bluuebunny/crossref_metadata_2025 huggingface dataset:
Impermeability of the rat placenta to insulin during organogenesis
Authors: Widness John A. , Goldman Allen S. , Susa John B. , Oh William , Schwartz Robert
Published: June 2005

The cause of the embryopathy associated with diabetes mellitus is uncertain. To examine whether exogenously administered insulin may be teratogenic, tracer amounts of radiolabelled insulin were infused for two hours during organogenesis (day 12 1/2 of gestation) into three groups of pregnant rats: control (n = 8), diabetic (n = 5), and hyperinsulinemic (n = 4). For maternal plasma, no differences were found among the three study groups in the perecentage of the protein‐precipitable (insulin‐containing) radioactivity. Tissue radioactivities were expressed relative to the two‐hour maternal plasma sample. Maternal kidney samples had the highest total and protein precipitable counts followed in descending order by the maternal plasma, maternal liver, placenta, and embryo. No differences in radioactivities were noted among the three study groups for specific tissues studied. Protein‐precipitable radioactivities in the embryo were more than 100‐fold less than the maternal plasma values. In 11 of the 17 litters, the acid‐insoluble fractions of the embryos were not distinguishable from background counts, and none of the remaining six were greater than twice background. These studies demonstrate that during the period of organogenesis, the rat embryo is protected from maternal insulin by the placenta, and hence, maternal insulin in an unlikely teratogen.
The effect of aminothiadiazole on glycogenesis and glycogenolysis in fetal and neonatal rat liver
Authors: Beaudoin Allan R.
Published: June 2005

The effect of the teratogen 2‐amino‐1,3,4‐thiadiazole on glycogenesis and glycogenolysis was investigated in the fetal and neonatal rat liver. At day 15, 16, or 17 of gestation (sperm day = day 0) pregnant Sprague‐Dawley rats received a single IP injection of an aqueous solution of aminothiadiazole. Dosages used were teratogenic (100 mg/kg maternal body weight) and nonteratogenic (10 mg/kg). At day 16 some rats received nicotinamide (100 mg/rat) in addition to a teratogenic dose of aminothiadiazole. Livers were recovered for assay at fetal day 20 and postnatal day 1. Only at day 16 did a teratogenic dose induce a significant depression in the fetal activity of glycogen synthetase (to 49.6% of control activity) and glucose‐6‐phosphatase (to 72.2% of control activity), and in glycogen accumulation (to 72.6% of control accumulation). At day 15, a teratogenic dose significantly depressed glucose‐6‐phosphatase activity but not glycogen synthetase activity or glycogen accumulation. Nicotinamide, given immediately after aminothiadiazole, was effective in blocking the inhibition. Teratogenic treatment had no effect on the postnatal activity of glucose‐6‐phosphatase. Apparently some event associated with birth releases the enzyme from its prenatal inhibition. These results demonstrate a parallelism between the perturbing effect of aminothiadiazole on biochemical development and morphological development with respect to time of insult, dose response, and protection with its antitertogen. The mechanism of action whereby aminothiadiazole depresses the activity of glycogen synthetase and glucose‐6‐phosphatase remains to be determined.
Sites of lead localization in embryonic chick tissues following treatment
Authors: Kuettel Michael R. , Kaplan Stanley
Published: June 2005

Lead treatment by subgerminal injection causes rupture of embryonic chick dorsal aortae during early morphogenesis, followed by localized caudal hematoma formation. Shortly thereafter, damaged tissues are resorbed, leading to a condition known as rumplessness (caudal dysplasia syndrome in humans). We have studied this process by light microscopy and have found that the caudal dorsal aortae exhibit morphological alterations as early as 4 hr after injection. Further, we used energy dispersive X‐ray analysis (EDXA) to establish the precise localization and distribution of lead in the developing embryo, 4 hr after Pb(NO3)2 treatment. Embryos treated with NaNO3 were used as controls. The hierarchy of lead concentrations was endothelium of the caudal dorsal aortae > caudal endoderm > blood cells. The surrounding mesenchyme, neural tube, and notocord, as well as all control embryonic tissue, exhibited no detectable lead levels. These results suggest that lead has a high degree of specificity for entering and damaging the developing caudal dorsal aortae. A possible mechanism for this phenomenon is that lead gains access to the vascular net surrounding the caudal region of the embryo at the time of injection. Parts of this vascular net including the lead are then incorporated into the developing caudal dorsal aortae as they grow distally, thus further concentrating the lead.
Importance of the route of administration for genetic differences in benzo[a]pyrene‐induced in utero toxicity and teratogenicity
Authors: Legraverend Catherine , Guenthner Thomas M. , Nebert Daniel W.
Published: June 2005

