse mutation brachypodism
Authors: Krotoski Danuta M. , Elmer William A.
Published: June 2005

A reduction in alkaline phosphatase activity was demonstrated histochemically and biochemically in the hind limbs of brachypod fetal mice. Seventeen‐day brachypod tibias had a 2–3‐fold lower alkaline phosphatase activity than controls of a similar age. In mutant femurs of this age the decrease in activity was as much as 3–4‐fold. Brachypod fibulas never demonstrated enzyme activity in the stages studied. The enzyme from mutant limb tissues showed the same kinetics, thermal stability, and electrophoretic mobility as that from non‐mutant tissues. Embryo extract from 13‐day brachypod mice, reported to inhibit the growth of normal rudiments in vitro, had no effect on the activity of the normal enzyme. It is proposed that the reduction in enzyme activity is a secondary effect related to the disruption and retardation of limb development in the mutant.
Correlation of teratogenicity and molecular structure: Ethylenethiourea and related compounds
Authors: Ruddick Joseph A. , Newsome W. H. , Nash L.
Published: June 2005

Sixteen compounds related to ethylenethiourea and to its parent compound, ethylenebisdithiocarbamate, were investigated to determine the structural requirement for teratogenicity. Modifications of the molecular structure of ethylenethiourea involved altered ring size and added heteroatoms and substituents. Only ethylenethiourea and 4‐methylethylenethiourea were teratogenic, indicating that teratogenicity was intimately linked with the imidazolidinethione structure.
Phenotypic expression of lethal chromosomal anomalies in human abortuses
Authors: Bouié Joëlle , Philippe Emile , Giroud Antoine , Boué André
Published: June 2005

From anatomical and cytogenetic studies of 1500 spontaneous abortuses attempts were made to establish correlations between the phenotype and karyotype of the specimens. The criteria used to determine the phenotype were based on estimated developmental age and macroscopic and microscopic examinations of embryo and placenta. Main features were described permitting, on anatomic examination of the conceptus, diagnosis of genetic anomalies, and in some instances possibly assigning the type of chromosomal aberration: viz., in monosomy X, triploidies, tetraploidies, and some trisomies. Phenotypic expression at the cellular level was studied by morphometry of the placenta and by study of in‐vitro growth characteristics of cells lines initiated from aneuploid embryos. Study of growth rate characteristics may reveal the basis for the pathogenesis of developmental arrests.
Placental morphology in spontaneous human abortuses with normal and abnormal karyotypes
Authors: Honore Louis H. , Dill Frederick J. , Poland Betty J.
Published: June 2005

A systematic gross and microscopic study of the placenta was done on human spontaneous abortions, correlating placental morphology and karyotype of the conceptus. Consistent abnormalities were seen in the four major forms of human heteroploidy, so that a fairly accurate “karyotypic diagnosis” could be made from careful gross and microscopic examination of the aborted material. Depressed growth activity and dysmorphogenesis characterized these placentas, reflecting placental participation in the disturbed phenotypic expression of heteroploidy.
The multifactorial/threshold concept—uses and misuses
Authors: Fraser F. C.
Published: June 2005

The common congenital malformations have familial distributions that cannot be accounted for by simple Mendelian models, but can be explained in terms of a continuous variable, “liability,” with a threshold value beyond which individuals will be affected. Both genetic and environmental factors determine liability, making the system multifactorial. Cleft palate is a useful experimental model, illustrating a number of factors that contribute to palate closure, the nature of a developmental threshold, and how genes and teratogens can alter the components of liability to increase the probability of cleft palate. The nature of the genetic component to liability in human malformations is not clear, and various possibilities, ranging from polygenic in the strict sense to a major gene with reduced penetrance are compatible with the data—but the important feature is the threshold. Much of the confusion over the concept results from inconsistent use of terminology. The term “multifactorial” should be used for “determined by a combination of genetic and environmental factors,” without reference to the nature of the genetic factor(s). “Polygenic” should be reserved for “a large number of genes, each with a small effect, acting additively.” When several genes, with more major effects are involved, “multilocal” can be used. When it is not clear which of these is applicable the term “plurilocal” is suggested, in the sense of “genetic variation more complex than a simple Mendelian difference,” Since teratological data often represent threshold characters the concept also has important implications for the interpretation of data on dose‐response curves, synergisms, and strain differences in response to teratogens.
Exencephaly in fetal hamsters following exposure to hyperthermia
Authors: Kilham Lawrence , Ferm Vergil H.
Published: June 2005

