bluuebunny/crossref_metadata_2025 huggingface dataset:
Teratogenic evaluation of 2‐nitro‐p‐phenylenediamine, 4‐nitro‐o‐phenylenediamine, and 2,5‐toluenediamine sulfate in the mouse
Authors: Marks Thomas A. , Gupta Bhola N. , Ledoux Thomas A. , Staples Robert E.
Published: June 2005

Pregnant outbred albino (CD‐1) mice were given 2‐nitro‐p‐phenylenediamine (2NPPD; 32–256 mg/kg/day), 4‐nitro‐o‐phenylenediamine (4NOPD; 16–1024 mg/kg/day) or 2,5‐toluenediamine sulfate (2,5TDS; 16–64 mg/kg/day) by subcutaneous injection on Days 6–15 of gestation. The mice were killed on Day 18, the general health and reproductive health of the dams evaluated, and the fetuses examined and processed in order to characterize external, visceral, and skeletal malformations. The 32 and 128 through 256 mg/kg/day dose levels of 2NPPD produced a significant (p < 0.05) reduction in average weight gain by the dam during pregnancy. There was also a significant reduction in average fetal weight at 128 mg/kg/day and above. Although 2NPPD administration led to a significant increase in the average percentage of malformed fetuses at 160 mg/kg/day and above, these effects occurred only at dosages which produced significant maternal toxicity. Teratogenic effects were observed with 4NOPD, as administration of this dye led to a significant increase in the average percent of malformed fetuses at 256 mg/kg/day and above. A significant reduction in average weight gain by the dam during pregnancy also was observed at these dose levels, as well as a significant reduction in average fetal weight. Although 2,5TDS killed 4 of 31 dams at 48 mg/kg/day, and 9 of 11 dams at 64 mg/kg/day, this compound did not cause a significant increase in the average percent of malformed fetuses. There were indications of embryotoxicity, however, as dosages of 32 mg/kg/day and above led to significant reductions in average fetal weight.
Deleterious effects of prenatal prednisolone exposure upon morphological and behavioral development of mice
Authors: Gandelman Ronald , Rosenthal Caren
Published: June 2005

The influence of prenatal exposure to the synthetic glucocorticoid prednisolone (PRED) was examined in female offspring of mice administered the drug on Days 13–18 of pregnancy. The offspring weighed significantly less than control animals at birth and weaning. Animals born of mothers given the highest dosage of the drug (400 μg) weighed less than controls in adulthood. Fetal exposure to PRED also resulted in morphological masculinization as evidenced by an increase in anogenital distance. In addition to its marked influence, prenatal PRED exposure retarded the attainment of the developmental milestones of eye opening, lifting, walking, and gripping. The effect of PRED upon the fetus is relatively rapid in that a reduction of fetal weight was observed in 13‐day‐old conceptae 7.5 hr following a maternal injection of PRED. The administration of an antiestrogenic compound (MER‐25) concurrently with PRED prevented the reduction in birth weight, thereby suggesting that PRED acts, in part, by its known attenuation of fetoneonatal estrogen‐binding protein. And finally, fetal exposure to PRED had virtually no effect upon reproductive competence as assessed by proportion of successful pregnancies, lactation performance, and postpartum fighting behavior. It is concluded that prenatal exposure to PRED markedly affects somatic and muscular/motor development and it may be worthwhile to examine the influence of the drug upon levels of gonadal hormones in an attempt to elucidate the mechanism through which its effects are produced.
Indicators of developmental toxicity following prenatal administration of hormonally active compounds in the rat. I. Gestational length
Authors: Rands Peggy L. , White Randy D. , Carter Melvin W. , Allen Stanley D. , Bradshaw William S.
Published: June 2005

Prenatal administration of 3,4,3′,4′‐tetrachlorobiphenyl, zeranol, or diethylstilbestrol was observed to delay parturition in the rat and result in a concomitant increase in perinatal mortality. Even among control animals, those litters in which birth occurred after the beginning of day 22 of pregnancy contained significantly fewer survivors one day after birth. Increases in the length of gestation were correlated with increased weight of newborn control pups independent of litter size. The relationship between weight and litter size was anomalous, however, in treated animals. Gestational length is a sensitive indicator of a developmental effect even in the absence of overt teratogenicity.
Facial duplication: Case, review, and embryogenesis
Authors: Barr Mason
Published: June 2005

The craniofacial anatomy of an infant with facial duplication is described. There were four eyes, two noses, two maxillae, and one mandible. Anterior to the single pituitary the brain was duplicated and there was bilateral arhinencephaly. Portions of the brain were extruded into a large frontal encephalocele. Cases of symmetrical facial duplication reported in the literature range from two complete faces on a single head (diprosopus) to simple nasal duplication. The variety of patterns of duplication suggests that the doubling of facial components arises in several different ways: Forking of the notochord, duplication of the prosencephalon, duplication of the olfactory placodes, and duplication of maxillary and/or mandibular growth centers around the margins of the stomatodeal plate. Among reported cases, the female:male ratio is 2:1.
Pathogenesis of congenital tumors and malformations of the sacrococcygeal region
Authors: Lemire Ronald J. , Beckwith J. Bruce
Published: June 2005