C57BL/6N (Ahb/Ahb) mice have a high‐affinity Ah receptor in tissues, whereas AKR/J and DBA/2N (Ahd/Ahd) mice have a poor‐affinity Ah receptor. The cytochrome P1‐450 induction response (enhanced benzo[a]pyrene metabolism) occurs much more readily in Ahb/Ahb and Ahb/Ahd than in Ahd/Ahd mice, at any given dose of the inducer benzo[a]pyrene.

Embryos from the AKR/J × (C57BL/6N)(AKR/J)F1 and the reciprocal backcross were studied during benzo[a]pyrene feeding of the pregnant females. Oral benzo[a]pyrene (120 mg/kg/day) given to pregnant Ahd/Ahd mice between gestational day 2 and 10 produces more intrauterine toxicity and malformations in Ahd/Ahd than Ahb/Ahd embryos. This striking allelic difference is not seen in pregnant Ahb/Ahd mice receiving oral benzo[a]pyrene. Pharmacokinetics studies with [3H]benzo[a]pyrene in the diet and high‐performance liquid chromatographic analysis of benzo[a]pyrene metabolism in vitro by the maternal intestine, liver, and ovary and the embryos of control and oral benzo[a]pyrene‐treated pregnant females are consistent with “first‐pass elimination” kinetics and differences in benzo[a]pyrene metabolism by the embryos and/or placentas versus maternal tissues. In the pregnant Ahd/Ahd mouse receiving oral benzo[a]pyrene, little induction of benzo[a]pyrene metabolism occurs in her intestine and liver; this leads to much larger amounts ofbenzo[a]pyrene reaching her embryos, and genetic differences in toxicity and teratogenesis are manifest. In the pregnant Ahb/Ahd mouse receiving oral benzo[a]pyrene, benzo[a]pyrene metabolism is greatly enhanced in her intestine and liver; this leads to less benzo[a]pyrene reaching her embryos, much less intrauterine toxicity and malformations, and no genetic differences are manifest. More toxic metabolites (especially benzo[a]pyrene 1,6‐ and 3,6‐quinones) are shown to occur in Ahd/Ahd embryos than in Ahb/Ahd embryos. In additional studies, no prenatal or neonatal “imprinting” effect in C57BL/6N mice by 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin or Aroclor 1254 on benzo[a]pyrene metabolism later in life was detectable.

These genetic differences in intrauterine toxicity and teratogenicity induced by oral benzo[a]pyrene are just opposite those induced by intraperitoneal benzo[a]pyrene (Shum et al., '79; Hoshino et al., '81). The data in the present report emphasize the importance of the route of administration when the teratogen induces its own metabolism.
The effects of prenatal ethanol in cynomolgus monkeys
Authors: Scott William J. , Fradkin Rochelle
Published: June 2005

Ethanol was administered to pregnant cynomolgus monkeys (Macaca fascicularis) from day 20 to 150 of gestation. The ethanol was delivered by intragastric intubation twice a day at 8 AM and 5 PM. Dosage was begun at a relatively low level, 2 g/kg/day and increased gradually to attain a final dosage of 4 or 5 g/kg/day. The offspring were allowed to be delivered naturally and remained with their mother until 23 days of age when they were sacrificed. Maternal blood ethanol and acetaldehyde levels were monitored at weekly intervals throughout pregnancy. Pregnancy wastage in the form of abortions and stillbirths was increased by ethanol treatment especially at the high dose. Birthweight was significantly lowered in offspring of mothers receiving 5 g/kg/day of ethanol. However, no structural malformations or facial changes suggestive of those seen in the human fetal alcohol syndrome were found in any of the offspring. We conclude that the conditions of our study did not produce a satisfactory model of human fetal alcohol syndrome.
Growth parameters in normal fetuses
Authors: McBride Mary L. , Baillie Joan , Poland Betty J.
Published: June 2005