Exposure of pregnant hamsters on gestation day 8 to 40 or 41°C for one hour caused an increased rate of resorption and a high frequency of exencephaly and encephatocele. Longer exposures often killed pregnant females. Hamsters that had fetuses with abnormalities usually experienced body temperature elevations of 3‒4°C above normal (37°C).
An evaluation of the embryotoxic effects of blighted potatoes on chicken embryos
Authors: Jelínek Richahd , Kyzlink Vladimír , Blattný Ctibor
Published: June 2005

The embryotoxic properties of an ethanol extract of boiled potatoes infected with Phytophthora infestans were investigated in White Leghorn chicken embryos, using controlled subgerminal injection on the second day of incubation and intraamniotic injection on the third and fourth days. A dose of 0.3 mg of sublimation‐dried extract interfered at the somite stages with the function of the caudal morphogenetic system and induced various degrees of the caudal regression syndrome. Administration on the third and fourth days led to the development of a malformation syndrome comprising cranioschisis, celosoma, and cardiac septal defects. An equivalent amount of extract of healthy potatoes of the same variety and injection of pure solanine had the same effect. The results warrant the claim that the main factor responsible for the direct embryotoxicity of potatoes attacked by P. infestans is solanine, which evokes tonic contract ion of the smooth muscle elements of the amnion.
Teratogenicity studies on late blighted potatoes in nonhuman primates (Macaca mulatta and Saguinus labiatus)
Authors: Allen J. R. , Marlar R. J. , Chesney C. F. , Helgeson J. P. , Kelman A. , Weckel K. G. , Traisman E. , White J. W.
Published: June 2005

Female rhesus monkeys and marmosets were fed a diet containing blighted potatoes (Phytophthora infestans) at a level of 10 g/kg per day for at least two weeks prior to breeding and six weeks following conception in order to gain additional information on the association of blighted potatoes and the development of anencephaly and spina bifida in primate species. There was an absence of either of these neural‐tube defects in 32 rhesus and 14 marmoset infants whose mothers had received a blighted potato diet. In addition there were no cranial osseous defects. There were, however, two rhesus monkey infants with internal hydrocephalus whose mothers had consumed blighted potatoes.
Prenatal toxicity of medroxyprogesterone acetate in rabbits, rats, and mice
Authors: Andrew F. D. , Staples R. E.
Published: June 2005

Medroxyprogesterone acetate (MPA) was given once daily sc at 0.1–3,000 mg/kg/day for 3, 6, or 9 consecutive days during gestation days 7 to 15 to GDI and A/J mice, and New Zealand (NZ) and Dutch Belted (DB) rabbits, and during days 8 to 16 to CD rats. Malformations attributable to MPA did not occur in fetuses of mice or rats exposed to the largest dosage tested. However, 1, 3, or 10 mg/kg on days 13 to 15 to NZ rabbits resulted in 6, 28, and 42% cleft palate, respectively. Comparable cleft palate frequencies were seen in DB offspring.
Vater syndrome: Hypothesis and report of two further cases
Authors: Lloyd David J. , McKenzie John , Kaye Henry H. , Russell George
Published: June 2005

Two cases are reported of the association of a group of abnormalities defined as the Vater syndrome, together with a hypothesis, based on the presence of normal cell death during embryogenesis, on how they occur together so frequently. Althouh the medhanism of normal cell death is unknown, adjacent cells are probably affected sublethaly and subsequently recover. A teratogenic situation introduced simultaneously with the occurrence of normal cell death may further diminish the viability of those adjacent cells, causing increase in the necorotic zone and loss of both normal tissue and growth potential.
Human fetal development between 90 and 170 days postmenses
Authors: Golbus Mitchell S. , Berry Leonard C.
Published: June 2005

Linear measurements, total weights, and organ weights of 133 fresh human fetuses were obtained after therapeutic abortion between 90 and 170 days postmenses. Great apparent variation was observed in fetuses of given ages, especially in organ weights. There was no evidence of sex or parity differences.
Comparison of the effects of retinol and retinoic acid on postimplantation rat embryos in vitro
Authors: Morriss G. M. , Steele C. E.
Published: June 2005

Rat embryos were explanted on day 8 or 9 of pregnancy and cultured for up to 48 hours in serum containing added retinol (vitamin A), retinoic acid (vitamin A acid), or absolute ethanol. They were examined morphologically and their protein content determined. Retinoic acid was more teratogenic and growthretarding than retinol. Electron microscopy of embryos cultured for 30 minutes or one hour revealed that both forms of vitamin A brought about similar ultrastructural effects on the embryonic cells; however, the abnormally large intracellular lipid droplets observed in a previous study following exposure to retinol in vitro and retinyl palmitate in vivo were not observed in embryos exposed to retinoic acid. It is possible that the differential teratogenicity may be due to the inability of the embryonic cells to convert and store retinoic acid in a less teratogenic form.
Drug‐induced limb dysplasias in fetal rabbits
Authors: Desesso John M. , Jordan Robert L.
Published: June 2005