Skin‐covered lesions in the sacrococcygeal region include an unusual array of congenital tumors and malformations. Excluding the easily recognized meningomyelocele, there are over 50 other conditions that occur, many of which seem to be important in linking the disciplines of teratology and oncology. While it is impossible to precisely determine the manner in which these arise, there is suggestive evidence that early structures incorporated within the caudal cell mass of the embryonic tail may play an important role. The present paper reviews the basis for this speculation from both the literature and a series of 136 cases.
Ectopia cordis cervicalis: A case report
Authors: Müller G. , Schaller A.
Published: June 2005

A case of ectopia cordis cervicalis is reported; it seems to be the seventh one in the available literature. It concerns a completely ectopic cor biloculare with a truncus arteriosus persistens, located above the apertura thoracis superior, being covered by soft tissue. A survey of the cases cited in the available literature since 1712 is given.
An epidemiologic study of neural tube defects in Los Angeles County II. Etiologic factors in an area with low prevalence at birth
Authors: Sever Lowell E.
Published: June 2005

Epidemiologic characteristics of neural tube defect (NTD) births occurring in Los Angeles County, California, residents during the period 1966–1972 are presented. The prevalence at birth was 0.52/1000 births for anencephalus, 0.51/1000 for spina bifida, and 0.08/1000 for encephalocele, rates considered to be low for a predominantly white population.

We hypothesized that environmental (nongenetic) factors are of less etiologic importance in a low‐prevalence population than in areas or time periods with high prevalence. We tested that hypothesis by examining epidemiologic characteristics of NTDs in Los Angeles County and comparing them with high‐prevalence populations. The data did not support a major etiologic role for environmental factors: (1) no significant differences between rates by month of birth or conception; (2) no significant association with maternal age or parity for anencephalus; for spina bifida a significant maternal age effect (P < 0.01) and for encephalocele a parity effect (P < 0.02); and (3) no significant relationship with father's occupational class for either anencephalus or encephalocele but a marginally significant (P < 0.05) inverse association for spina bifida when a statistic based on ordinal relationships was used.

Findings supporting the importance of genetic factors in etiology included: (1) a high percentage of males; (2) a higher twin concordance rate than in high‐prevalence populations; and (3) an anencephalus rate among blacks comparable with rates for blacks in other United States populations. Our findings in conjunction with those from other areas and times of low prevalence suggest environmental factors play a relatively insignificant role in the etiology of NTDs in such populations.
Differences in frequency of cleft lip among the a strains of mice
Authors: Juriloff D. M.
Published: June 2005

The frequency of spontaneous cleft lip on Day 14 of gestation was examined in the A/J, A/HeJ, A/WySn, A.BY/Sn, A.SW/Sn, Bl0.A/SgSn, and B10.A(2R)/SgSn inbred strains of mice. A/WySn was found to have a higher frequency of cleft lip (20–30%) than A/J or A/HeJ (10%). Differences among strains in laterality of clefting and in rates of differential mortality of affected embryos were also found. Results of crosses between A/WySn and A/HeJ suggested that the difference in rate of clefting may be due to a genetic maternal effect. The results for A.BY/Sn, A.SW/Sn, Bl0.A/SgSn and B10.A(2R)/SgSn indicated that no association of cleft lip liability and the H‐2 complex was detectable.
The teratogenicity of cocaine
Authors: Fantel Alan G. , MacPhail Bonita J.
Published: June 2005

Pregnant rats and mice received high doses of cocaine hydrochloride by intraperitoneal injection. Despite treatment periods which included most of organogenesis, no increase in congenital abnormalities was observed. Rats showed significant reductions in maternal and fetal weights as well as increased resorption frequencies. Fetal edema was also found. Mice showed only decreased fetal weights with no increase in malformations.
In vitro effects of the teratogen and folic acid antagonist, 9‐methyl pteroylglutamic acid, on glycosaminoglycan accumulation in fetal rat limbs
Authors: Schmidt Richard R. , Abbott Patricia K. , Cotler Jerome M.
Published: June 2005

Fetal rat limbs were obtained from pregnant females on the 14th day of gestation. Forelimbs and hindlimbs were pooled separately and preincubated for 22 hours at 37°C in Eagle's MEM containing the teratogen and folic acid antagonist, 9‐methyl pteroylglutamic acid (9‐mePGA). Following removal of old medium, fresh medium together with the teratogen were added at the same concentration as before. Tritiated glucosamine (10 μCi) was added to each vial and the incubation continued for 4 hours at 37°C. Tissues were homogenized, digested with pronase, and glycosaminoglycans (GAG) selectively precipitated with cetylpyridinium chloride. In vitro exposure of fetal limbs to various doses of 9‐mePGA resulted in a significant increase in the accumulation of labeled GAG by fetal forelimbs at the high and intermediate dosage levels. No effect was observed at the lowest dose. Accumulation of labeled GAG by fetal hindlimbs although similar to fetal forelimbs in control incubations, was unaffected by in vitro exposure to 9‐mePGA at any of the dosage levels studied.
Trisomy 13 in the mouse
Authors: Hongell Karin , Gropp A.
Published: June 2005