A total of 14 linear measurements, seven ratios of linear measurements, and the weights of eight organs were taken from 100 normal fetuses. The fetuses had been therapeutically aborted between 11 and 19 weeks of gestational age by prostaglandin induction or hysterotomy. Measurements were obtained from at least five fetuses for each week of development age. A correlation matrix was calculated in order to identify those variables that showed a significant relationship with each other and with total body measurements. Significant correlations were obtained between crown–rump length and the following: head circumference, femur length, and humerus length. These three measurements were also significantly correlated with body weight. First‐order regression equations were produced for these significantly correlated variables. This information can be used to estimate fetal growth even when the fetus is incomplete.
The effects of ethanol exposure during the brain growth spurt in rats
Authors: Burns Elizabeth M. , Kruckeberg Thomas W. , Stibler Helena , Cerven Erik , Borg Stefan
Published: June 2005

The purpose of this study was to determine whether micromorphological changes occur at a low level of ethanol exposure previously shown by us to induce alterations in synaptosomal biochemistry. The results suggest that 4 g ethanol per kg body weight daily throughout the brain growth spurt causes no significant structural changes in the cerebellum, lobule IX, at the light and electron microscopic levels. Although ethanol‐ and isocaloric sucrose‐treated groups did not differ from each other in cumulative percent body weight gain throughout the treatment period, both groups differed significantly in this parameter from isocaloric milk‐treated and “handled” control groups. On the day following completion of the treatment period, brain weight in the ethanol‐treated group was significantly less than that of all other groups. Further, the results indicate that isocaloric sucrose “pair feeding” is contraindicated in postnatal studies and that nutritional status is better controlled by daily gavage of neonates than by other methods currently used in ethanol studies in postnatal animals.
A short‐term screening test for teratogens using differentiating neuroblastoma cells in vitro
Authors: Mummery C. L. , van den Brink C. E. , van der Saag P. T. , de Laat S. W.
Published: June 2005

Thirty‐nine teratogenic and 18 nonteratogenic compounds were tested using an assay based on the ability of agents to interfere with normal growth and differentiation of murine neuroblastoma cells (clone N1E‐115) in culture. Induction of differentiation in cells under growth‐promoting conditions and inhibition of differentiating cells over a period of 7 days was dose‐dependent, with the lowest effective dose not being highly toxic. Eighty‐six percent of the compounds were correctly identified by the assay. The proportions of both false negatives (10%) and false positives (22%) were of the same order or better than in current, comparable tests. The possibilities offered by the system in rapid screening for teratogenic potential of environmental agents are discussed.
The neuroteratogenicity of procarbazine in the rat: Behavioral, morphological, and neurochemical aspects
Authors: Johnson J. M. , Thompson D. J. , Burek J. D. , Haggerty G. C. , Dyke I. L. , Lower C. E. , Solomon J. L.
Published: June 2005

Pregnant female sprague‐Dawley rats were treated from day 12 through day 15 of gestation with procarbazine, an antineoplastic drug, and their offspring were subjected to tests of locomotor development and behavior. Treatment levels ranged from 0.5 mg/kg/day, a dose that produced no abnormalities, to 10 mg/kg/day, a dose that caused a marked micrencephaly in the absence of other teratological changes. Despite marked morphological brain changes, preweaning locomotor development, as assessed by open‐field swimming activity and vertical grid climbing, was normal in all offspring. Postweaning passive avoidance learning and retention were also normal. Groups that had been treated prenatally with teratogenic doses (5.0 and 10.0 mg/kg/day) displayed less rearing behavior in the open field, while ambulation in the periphery of the open field arena was unaffected. Groups treated with subteratogenic doses (0.5 and 1.0 mg/kg/day) did not differ from control. In addition to the behavioral studies, sodium‐dependent high‐affinity choline uptake and choline acetyltransferase activity (CAT) were measured (per mg protein) in the cortex and hippocampus of animals that had been exposed prenatally to either teratogenic or subteratogenic doses of procarbazine. In spite of a substantial reduction in size of both brain structures in the group receiving a teratogenic dose, choline uptake and CAT did not differ from control.
Teratology of intravaginally administered contraceptive Jelly containing octoxynol‐9 in rats
Authors: Saad Dorothy J. C. , Kirsch Robert M. , Kaplan Leonard L. , Rodwell Dean E.
Published: June 2005