Pregnant New Zealand White rabbits were treated on gestation day 12 with 19.2 mg/kg methotrexate (MTX), 750 mg/kg hydroxyurea (HU), or 1,500 mg/kg acetazolamide. Rabbits were killed either 2–32 hours posttreatment for histological analysis of embryos or at day 29 for gross and skeletal examination of fetuses. MTX produced cleft palate, hydrocephalus, and fore‐ and hindlimb reduction defects. Histological analysis revealed pyknosis and edema in mesenchymal tissues at four to eight hours following treatment. The apical ectodermal ridges (AER) of treated embryos permanently lost their characteristic pseudostratified organization. By 32 hours the limb buds had regained their normal appearance except for the AER. HU affected all fetuses with skull and facial anomalies as well as severe reduction deformities of all limbs. Histologically HU‐treated embryos had numerous, basophilic, intercellular granules (presumably cell debris) which appeared within two to four hours in the limb bud mesenchyme, neural tube, and dorsal root ganglion. The architecture of the AER was unchanged. Acetazolamide produced bilateral retarded ossification or possible aplasia of the first metacarpal and talus in nearly 80% of fetuses. Microscopic examination disclosed no apparent alterations in limb‐bud morphology. Methyl green‐pyronin Y staining called attention to green intracellular droplets within the endoderm of the trachea and bronchi at two hours posttreatment. It was concluded that the three drugs do not produce limb dysplasias by a common teratogenic mechanism.
Palatomandibular and maxillo‐mandibular fusion, partial aglossia and cleft palate in a human embryo. Report of a case
Authors: Shah Ravindra M.
Published: June 2005

A 32‐mm CRL male human embryo was examined for malformation. Histological observation showed fusion between the left vertical palatal shelf and mandible and the maxilla and mandible in the posterior part of the oronasal cavity. The right shelf was horizontal anteriorly, vertical posteriorly and changing its position from a vertical to a horizontal plane in the middle. The tongue was underdeveloped anteriorly and completely absent posteriorly. The mandibular tooth buds were not formed. Both clinical and experimental literature were analyzed to find the mechanism of statu nascendi defect observed in the present case. It was deduced that the tongue may not play an active role during normal palatal development and that it may not have played any role during the fusion between different intraoral structures observed in the present case. It was concluded that, had the embryo developed further, then at the birth a cleft palate, partial aglossia and associated intraoral malformation would have been expected.
Litigation‐produced pain, disease and suffering: An experience with congenital malformation lawsuits
Authors: Brent Robert L.
Published: June 2005

The exponential rise in malpractice litigation is due to attitudes and happenings in the medical, legal and lay sectors of our society. Evaluation of congenital malformation lawsuits provides a unique opportunity to evaluate the process of litigation. Because the cases are rarely meritorious, the litigation process is detrimental to the plaintiff, society and frequently unfair to the defendant. There is no area of our legal system with such a high percentage of innocent defendants. When the family of a malformed infant becomes orchestrated by an attorney into a position of devoting their energy to winning a lawsuit, many high priority family responsibilities may be ignored and important ethical standards are distorted. To win at all costs may be appropriate for a football team but it can be detrimental to a family. The family enters the litigation arena unaware of the lengthiness of the litigation process and ignorant of the fact that only a small portion of the malpractice premium dollar ever reaches the patient. The plaintiffs are not the only participants who lose their objectivity and lower their ethical standards. The quality and veracity of the testimony of expert witnesses has deteriorated to the point that drastic corrective measures have to be instituted. It is believed that recommendations for solving the malpractice crisis, which are based on the experience with congenital malformation lawsuits, should have applicability to the overall malpractice problem and must involve changes in the medical, legal and lay sectors of our society. These recommendations are discussed in detail. It must be recognized that it is difficult to alter the laws and procedures that are not of benefit to the legal profession because so many legislatures are dominated by elected officials who happen to be attorneys. But it is emphasized that of all the recommendations put forth, the one having the greatest beneficial effect on the present malpractice crisis would be the elimination of the contingency fee system and replacing it with no‐fault compensation or legal‐fee insurance. The contingency fee system provokes and promotes malpractice litigation. The process of litigation rarely solves the patient's problems and frequently develops into a disease all its own.
Methylmercury teratogenesis in the killifish, Fundulus heteroclitus
Authors: Weis Peddrick , Weis Judith S.
Published: June 2005