The fetal development of mice trisomic for chromosome 13 (Ts 13) was investigated. Trisomic fetuses were obtained from the progeny of male mice heterozygous for the two Robertsonian translocation chromosomes Rb (11.13)4Bnr and Rb (6.13)3Rma mated to “all acrocentric” NMRI females. Trisomic fetuses were found at all stages between days 12 and 19 of gestation (vaginal plug day counted as day 1). The frequency of trisomy was 24.8% of all surviving implants. The frequency of Ts decreased slightly but not significantly with progressing pregnancy. In eight newborn litters, two dead and four living trisomic newborns (13.6%) were found. The latter died within a few hours after birth. The most conspicuous features of Ts 13 fetuses were their small size and a marked hypoplasia as compared with their normal euploid in utero mates. The weight of the the trisomic fetuses and that of their placentas was significantly lower than of the normal controls at all stages studied. The general developmental delay and the delay of the ossification of Ts 13 fetuses were about 1 to 1 1/2 days. Cleft palate was observed in 86% of the Ts 13 fetuses. Edema developed in the neck and back of the trisomic fetuses from day 14 on; this disappeared after day 17. It is suggested that the hypoplasia and general retardation of growth found in trisomy 13 and in other autosomal trisomies, as well as the more or less specific palatal and cardiovascular malformations in this disorder, may be caused by impaired proliferation of trisomic cells. This postulated impairment of cell growth may also affect the fetal part of the placenta.
Teratogenic and clastogenic effects of BUdR in mice
Authors: Fränz J. , Kleinebrecht J.
Published: June 2005

Pregnant mice (C57B1/6JFfm) were treated with BUdR on day 9 of gestation. For doses ranging from 300 to 1,200 mg/kg b.w. of BUdR the teratogenic effect in near‐term fetuses was analyzed. The findings confirm the phase and dose dependency of the induced malformations found by other authors. They also demonstrate, however, a BUdR‐specific induction of special malformations. For a dose of 1,200 mg/kg of BUdR the effect on mitotic rates and the induction of chromosomal aberrations were investigated. Mitotic rates were counted in single organs as well as in total homogenized embryos. The methods are equally useful. The embryos were analyzed 3, 6, 12, and 24 hours after BUdR treatment either after homogenization or in serial sections. Decrease of mitotic rates has been found to be most remarkable at 3 and 12 hours after treatment. At 24 hours only the neural tissue showed a slight decrease of the mitotic rate. Chromosomal aberrations are induced at all times, but the highest rates are seen at 3 and 12 hours after treatment. The aberrations are of the chromatid type.
Teratogenic effects of 27.12 MHz radiofrequency radiation in rats
Authors: Lary Joseph M. , Conover David L. , Foley Edward D. , Hanser Peggy L.
Published: June 2005

High‐intensity 27.12 MHz radiofrequency (RF) radiation was determined to be teratogenic in rats during most of the gestation period. Eight groups of pregnant rats were exposed to a magnetic field strength of 55 amps/meter and an electric field strength of 300 volts/meter on gestation days 1, 3, 5, 7, 9, 11, 13, or 15. Exposures ceased once the dam's colonic temperature reached 43.0°C (about 20–40 minutes' duration). Eight matching control groups were sham‐irradiated for 30 minutes at 0 amps/meter and 0 volts/meter. An additional group of pregnant rats received no treatment. With one exception, no significant differences occurred between sham‐irradiated and untreated control groups. RF exposure, however, caused a significant incidence of fetal malformations throughout the postimplantation period (days 7 through 15). It also caused a low but significant incidence of preimplantation malformations. Fetal weight and crownrump length were reduced in all postimplantation exposure groups but were not affected by preimplantation exposure. The incidence of dead or resorbed fetuses was significantly increased in rats irradiated on days 7 or 9. The effects observed appeared to be caused by RF‐induced hyperthermia in the treated dams. Since a number of industrial, scientific, and medical devices operating at or near 27.12 MHz can cause hyperthermia in humans, women of childbearing age should avoid exposure to RF‐radiation levels that exceed current US occupational standards.
The use of early chick embryos in experimental embryology and teratology: Improvements in standard procedures
Authors: Fisher Marilyn , Schoenwolf Gary C.
Published: June 2005

The chick embryo is a convenient experimental system for embryologic and teratologic studies. However, windowing eggs during the first day of incubation, a procedure that is required to expose embryos in ovo, frequently results in dysmorphogenesis. The frequency and severity of the particular anomalies caused by windowing are greater the younger the embryo at the time this procedure is done. At all stages examined, dysraphic defects of the neural tube are the most common anomaly present following windowing. Defects of the neural tube are virtually eliminated if the air space introduced over the embryo by windowing is filled with albumen or saline, and the egg (with its window sealed with tape) rotated 180°, so that the embryo rests subjacent to an undisturbed area of the shell. Subblastodermic injection of saline, a vehicle often used for teratogenic agents, has no adverse effects when eggs are subsequently filled with albumen or saline and rotated. Furthermore, known teratogens (e.g., colchicine, hyaluronidase) injected subblastodermically after windowing are active in eggs that are then filled with albumen or saline and rotated. Finally, the addition of albumen or saline, followed by rotation, may be delayed up to 3 hours without reducing the restorative effects of these two procedures. Our modified procedures for the handling of windowed eggs significantly increase the value of young chick embryos for studies of early developmental events.
Relationship of developmental stage to effects of vinblastine on the artificial “embryo” of hydra
Authors: Chun Yong H. , Johnson E. Marshall , Gabel Bradley E. G.
Published: June 2005

Three milligrams of vinblastine sulfate per liter of culture medium prevented normal development of all reaggregated artificial hydra “embryos” at the 66‐hour stage of regeneration. One milligram of vinblastine per liter of medium had no effect on development, and 100 mg did not markedly accelerate the developmental disruption beyond the pace of the 2 mg/liter concentration which was the lowest effective concentration. Treatment with vinblastine through the first few hours of development was sufficient to produce the toxic endpoint at 66 hours of incubation, but effects were delayed in appearance when treatment was initiated later in development. Early development of exposed preparations proceeded normally even in the presence of rather high concentrations of the test substance, and the pellet was resistant to the effects of vinblastine treatment begun after 24 hours of development. From these results, it would appear that interference with cell division is not the primary means by which vinblastine perturbs this developing system.
Embryotoxicity of Norlestrin, a combined synthetic oral contraceptive, in rhesus macaques (Macaca mulatta)
Authors: Prahalada S. , Hendrickx A. G.
Published: June 2005