Octoxynol‐9, a nonionic surfactant used as a spermicidal agent in ORTHO‐GYNOL (registered trademark) Contraceptive Jelly (Ortho Pharmaceutical Corporation, Raritan, NJ), was administered intravaginally to pregnant Sprague Dawley COBS CD rats at dosages of 0.5 mg/kg/day and 5 mg/kg/day (two‐thirds and six times the clinical dosage) on days 6–15 of gestation in order to assess its teratogenic potential. Untreated, sham, and vehicle control groups were also incorporated into the study protocol. No meaningful differences were observed between the treated and control groups in maternal toxicity, maternal reproductive parameters, fetal toxicity, and the incidence of external, visceral, and skeletal malformations or developmental variations. It is concluded that octoxynol‐9 is not embryotoxic or teratogenic when administered intravaginally to rats during organogenesis.
Zinc amelioration of cadmium‐induced teratogenesis in vitro
Authors: Warner C. W. , Sadler T. W. , Tulis S. A. , Smith M. Kate
Published: June 2005

Mouse embryos were exposed to cadmium (5.35 μg/ml) for either 0.5h or 1h and then transferred to fresh serum for the duration of the experiment. Embryos exposed for 0.5h developed numerous malformations that were primarily localized to the craniofacial region. Embryos exposed for 1h to the same level of cadmium all failed to thrive. In a separate series of experments zinc (10 μg/ml) was added 15 minutes prior to the addition of cadmium. Embryos treated with cadmium for 30 min. after the addition of zinc, resulted in 15 of 16 embryos developing normally. The second group of embryos treated for 1h after preincubation with zine resulted in 93% of the embryos surviving after 48h, albeit malformed. These results suggest that: (1) Exposure time to a teratogen is a critical parameter to consider when designing in vitro experiments (2) zinc is effective in protecting embryos against cadmium induced teratogenesis and (3) the whole embryo culture system is effective in demonstrating biological interactions between agents.
Novel accessory skull bone in fetal rats after exposure to aspirin
Authors: Mitala J. J. , Boardman J. P. , Carrano R. A. , Iuliucci J. D.
Published: June 2005

Aspirin was administered by oral gavage to 25 gravid Sprague‐Dawley rats on gestation day 10, as a single dose of 500 mg/kg, in a concentration of 50 mg/ml. The aspirin was suspended in a mixture of 0.5% w/v hydroxypropylmethylcellulose (Methocel E‐4M) and 0.1% w/v polysorbate 80 (Tween 80). A control group of 25 gravid rats was given 10 ml/kg/day of the suspending vehicle alone, by oral gavage, on gestation days 6 through 15. C‐sections were performed on gestation day 20. Approximately two‐thirds of the fetuses were processed for skeletal examination with Alizarin Red S; the remaining fetuses were placed in Bouin's solution. Examination of the fetal skeletal specimens from the aspirin‐treated group revealed a 20% fetak (43% litter) incidence of an accessory skull bone, located between the nasal and frontal bones. This structure ranged in size from a small, barely discernible, circular ossification site (<0.5 mm) to a relatively large, bilobate bone (∼2 mm). This anomaly has not been previously reported in fetal rats.
Epigastrius with omphalocele—report of a case
Authors: Yasuda Yoshiko , Ohtsuki Hitoshi , Torii Shozo , Tomoyoshi Eiko , Clark Clarence F.
Published: June 2005