Exposure of developing eggs of the killifish, Fundulus heteroclitus, to 0.03 or 0.04 mg/1 of methylmercuric chloride resulted in a variety of abnormalities. Percentage of axis formation was reduced somewhat, and many embryos developed cyclopia or intermediate conditions leading to cyclopia, reflecting interference with induction of the forebrain. Defects in the cardiovascular system also appeared in the form of failure of the heart to differentiate properly into chambers. The heart was a thin, feebly beating tube, incapable of causing the blood to circulate. Other tissues, however, continued developing fairly normally, and embryos showed spontaneous movement comparable to controls. Embryos with severe cardiovascular or optic defects did not hatch. Upon hatching, some embryos which had previously appeared normal, were found to have skeletal malformations in the form of vertebral bends or the inability to uncurl from the position which they had had while still inside the chorion. Exposure to the toxicant for shorter periods of time (6, 12, or 24 hours) reduced the incidence of abnormalities. The second day of development was found to be the most sensitive period.
Epidermal growth factor potentiates cortisone‐induced cleft palate in the mouse
Authors: Bedrick Alan D. , Ladda Roger L.
Published: June 2005

Epidermal growth factor (EGF) injected into pregnant mice increased the frequency of cleft palate (CP) in cortisone‐treated mouse fetuses. EGF alone produced proliferation and thickening of the epithelium of the palatal processes, but CP was not significantly increased over saline injected controls. Cortisone alone produced thinning of the palatal epithelium and caused CP in 61 percent of formed fetuses. The combination of EGF and cortisone treatment induced CP in 100 percent of formed fetuses; epithelial thickening still occurred with the combination treatment. Thus, EGF may be teratogenic under special circumstances. These observations suggest that the relative thickness of the palatal shelf epithelium may not be a critical factor in the fusion of the palatal shelves.
Potentiation of methotrexate embryolethality by aspirin in rats
Authors: Woo David C. , McClain R. M. , Hoar Richard M.
Published: June 2005

The augmentation of methotrexate‐induced embryotoxicity by aspirin was studied. Pregnant Charles River CD rats were given methotrexate or aspirin alone or in combination on gestation day 9 or 12. The frequency of fetal abnormalities was not affected and fetal body weight loss was not additive in the combined treatment. However, pretreatment with aspirin (200 mg/kg) significantly enhanced the embryolethality of methotrexate given at doses of 0.2 mg/kg on day 9 and 1.5 mg/kg on day 12. Studies with tritiated methotrexate in pregnant rats demonstrated that aspirin delayed the renal excretion of methotrexate and increased the concentrations of methotrexate in maternal plasma and the embryos. It is suggested that these effects are responsible for the observed potentiation of embryolethality.
Methylmercury: Some effects on embryogenesis in the Japanese Medaka, Oryzias latipes
Authors: Dial Norman A.
Published: June 2005

Japanese Medaka (Oryzias latipes) eggs were treated with 40, 60, and 80 parts per billion (ppb) methylmercuric chloride (MMC) for a period of 10 to 25 days in order to observe gross teratogenic and lethal effects caused by methylmercury during embryogenesis. Over the period tested, 40 ppb‐treated embryos were less affected than other treated animals. Embryos treated with 60 ppb MMC showed greater effects in that there was a higher death rate and those which survived ranged considerably in size, degree of gross teratogenic defects, and behavior if development was normal enough for hatching to occur. Most did not hatch during the 25‐day test period. Embryos treated with 80 ppb MMC were very abnormal in development, being stunted, poorly pigmented, and they showed various eye defects. None hatched in 25 days. Many did not incorporate the heart into the body. Methylmercuric chloride in trace amounts caused various defects and presents a potential hazard to development of embryos of aquatic vertebrates.
Defects of the central nervous system in Finland. II. Birth order, outcome of previous pregnancies and family history
Authors: Granroth Gustav , Haapakoski Jaason , Hakama Matti
Published: June 2005

Seven hundred and ten cases with defects of the central nervous system (CNS) reported to the Finnish Register of Congenital Malformations in 1965‐73 were analysed with regard to possible etiological factors. A time‐area matched birth for every case, 259 cases of polydactyly, and official statistics for the entire country were used as controls. High birth order turned out to be a risk factor especially for the group of hydrocephaly, maternal age not taken into account. When this confounding factor had been ruled out, it was found that high birth order was associated with anencephaly and high maternal age with hydrocephaly. However, a combination of both these factors gave the most striking association in both groups of defects. Higher rates of abortions and stillbirths in previous pregnancies, previous live births with CNS defects or any kind of defects were significantly associated with the birth of children with CNS defects. The rate of twinning was found to be higher in the study group than in the general population, and in the great majority of twin births the CNS defective child was the later born partner. Parental profession did not seem to be associated with the outcome of pregnancy. The significance of the socio‐economic status and other confounding factors are discussed in connection with the concept of the marital status of mothers.
Frequency of down syndrome in livebirths by single‐year maternal age interval: Results of a Massachusetts study
Authors: Hook Ernest B. , Fabia Jacqueline J.
Published: June 2005