Thirty timed‐mated pregnant rhesus monkeys received Norlestrin (Norethindrone acetate, 2.5 mg, and ethinyl estradiol, 0.05 mg pertablet, Parke‐Davis) orally at four different dose levels. The dose levels were 5, 10, 25 and 50 mg/day/monkey and the doses were administered during early (days 21–35), late (days 33–46), and throughout (days 21–46) organogenesis, except for the 50‐mg‐dose‐group animals, which were treated only during early organogenesis (days 21–35). All except the animals in the 50‐mg‐dose group were allowed to go to term (165 days gestation). Pregnancy for the animals in the 50‐mg‐dose group was terminated by eesarean section on day 50 of gestation and the fetuses were fixed, serially sectioned, and examined histologically. No teratogenicity was observed. However, the prenatal mortality rate (38.5%) was higher for the Norlestrin‐treated animals than in the control colony (21%). Eight animals aborted between days 40 and 78 of gestation and two other cases resulted in stillbirths at 139 and 165 days of gestation. There was a higher incidence of abortion (44.4%) in the 25‐mg‐dose group. Norlestrin treatment during early organogenesis also resulted in a higher abortion rate (37.5%) compared to treatment during late organogenesis (22.2% abortions). No morphological abnormalities were found in infants observed at birth or in juvenile monkeys which died of natural causes or in those that were sacrificed over a period of two years. No histopathology was observed in the 50‐day‐old fetuses examined by serial section. Examination of endogenous maternal serum estrogen and progesterone levels in Norlestrin‐treated monkeys (25 mg/day, days 21–35) suggested that placental steroidogenesis was not affected; however, the lower levels of estrogen in maternal serum suggested that the ovarian steroidogenesis was affected. Although the precise pathogenesis of this selective embryolethality is not known, several observations in this study suggest a direct generalized embryotoxic effect. Thus, this study for the first time has demonstrated that, while Norlestrin may be embryolethal at 100 times the human contraceptive dose equivalent (25 mg/day) in the rhesus monkey, nevertheless it does not affect the offspring which survive the exposure.
Some teratogenic properties of ethanol and acetaldehyde in C57BL/6J mice: Implications for the study of the fetal alcohol syndrome
Authors: Webster W. S. , Walsh D. A. , McEwen S. E. , Lipson A. H.
Published: June 2005

To investigate the teratogenic effect of acute alcohol exposure, pregnant C57BL/6J mice were exposed to 25% ethanol (either two doses of 2.9g/kg or one dose 5.8g/kg) during the organogenic period either by intraperitoneal injections or by intubation. The incidence of malformations varied according to (1) the stage of embryonic development at the time of exposure, (2) the route of administration of the alcohol, and (3) the amount of alcohol given and the time period over which it was administered. Oral doses of alcohol were teratogenic although less so than the same dose given intraperitoneally, and two intraperitoneal doses four hours apart produced significantly more malformations than the same two doses six hours apart. The primary metabolite of alcohol, acetaldehyde, was also investigated for its teratogenicity. It was found that one or two doses of four percent acetaldehyde (0.32g/kg), administered intraperitoneally were teratogenic. A further attempt was made to raise blood acetaldehyde levels by exposing mice to disulfiram, an inhibitor of acetaldehyde dehydrogenase, prior to administration of alcohol. The disulfiram pretreatment did not increase the malformation rate. Treatment with alcohol on day 7 or 8 caused a variety of facial abnormalities, some of which were comparable to those seen in children with fetal alcohol syndrome. Exposure on day 9 or 10 resulted in limb defects. The results suggest that one or more episodes of heavy maternal drinking at critical periods in pregnancy may severly damage the embryo and may produce many features of the fetal alcohol syndrome.
Evaluation of the association between birth defects and exposure to ambient vinyl chloride
Authors: Thériault Gilles , Iturra Hilda , Gingras Suzanne
Published: June 2005

Birth defects incidence for infants born to residents of Shawinigan, Canada in 1966–1979 were significantly higher than in three comparison communities. Since there has been a vinyl chloride polymerization plant in this town since 1943 from which ten cases of angiosarcoma of the liver have been identified, this study explores the possible association between exposure to vinyl chloride monomer (VCM) in ambient air and the occurrence of birth defects in the community. The excess of birth defects fluctuated seasonally in a way that corresponded to changes in VCM concentration in the environment. Mothers who gave birth to malformed children were younger on average in Shawinigan than in the comparison communities. However, there was no excess of still‐births in Shawinigan. The excess in birth defects involved most organ systems, and variation in birth‐defect rates among school districts could not be accounted for by estimates of VCM in the atmosphere. The occupational and residential histories of parents who gave birth to malformed infants were compared with those of parents of normal infants. The two groups did not differ in occupational exposure or closeness of residence to the vinyl chloride polymerization plant. Some descriptive data from this study raised the hypothesis of an association between VCM in the air and birth defects in the exposed community, but as a whole, within the sample size available, such an association could not be substantiated.
Altered postnatal mitogenic responsiveness of adult rat splenic lymphocytes following in utero exposure to corn oil
Authors: Schmidt Richard R. , Abbott Patricia K.
Published: June 2005

Pregnant rats were administered 160,000 USP units of retinol acetate in 0.5 ml corn oil by gavage on the 15th–19th days of gestation. In addition to untreated pregnant controls, another group of pregnant animals received 0.5 ml corn oil only over the same gestational interval. Mitogenic responsiveness of splenic lymphocytes obtained from adult offspring was evaluated using an in vitro lymphocyte transformation assay. Splenic lymphocytes (5 ± 105/well) were cultured for either 48, 72, or 96 h in the presence of either concanavalin A (Con A), phytohemagglutinin (PHA), or pokeweed mitogen (PWM). Lymphocyte responsiveness to the T‐cell mitogens, Con A and PHA, was significantly reduced by 48 h of culture in the offspring of the corn oil control and retinol‐acetate‐treated groups and remained constant from 48 h to 72 h. Lymphocytes from the offspring of the untreated controls displayed a decreased mitogenic responsiveness to all three mitogens from 48 h to 72 h of culture. Responsiveness to the B‐cell mitogen, PWM, was similar for splenic lymphocytes of all three groups. Furthermore, a significant increase in cellularity was observed in spleens obtained from the mature offspring of the corn oil control and retinol‐acetate‐treated groups. No differences were observed between lymphocytes obtained from offspring of corn oil control and retinol‐acetate‐treated animals in any of the parameters studied. Results of the present study permit us to suggest that monitoring postnatal immune function subsequent to prenatal insult is an area that should be especially considered by teratologists.
Teratogenic action of hypolipidemic agents: An in vitro study with postimplantation rat embryos
Authors: Steele C. E. , New D. A. T. , Ashford A. , Copping G. P.
Published: June 2005

Two hypolipidemic agents known to be embryotoxic and teratogenic in vivo were found also to cause developmental abnormalities when added to the culture serum of rat embryos growing in vitro. However, development was normal when the embryos were grown in hypolipidemic serum (low in cholesterol and triglycerides) prepared from rats dosed with the hypolipidemic agents. The results indicated that it is a direct action of the agents on the embryos, and not the hypolidemia, which is harmful to embryonic development.
Retained developmental capacity of blastocysts transferred from lead‐intoxicated mice
Authors: Wide Mariann
Published: June 2005

Blastocysts from mice injected with an implantation‐inhibiting dose of lead were transferred nonsurgically to pregnant foster mothers. This was done to obtain information about the ability of these blastocysts to implant and to develop into late fetal stages. There was no difference in the ability of lead‐treated blastocysts to implant as compared with the transferred nontreated blastocysts. Nor was there any effect of the exposure to lead before implantation upon the development of the blastocysts into normal fetuses. The results indicate that the preimplantation blastocysts are protected from possible harmful influences from the lead treatment of the mothers, and that the implantation failure in lead‐treated mice is not due to the inability of the blastocysts to implant. A significant increase in the frequency of exencephaly was observed in fetuses derived from transplanted blastocysts as compared with those from normal pregnant mice.
The pathogenesis of retinoic acid‐induced vertebral abnormalities in golden Syrian hamster fetuses
Authors: Wiley M. J.
Published: June 2005

Administration of single doses of retinoic acid to hamsters on days 7, 8, and 9 of pregnancy resulted in missing, irregular, and abnormally fused centers of ossification in the vertebrae of fetuses recovered near term. A study of early events in embryonic tissues following maternal treatment with 60 mg/kg of the teratogen on day 8 revealed a variety of changes which could be linked to the development of the bony defects. By 12 hours following treatment, the mean number of somites in teratogen‐exposed embryos was significantly reduced in comparison to controls. Within 24 hours of maternal treatment lesions were observed in the aortae of the retinoic acid‐exposed embryos. The vessels were consistently damaged caudally with dissection of aortic contents into the adjacent unsegmented mesoderm. Kinking of the neural tube, notochordal irregularities, and a loss of intercellular relationships in the paraxial mesoderm accompanied the vascular lesions. By 36 hours following treatment, abnormalities were evident in the appearance of the caudal somites, and at later stages these appeared to translate into defects in the sclerotomes and subsequently, the vertebrae. The observations suggest that vascular damage plays a significant role in the induction of the vertebral defects by disrupting somitogenesis. Moreover, the results support the hypothesis that retinoic acid produces abnormalities in the vertebral skeleton by a mechanism different from that which has been suggested to operate in the induction of defects in the limb skeleton.
Arsenic‐induced exencephaly in the mouse and associated lesions occurring during neurulation
Authors: Morrissey Richard E. , Mottet N. Karle
Published: June 2005

Early tissue damage following a teratogenic dose of arsenic to the dam was studied in mice with the objective of detecting the primary lesion associated with the development of exencephaly. Animals were killed 6 to 21 h after a single 45 mg/kg intraperitoneal injection of sodium arsenate on day 8 of pregnancy and neurulation‐stage embryos were fixed for histological and ultrastructural examination. In the prospective hindbrain, the most consistent feature associated with arsenate treatment was the widely separated neural folds which were not positioned for closure. Intracytoplasmic inclusions, interpreted as necrotic debris, were most numerous in the apical portion of the neural folds, sometimes extending into the mesenchyme, but they were not extensive in most embryos. In the prospective forebrain, necrotic debris was found throughout the neuroepithelium, in contrast to the posterior portions of the developing brain. It is not clear that necrosis of the neuroepithelium or mesenchyme would in itself be the primary lesion associated with exencephaly, although death of specific cells such as those participating in the fusion process could be involved. The potential effect of arsenate on physiological and biochemical processes which could affect neural tube closure is discussed.
Abnormal head posture associated with induction of cleft plate by methylmercury in C57BL/6J mice
Authors: Diewert Virginia M. , Juriloff Diana M.
Published: June 2005