An analysis of rates of intra‐state Down syndrome livebirths to Massachusetts residents by single‐year maternal age interval in 1958‐1965 inclusive was carried out. A gradual increase of rate of the Down syndrome occurred from age 20 to about age 31, and a steeper increase thereafter. Different regression equations were derived in the 20‐31 and the 33‐45 age group. The regression equations were In y = 0.04515 x −1.45759 for those age 20‐31 and ln y = 0.24302 x −7.57870, for those age 33‐45, where y = rate per 1,000 and x = maternal age. The regression‐derived rates are slightly lower than those reported in similar analyses of data from Sweden and New York State, but they are not markedly discrepant.
The relationship of gestational age to vitamin A induced postnatal dysfunction,
Authors: Vorhees Charles V. , Brunner Robert L. , McDaniel Cynthia R. , Butcher Richard E.
Published: June 2005

In an effort to determine the relationship between time of administration and consequent behavioral effects on progeny, a uniform sub‐teratogenic dose of vitamin A (80,000 i.u./kg) was administered to gravid Sprague‐Dawley rats during one of five periods of gestation (days 5‐7, 8‐10, 11‐13, 14‐16 and 17‐19). Offspring were examined for changes in rate of weight gain, locomotor activity and maze learning ability (T‐maze with return to nest as, reward and multiple T water maze escape). Vitamin A 8‐10 animals were hyperactive, vitamin A 11‐13 animals acquired T‐maze slower than controls and both vitamin A 8‐10 and 11‐13 acquired water maze slower than controls. Vitamin A 11‐13 animals were significantly lighter than controls and all other vitamin A groups.
Abnormalities induced in cultured rat embryos by hyperthermia
Authors: Cockroft D. L. , New D. A. T.
Published: June 2005

Rat embryos were explanted at nine and one‐half days of gestation and cultured for 48 hours in rotating bottles containing rat serum and a gas phase, at temperatures of 38, 40, 40.5 and 41°C. The embryos cultured at 40.5°C were retarded and many of them were abnormal, and at 41°C, all the embryos were malformed and retarded. The most frequent abnormalities occurring at both these temperatures were microcephaly and oedema of the pericardium. Development of the embryos cultured at 40°C was similar to that of the corltrols at 38°C, and superficially they appeared to be normal. However, measurement of the head dimensions, and separate determinations of head and body protein contents showed that the 40°C embryos were microcephalic.
Relationship of dietary zinc to 6‐mercaptopurine teratogenesis and DNA metabolism in the rat
Authors: Hirsch Kenneth S. , Hurley Lucille S.
Published: June 2005

The possible interaction between the level of maternal dietary zinc and the teratogenic activity of 6‐mercaptopurine was investigated. Pregnant Sprague‐Dawley rats were fed diets, containing 9, 100 or 1,000 ppm zinc from day zero of pregnancy and were given a single intraperitoneal injection of 6‐MP (55 mg/kg) on day 11. At term, females in the group fed 1,000 ppm zinc (a high intake) showed less pronounced effects on reproduction and embryogenesis than did those fed 9 ppm (marginally deficient) or 100 ppm (normal) zinc. Embryos examined on day 12 of gestation had similar concentrations of protein and RNA; however, the DNA content was lower and the incorporation of 3H‐thymidine was greater in the drug treated groups than in non‐drug treated controls These results indicate that 6‐mercaptopurine is acting to alter embryonic DNA. metabolism and that high levels of dietary zinc may ameliorate some of the deleterious effects of this drug on embryonic and maternal toxicity.
Attenuating effect of zinc on abnormal placental morphology in 6‐mercaptopurine treated rats
Authors: Shrader Ruth E. , Hirsch Kenneth S. , Levin Jacqueline , Hurley Lucille S.
Published: June 2005