Maternal treatment with methylmercury (MeHg) has been shown to induce a high frequency of cleft palate and produce growth retardation in rat and mouse fetuses, but the relation between these effects is unknown. The objective of this study was to determine if mandibular growth retardation was a factor that contributed to induction of cleft palate in C57BL/6J mice. Two dose of MeHg (10 mg/kg maternal body weight) were given subcutaneously on days 10 and 11 of gestation, and the fetuses were morphometrically studied on days 14, 15, and 18. Full clefts of the secondary palate were present in approximately half of the treated day 15 and 18 fetuses; therefore, the cleft palate (CP) and noncleft palate (NCP) groups were analyzed separately to facilitate identification of morphologic changes associated with the clefting. The results showed that, compared with controls, the day 14 MeHg‐treated fetuses had significantly smaller placental weights, but only half of the fetuses had delayed palatal shelf elevation, reduced body weight, and delayed morphological development. However on day 15, the CP and the NCP groups had similar reductions in body weight and placental weight. A striking downward and forward positioning of the head was present in the MeHg‐treated fetuses with the CP group more severely affected than the NCP group. Significant differences between the three groups (control, NCP, and CP) were present with mean head‐to‐body angles of 67°, 60° and 51°, respectively. The absence of normal head lifting resulted in a relative mandibular retrognathia that when combined with a decrease in mandibular length produced alterations in spatial relations that were most severe in the CP fetuses. The results suggest that after exposure to MeHg, palatal closure is affected by altered tongue posture associated with the abnormal head positioning and shortening of the mandible that develop following placental and embryonic growth retardation.
Ultrastructure of trypan blue‐induced ocular defects II. Cornea and mesenchyme
Authors: Schmidt Karmen L. , Milner Karen , Hilburn Pamela J. , Schmidt Waldemar A.
Published: June 2005

Using scanning and transmission electron microscopy, the histological and cytological alterations induced in the developing eye by trypan blue were examined. Microphthalmic and anophthalmic eyes were analyzed from 16‐day rat fetuses whose dams had received a teratogenic dose of trypan blue. Cell and tissue damage within cornea and mesenchyme were assessed. Corneas from the treated groups were undulating and uneven owing to abnormal lens placement and corneal cell injury. Extensive extracellular spacing, few cell‐to‐cell contacts, patchy glycocalyces, and abnormal surface morphology characterized the corneal cells of treated tissues. Mesenchyme of severely malformed eyes typically filled the eye field in regions normally occupied by retina and lens. As a tissue, mesenchyme lacked organization and those surface features normally present in component cells were altered. Mesenchymal cells were packed so closely that extracellular spaces were nearly obliterated. Microvilli, filopodia, and lamellipodia, cell processes observed in normal mesenchyme, were altered in both number and structure. The cytoplasm of mesenchymal cells was condensed and decreased in volume. These data suggested that (1) in this trypan blue ocular model, virtually all major tissue types were morphologically altered; (2) because healthy mesenchyme and cornea are required for normal development of lens, optic vesicle and ocular adnexa it follows that abnormal cornea and mesenchyme also will compromise these tissues; and (3) since necrotic reminants were not present, this trypan blue model probably causes developmental arrest. The most likely teratogenic pathway is presented with emphasis on the cell surface as a probable site of dye action.
Calvarial defect in human anencephaly
Authors: Chaurasia B. D.
Published: June 2005

The calvarial defect in human anencephaly has been studied on 21 anencephalic skulls in all of which the defect extended into the vertebral column. Based on the boundaries of the defect, a nomenclature of the anomaly has been proposed that is simpler, more scientific, and more informative than previous ones because it expresses the precise extent of destruction of the cranial vault. In the present study, the defect was “fronto‐occipito‐vertebral” in 71.4%, “occipito‐vertebral” in 23.8%, and “parieto‐occipito‐vertebral” in 4.8% of cases. The morphologic details of the cranial bones bounding the calvarial defect have been described.
Norethisterone acetate and ethinylestradiol in early human pregnancy
Authors: Pulkkinen M. O. , Düsterberg B. , Hasan H. , Kivikoski A. , Laajoki V.
Published: June 2005

In a double‐blind randomized trial, 25 women (8–9 weeks pregnant) received 20 mg norethisterone acetate (NET‐AC) and 0.04 mg ethinylestradiol (EE2), 25 women receiving placebo. The patients were followed by ultrasound and the products at curettage studied macroscopically and microscopically. In an open trial, ten patients (5–9 weeks pregnant) received NET‐AC + EE2, 11 serving as controls. The concentrations of plasma progesterone, estradiol‐17β, 17α‐hydroxyprogesterone, norethisterone, and FSH were followed.

The frequency of intrauterine hemorrhage in early pregnancy was not affected by NET‐AC + EE2. Ultrasound was not reliable when studying the occurrence of decidual hemorrhages during early pregnancy. The pharmacokinetics and bioavailability of NET remain unchanged during early pregnancy. The treatment with NET‐AC + EE2 had no effect on the heights and the time courses of the mean plasma values of progesterone, estradiol‐17β, 17α‐hydroxyprogesterone, and FSH. No differences were found between treated and nontreated patients in the pathology of the placenta or decidua as determined by both macroscopic and microscopic examinations.

The hypothesis of Papp and Gardo, that decidual hemorrhages may be induced in early pregnancy as a consequence of a “withdrawal effect” of hormonal pregnancy tests, is not supported by the results of this investigation.
An embryotoxicity study of the fungicide tridemorph and its commercial formulation Calixin
Authors: Merkle J. , Schulz V. , Gelbke H. P.
Published: June 2005

Tridemorph (N‐tridecyl‐2,6‐dimethylmorpholine), the active ingredient of the commercially formulated fungicide Calixin, is a teratogen in rats and mice. The no‐effect level for embryotoxic effects was 27.5 mg/kg for mice and 20.6 mg/kg for rats.

By contrast, when Calixin, which contains 83% tridemorph, was administered orally at dose levels of 0.156, 0.722, and 3.909 mg/kg, no embryotoxic effects were observed in two strains of rats. Our extensive investigations, carried out under exposure conditions resembling as closely as possible those reported in another study, did not reproduce the previous findings of teratogenicity of Calixin.
Cortisone cure of the lidgap defect in fetal mice: A dose‐response and time‐response study
Authors: Harris M. J. , Juriloff D. M. , Biddle F. G.
Published: June 2005

Cortisone administered during pregnancy prevents the phenotypic expression of lidgap‐Miller (lgMl), a genetically determined congenital defect in mice. The dose‐response, on a probit log dose scale, is linear to a dose of 60 mg/kg maternal body weight, giving an observed maximum cure of 94% and an ED50

Median effective dose.

of 27 mg/kg. At higher doses the rate of prevention diminishes, to 56% at 320 mg/kg. Fetal (18‐day) weight remains unaffected for doses of up to 60 mg/kg and then drops sharply at higher doses, suggesting that cortisone is toxic in this higher range. The severity of lidgap, measured in two ways (as one or both eyes open and as width of gap), decreases as its frequency falls. This finding is in keeping with the threshold model for birth defects. The threshold appears to be in the embryos rather than in their mothers. There is a broad optimum time of treatment: days 13–14 for the 80 mg/kg dose, and days 14–15 for the 30 mg/kg dose. Treatment on day 16 has little or no effect. It is not known how cortisone cures the lidgap trait. The action may be specific–to stimulate transcription of a specific gene, possibly of the lidgap locus itself–or more general, e.g., to alter cell division rate or extracellular matrix constituents.
Taste aversion learning in preweanling rats exposed to alcohol prenatally
Authors: Riley Edward P. , Barron Susan , Driscoll Cynthia D. , Chen Jaw‐Sy
Published: June 2005

The effects of prenatal alcohol exposure on the development of a conditioned taste aversion were examined in preweanling rat pups. Mothers of these pups were fed isocaloric liquid diets containing either 35 or 0% ethanolderived calories (EDC) from gestation days 6 through 20. A pair‐feeding procedure was employed, and an ad lib lab chow control group was also included. At 5, 10, or 15 days of age, pups were infused with a saccharin solution through a cannula implanted in the oral cavity. Half of the pups in each group were then injected with lithium chloride (LiCl), which served as the poisoning agent, and the other half with sodium chloride (NaCl) as a control. Animals were subsequently tested for a conditioned aversion to the saccharin solution. At 15 days of age, all of the pups in the LiCl‐poisoned group demonstrated a conditioned taste aversion to the saccharin solution, but the degree of this aversion was less in alcohol‐exposed offspring. At 10 days of age, a taste aversion was learned, although it was not as strong as that shown by 15‐day‐old pups, and it appeared to be learned equally well by all of the prenatal treatment groups. At 5 days of age, there was marginal support for taste aversion learning. Again, it did not interact with prenatal treatment. The ontogenic differences in taste aversion learning exhibited by alcohol‐exposed offspring relative to controls are discussed in terms of altered hippocampal development.
Potentiation of acetazolamide induced ectrodactyly in SWV and C57BL/6J mice by Cadmium Sulfate
Authors: Kuczuk Maureen H. , Scott William J.
Published: June 2005

CdSO4 and acetazolamide each induce postaxial ectrodactyly in rodents when administered at a critical time in forelimb development. C57BL/6J mice are extremely sensitive to the teratogenic action of both agents, whereas SWV mice are relatively resistant. Additionally, both of these agents can inhibit carbonic anhydrase. In the present study administration of CdSO4 and acetazolamide in combination to either strain of mice potentiates the incidence of forelimb ectrodactyly. These results, in combination with the aforementioned similarities of teratogenesis, suggest a common mechanism of teratogenesis.
Prenatal repair of experimentally induced clefts in the secondary palate of the rat
Authors: Schuepbach Peter M. , Schroeder Hubert E.
Published: June 2005