Pregnant Sprague‐Dawley rats were fed diets containing 9 (marginal level), 100 (control level), or 1,000 (very high level) ppm zinc and were given a single intraperitoneal injection of 6‐mercaptopurine (6‐MP, 55 mg/kg) or an equivalent volume of carboxymethylcellulose on day 11 of gestation. Live young and their placentas were recovered at surgery on day 21 of gestation: they were weighed, measured, and placentas were examined histologically. Placentas from drug treated animals were smaller in diameter and lighter in weight than controls; however, the placentas of animals fed the 1,000 ppm zinc diet were significantly heavier than those of the other drug‐treated groups. Histologically, the placentas of the 6‐MP treated dams showed a highly disproportionate reduction in the labyrinthine layer with larger, less subdivided maternal sinuses than in controls, reduction of fetal vasculature, vesiculation of trophoblast nuclei, deposition of PAS positive material in the septal wall, and fibrinous degeneration of trophoblast cells. These morphological changes were reduced in placental tissues of drug treated rats given 1,000 ppm of zinc. In contrast, no placental abnormalities were observed in rats not treated with 6‐MP.
Teratogenic action of a bis(dichloroacetyl)diamine on rats: Patterns of malformations produced in high incidence at time‐limited periods of development
Authors: Taleporos Plato , Salgo Miklos P. , Oster Gerald
Published: June 2005

Win 18,446, a bis(dichloroacetyl) diamine, is a drug that was previously shown to suppress spermatogenesis and to be an effective oral abortifacient in rats. The present study shows that the drug is capable of producing characteristic congenital malformations in high incidence, by a single treatment, and with high survival of fetuses to day 21. Gestation day 11 is the most sensitive time. The teratologies obtained after various schedules of treatment include malformations of the snout (100%), septal heart defects (100%), diaphragmatic hernias (100%), cryptorchism (100%), cervical pockets (100%) and absent or small irregular thymus (92%). Some of these data, namely of the heart, face and thymus, cluster in patterns that indicate that the action of the drug is upon a time‐restricted developmental process. These periods of sensitivity are subsiding or have ended before primordia of these structures appear, but they coincide with the proliferation and migration of those mesenchyme cells that will eventually form or contribute to the structures affected. It is postulated that the drug acts on these mesenchyme cells, or on the extracellular matrix that provides the necessary framework for their dispersal.
The effect of trypan blue on the development of the ferret and rat
Authors: Beck F. , Swidzinska P. , Gulamhusein A.
Published: June 2005

The teratogenic effects of trypan blue given to pregnant rats and ferrets at equivalent stages of embryonic development are described. In the rat the well known teratogenicity of the dye at 8.5 days of gestation and the surprising cessation of teratogenic effect at 11.5 days (20+ somites) is confirmed. In the ferret the drug is teratogenic both at 13 and 18 days of gestation though the principal abnormalities seen are different to those described in the rat. It has been suggested that the teratogenic action of trypan blue in rats is due to an interference in the function of the yolk sac which is an organ of histiotrophic nutrition and provides the principal source of nutrition for the 8.5‐day embryo that is largely replaced by a functional chorio‐allantoic placenta after 11.5 days of gestation. In ferrets histiotrophic nutrition does not involve an inverted yolk sac placental system. In this species endometrial symplasma provides histiotroph which is ingested by the invading trophoblast. Histiotrophic nutrition is still of great importance at 18 days and morphological evidence indicates that chorio‐allantoic placentation becomes important by about 20 days (35+ somites).
Chlorcyclizine induction of cleft palate in the rat: Degradation of palatal glycosaminoglycans
Authors: Wilk Ann L. , King C. T. G. , Pratt Robert M.
Published: June 2005

Administration of the cleft palate teratogen chlorcyclizine or norchlorcyclizine to pregnant rats causes an alteration in glycosaminoglycans (GAGs) in embryonic palatal shelves. Pulse‐chase experiments in vitro indicate that norchlorcyclizine enhances the degradation of hyaluronic acid and chondroitin sulfate but has little or no effect on their synthesis. These changes in GAGs are caused by concentrations of norchlorcyclizine that have no appreciable effect on DNA or protein synthesis. These findings suggest that degradation of palatal GAGs may be the primary biochemical defect responsible for the inhibition of palatal shelf elevation by norchlorcyclizine.
Early changes in the mouse neuroepithelium preceding exencephaly induced by hypervitaminosis A
Authors: Theodosis Dennise T. , Fraser F. Clarke
Published: June 2005

Excess vitamin A orally administered to pregnant mice during neurulation causes most of the embryos to become exencephalic. The study presents light and electron microscopic observations that trace the origin and course of the early cellular and tissue alterations associated with the malformation. The main effects of the teratogen are seen in the neuroepithelial cells of the cephalic region of the presumptive nervous system. The degree to which each embryo is malformed varies but no matter how extensive the abnormalities in each embryo, the neuroepithelium is always affected and the lesions are similar. Mesodermal abnormalities appear only in the most seriously affected embryos.