A refined technique of amniotic sac puncturing at day 16.2 (i.e., 16 + 2/10 days) of gestation was employed in order to produce a series of total clefts and rare forms of partial clefts in Sprague‐Dawley rat fetuses. From a total of 410 fetuses of a precise, individually determined age, 95 upper jaws were examined in the scanning electron microscope and, in part, in serial Epon sections. All fetal heads were examined macroscopically. Total clefts were found in 48.9% of a total of 184 viable rat fetuses examined at day 17.8 of smear age and in 21.8% of a total of 211 fetuses examined at day 19.3. Partial clefts were observed in 14.1% and 18.5% of fetuses at days 17.8 and 19.3 of smear age, respectively. At day 19.3, 16.1% of the viable fetuses showed a very inconspicuous, small abnormality (with residual clefting and incomplete fusion with the nasal septum) in the region of the palatine foraminae. Morphological observations suggested that under conditions of detained palatal closure (1) fusion of the soft palatal shelves commences independently from and prior to fusion of the hard palate, (2) delayed palatal shelf fusion proceeding in the anterior direction may occur with or without remaining sickle‐shaped clefts in the anterior hard palate, and (3) in fetuses with small sickle‐shaped clefts, fusion of the palatal shelves with the nasal septum does not occur. The present data imply that an almost total prenatal repair and delayed closure of the secondary palate may occur in rats that, at day 16.2 of multiple analysis age, most certainly had a total palatal cleft resulting from tongue resistance.
The effect of medroxyprogesterone acetate (Depo‐provera) on prenatal development in the baboon (Papio anubis): A preliminary study
Authors: Tarara R.
Published: June 2005

Six female olive baboons (Papio cynocephalus anubis) were treated with a single dose of 150 mg of Depo‐Provera i.m. at day 30 of pregnancy, approximately three times the human dose equivalent on a body weight basis. Fetectomies were performed at day 100 of gestation. The body weights and measurements of the five live fetuses were comparable to age‐matched controls and no gross or histologic abnormalities were seen. The dead fetus was in an advanced state of decomposition. This preliminary study suggests that, at levels up to three times that used for human contraception, Depo‐Provera does not appear to have any adverse effects on fetal development.
Synergistic effect of subteratogenic doses of antisera on the development in the rat
Authors: Miyata Koichiro , Munakata Shuzo , Takesue Tetsuo , Yamamoto Eiji , Ninomiya Makoto , Ono Seigo
Published: June 2005

Wistar rats were administered rabbit anti‐rat‐umbilical‐cord serum (AUCS) alone on day 9 of gestation or in combination with subteratogenic doses of rabbit anti‐rat‐kidney serum (AKS). The results showed that the incidence of malformation was low (13.1% ± 7.0 S.E.) even when very high doses of AUCS alone were administered. However, the incidence markedly increased to 61.0% ± 9.3 S.E. when a small dose (0.10 ml/100 gm) of AKS was administered on day 9 followed by 0.90 ml/100 gm of AUCS on day 10. The malformations included microphthalmia, hydrocephaly, aortic arch anomalies, ventricular septal defect, and anophthalmia, being similar to the effects of a medium dose of AKS. These results suggest that a combination of subteratogenic doses of teratogenic antisera produces malformations, possibly by mechanisms that potentiate the teratogenic action of the sera.
Oxidative metabolites of diethylstilbestrol in the fetal Syrian golden hamster
Authors: Maydl Regina , Metzler Manfred
Published: June 2005

14C‐Diethylstilbestrol was administered orally, intraperitoneally, and intrafetally to 15‐day pregnant hamsters at a dose of 20 mg/kg body weight, and the radioactivity was determined in the fetus, placenta, and maternal liver after 6 hours. Significant amounts of radioactivity were found in these tissues in every case, indicating maternal‐fetal and fetal‐maternal transfer of diethylstilbestrol. Part of the radioactivity found in the tissues could not be extracted even after excessive washing. This implied the presence of reactive metabolites. In the fetal and placental extracts, eight oxidative metabolites of diethylstilbestrol were identified by mass fragmentography as hydroxy‐ and methoxy‐derivatives of diethylstilbestrol, pseudodiethylstilbestrol, and dienestrol. The presence of oxidative metabolites in the hamster fetus and the covalent binding to tissue macromolecules are possibly associated with the fetotoxic effects of diethylstilbestrol.
Neural‐tube defects produced in Syrian hamsters by potato glycoalkaloids
Authors: Renwick J. H. , Claringbold W. D. B. , Earthy Marion E. , Few J. D. , Carolines A. , McLean S.
Published: June 2005

Keeler et al. (78) showed that potato sprouts could be teratogens for the central nervous system in the Syrian hamster. We demonstrate here the same teratogenic effects from a British cultivar, Arran Pilot. Most of the activity was traced to the two solanidine triglycosides, α‐chaconine and, at a higher dose level, α‐solanine. Some possible implications for the study of human neural‐tube defects are considered.
Epithelial changes of the nasal columella of the palatal slit and cleft palate defects in C57Bl/6 mouse fetuses
Authors: Kusanagi Takao
Published: June 2005

Palatal slit and cleft palate are induced in fetuses of C57BL/6 female mice treated with triamcinolone acetonide. In this study, the progressive changes in the epithelia of the presumptive fusion areas of the nasal columella and the anterodorsal part of the secondary palate were examined histologically. No difference was seen in the epithelial changes of the nasal columella of fetuses with palatal slit and those with cleft palate. In the treated palates the basal cuboidal epithelial cells in the presumptive fusion area of the nasal columella extended further toward the nasal cavity, and the vacuolization of the nasal epithelial cells appeared earlier than in the untreated palates. Although the treatment produced epithelial changes of the presumptive fusion area, its primary effect does not seem to be the disturbance of the epithelial fusion processes. The induction of palatal slit may be due to a failure of the primary and secondary palates to make adequate contact and fuse at the appropriate developmental stage because the secondary palate closure is delayed.