With the electron microscope, changes are apparent in the neuroepithelial cells within a few hours after maternal treatment. These changes include the formation of abnormally shaped nuclei with swollen nuclear envelopes, dilation of the rough endoplasmic reticulum, and formation of cytoplasmic inclusions that contain DNA and/or RNA. The inclusions are thought to arise as an autophagocytic response of the cells to the sub‐lethal injury induced by the teratogen. In addition, a number of cells are more severely affected and degenerate. Light microscopic examination of serial sections reveals that by 20 hours after treatment, the neuroepithelium becomes disorganized: the cells are round and misaligned and intercellular connections are lost.

We postulate that the early cellular alterations lead to a disruption of the architecture of the early neuroepithelium so that the neural folds fail to meet and close. The tissue may survive the initial insult, but continues to grow in the everted manner characteristic of exencephaly.
An anatomic and genetic study of canine cryptorchidism
Authors: Cox Victor S. , Wallace Larry J. , Jessen Carl R.
Published: June 2005

Twelve cases of cryptorchidism were found in a colony of Miniature Schnauzer purebred and crossbred dogs. At least nine affected dogs were derived from the same sire directly or indirectly. Of 12 affected dogs, five cases were unilateral and seven were bilateral. Eight of the 12 cases were subjected to anatomic study. Fixation of affected organs was by vascular perfusion or immersion. Testes were separated from epididymides and both were weighed. All unilateral retained testicles were on the right side, and right sided bilaterally retained testes were always smaller than their left sided counterparts. With only one exception, ectopic testes were in the abdominal position. Developmentally, the morphologic appearance of the epididymis of abdominal testes was very primitive in bilateral cases but nearly normal in the unilateral cases. Degree of inbreeding was greater for bilateral cases than unilateral cases. High incidence of cryptorchidism in this colony provided good evidence for hereditary nature of the condition in the Miniature Schnauzer dog. Morphologic observations were suggestive of a multiple gene defect.
Teratogenic effect of N‐methyl‐N′‐nitro‐N‐nitrosoguanidine in mice
Authors: Inouye Minoru , Murakami Ujihiro
Published: June 2005

The teratogenic effect on the mouse fetus of a potently mutagenic and carcinogenic agent, N‐methyl‐N′‐nitro‐N′‐nitrosoguanidine (MNNG), was studied. Pregnant mice were injected on one of gestation days 7–12 with an intraperitoneal dose of 40, 60 or 80 mg/kg of MNNG, and fetuses were examined on day 18 of gestation. Various malformations affecting the brain, face, vertebra, rib and limb appeared in high frequency. Brain malformations were the most predominant; hydrocephalus, hydromicrocephaly and microcephaly appeared in sequence with developmental stages of treatment, although exencephaly occurred infrequently. Cleft palate, sometimes associated with microglossia and micrognathia, and vertebral anomalies including tail defect were observed following almost every gestation‐day treatment. Long‐bone defects of fore‐ and hindlimbs were also predominant. Polydactyly, ectrodactyly and microdactyly frequently occurred together in the fore‐ or hindlimbs or both in sequence with treatment stages. Ectrodactyly and microdactyly appeared with greater frequency on the left than on the right in both fore‐ and hindlimbs, but polydactyly and long‐bone defects appeared bilaterally.
Development in the first half of gestation of genetically abnormal human fetuses
Authors: Golbus Mitchell S.
Published: June 2005

Linear measurements, total weight and organ weights were determined for 24 second trimester human fetuses with a cytogenetic or metabolic defect. The three fetuses with trisomy 13 or 18 tended to be smallest in all parameters. This data should be of value to other laboratories interested in human fetal growth. It demonstrates that the intrauterine growth retardation reported at term in cytogenetically abnormal newborns is already manifested at the eighteenth to twentieth week of gestation.
A comparison of behavioral and anatomical measures of hydroxyurea induced abnormalities
Authors: Brunner Robert L. , McLean Maria , Vorhees Charles V. , Butcher Richard E.
Published: June 2005

Hydroxyurea, a drug which has antimitotic effects was administered once (150 mg/kg) to pregnant dams on the sixth, ninth, twelfth, fifteenth and eighteenth day of gestation. Litters of these dams plus control subjects were tested behaviorally from two days of age until sacrificed at 21 days of age. The following tests were conducted: (i) surface righting, (ii) mid‐air righting, (iii) cliff avoidance, (iv) swimming development, (v) pivoting and (vi) startle. In righting, cliff and startle a litter was tested until all members displayed a criterion response and that age provided the score for statistical analysis. In swimming and pivoting, time and frequency measures were analyzed. There were no significant treatment effects on any of the behavioral measures. Rat pups of dams injected on Day 9 of pregnancy evidenced hydrocephaly and micropthalmia. The latter observation was confirmed by eye weights which were significantly reduced in this group at 21 days of age. Regional brain weight measurements did not distinguish among the groups. Hydrocephaly was variably associated with necrotic brain tissue, loss in weight, behavioral delays and early death. The results suggested that the assertion of greater sensitivity of behavioral compared to morphological measures in screening for drug hazards needs to be qualified. A step wise procedure for screening was proposed and it was suggested that behavioral studies need to include assessments of brain pathology as a bridge between functional and structural approaches.
Tail anomaly lethal, Tal: A new mutant gene in the rat
Authors: Hoshino Kiyoshi , Oda Sen‐Ichi , Kameyama Yoshiro
Published: June 2005

A new hereditary tail anomaly (gene symbol Tal) in rats was found in the course of teratological studies with trypan blue. The characteristic feature of the tail anomaly was a short and kinked tail. The genetic analysis indicated that the tail anomaly was caused by an autosomal dominant gene and the homozygotes were lethal in the prenatal stage. The first sign of degeneration in the homozygous embryo appeared in the late egg cylinder stage. The phenotype of this mutant is similar to that of T‐locus mutants in mice.
Interpretation of isolated agenesis of the pituitary
Authors: Roux Charles , Dupuis Rolande , Horvath Cécilia , Giroud Antoine
Published: June 2005

Cholesterol synthesis inhibitors administered to rats caused more or less complete forms of the holoprosencéphalic syndrome, consisting of severe abnormalities of the brain, sense organs and pituitary. The absence of the pituitary was also observed in fetuses without externally visible cephalic abnormalities.

These observations suggest that the isolated absence of the pituitary is the lesser form of the holoprosencephalic syndrome.

This interpretation is also valid for cases of isolated absence of the pituitary observed in humans.
Different teratogenic efficacy to mouse fetal CNS of 5‐azacytidine in combination with X‐irradiation depends on the sequence of successive application
Authors: Schmahl W.
Published: June 2005

The single treatment of pregnant mice on day 12 post conception with 5‐azacytidine (AzaCr), followed by a single irradiation dose of 200 rad two hours later, is exclusively neurotoxic to the fetus, as shown by a severe hyoplasia of the parieto‐occipital regions of the telencephalon. This effect is explicable by the specific function of the mitotic cell population for the integrity of the cortex wall. Combining these two hazards in the reverse manner, i.e., irradiation followed by AzaCr, resulted in no general hypoplastic effect in the forebrain and only caused a depletion of cells in the marginal cortex. This indicates a significantly diminished AzaCr sensitivity of fetal cortical cells subsequent to X‐irradiation. In addition, rosette‐like cell clustering in the cortex of all X‐irradiated animals occurs to a similar degree, irrespective of any additional AzaCr‐treatment. The only conformity between these different schedules is that a great portion of the surviving cells is most likely in the DNA synthesizing phase at the time of irradiation. It is therefore concluded that rosette formation starts perferentially from cells injured during the S‐phase.
Movement of palatal shelves during secondary palate closure in rat
Authors: Srivastava H. C. , Rao P. P.
Published: June 2005

The palatal shelves and tongue develop as bilateral mesenchymal elevations in the caudal portion of stomatodaeum on the medial surface of maxillary processes and the floor of stomatodaeum respectively. The shelves and tongue grow in a caudorostral direction. As the shelves are growing, their rostral ends are separated by stomatodial space from the sides of tongue and the floor of oral cavity, but their caudal portions come in close contact with the floor and the tongue. At day 15:8 the shelves are in close contact throughout their length with the tongue and the floor and there is no space in the oral cavity. The tongue grows in height and length and reaches the rostral end of nasal cavity before the beginning of shelf movement. Formation of a layer of desquamated cells between the epithelium lining the shelf and the epithelium lining the floor and the tongue precedes the separation of shelves from the floor and tongue which results in the development of space in oral cavity. The tongue which was in contact with the nasal septum and the roof of pharynx, descends and is separated from them by a uniform space. The moment the descent of tongue takes place, the shelves are ready to move to the horizontal position. Both shelves do not move at the same time, but one moves first and then the other. On assuming horizontal position both shelves fuse with each other immediately in midline during the critical period except in the most rostral region where they are separated by a gap, across which they must grow towards each other prior to fusion. Development of space in the oral cavity is an important feature during palate closure in which shelves take an active part.