An epigastrius (parasitic twinning in the epigastrium) was delivered via the vaginal route spontaneously and died 37 days later. The autosite had cardiac hypertrophy with VSD, PDA, and PFO and an omphalocele. The liver was partly conjoined. There was a small swelling at the lower part of the autosite's bifurcated sternum to which the parasitic left pelvis and lower extremity were attached. On the second day after birth, parasitectomy was performed. The amputated specimens consisted of a small left pelvic girdle with a free extremity, a scrotal mass, nipplelike structures and two small protuberances externally. The liver, intestines, two testes, one kidney, one ureter, and the bladder were contained within the omphalocele. Although all of the organs and external structures of the parasite had abnormal histopathological findings, differentiated muscle fibers and submucous and/or myenteric plexus were observed.
Left cleft lip predominance and genetic similarities of L line and CL/Fr strain mice
Authors: Trasler Daphne G. , Trasler Tessa A.
Published: June 2005

Newborn litters of the L line and CL/Fr and A/JFr strains were examined, and sex, frequency and type of cleft lip (left, right or bilateral) were recorded. Embryos and fetuses from crosses between these strains and line were collected on days 13 to 16 of gestation, and frequency and type of cleft lip recorded. Overall cleft frequencies in L × CL/Fr, CL/Fr × L, and CL/Fr × A/JFr crosses (female stated first) were similar, while in A/JFr × L (10.3%) they were significantly lower than in L × A/JFr (23.3%). The data suggested that the same maternal effect genes were present in CL/Fr and the related L line and absent from A/JFr. In the L, CL/Fr, and A/JFr newborns, there was a tendency for males to have higher frequencies of cleft lip and bilateral cleft lip and the latter was significant for L. Left cleft lip frequency was significantly higher than right for L and CL/Fr newborns and in embryos of the CL/Fr × L and L × CL/Fr cross. No significant differences in laterality were found in the A/JFr strain, A/JFr × L, L × A/JFr, and CL/Fr × A/JFr crosses. It was concluded that (1) the embryonic and maternal effect genes for cleft lip are similar or identical in CL/Fr and L; and (2) using data from the literature, there are additional genetic factor(s) increasing left cleft lip occurrence acting in the embryo, which are present in CL/Fr, L, A/HeJ, A/He, and A/St and absent from A/JKt, A/J, A/JFr, and A/WySn.
Teratogenic effect of maternal zinc deficiency and its co‐teratogenic effect with cadmium
Authors: Sato Fumihiko , Watanabe Toshiaki , Hoshi Eishin , Endo Akira
Published: June 2005

The teratogenic effects of feeding pregnant mice with the levels of zinc that were severely deficient (0.5 ppm), marginally deficient (10 ppm), or zinc replete (50 ppm) were studied. All groups of animals were fed the experimental diet from 1–18 days of gestation (dg) except for one additional group which received 0.5 ppm Zn diet from 5–14 dg. The effects of a single dose of 2.0 mg/kg of cadmium chloride (CdCl2) injected on 8 dg in mice fed the marginally zinc‐deficient or the zinc‐replete diets were also investigated. We found that more than 95% of fetuses exhibited a variety of external and skeletal malformations in the severely zinc‐deficient groups and that the frequency of malformed fetuses in the marginally zinc‐deficient group was similar to that of the control animals. Injection of CdCl2produced a significant increase in the incidence of malformations in the marginally zinc‐deficient mice, but not in zinc‐replete animals. These results demonstrate that severe zinc deficiency is teratogenic in mice and that a marginal zinc intake influences the teratogenic potential of cadmium.
The effect of isoproterenol on cardiovascular function in the stage 24 chick embryo
Authors: Clark Edward B. , Hu Norman , Dooley John B.
Published: June 2005

The developing cardiovascular system of the chick embryo is susceptible to teratogenic effects of catecholamines. Yet the mechanism for the teratogenetic action is unclear. Since catecholamines affect cardiovascular physiology, we studied the acute effect of the β‐agonist isoproterenol on mean atrial pressure, heart rate, mean dorsal aortic blood flow, mean arterial pressure and vascular resistance in stage 24 chick embryos. Dorsal aortic blood velocity was measured with a 20‐MHz pulsed‐Doppler velocity meter and intravascular pressure was measured with a servo‐null pressure system. Isoproterenol in doses of 2 × 10−4 μg (2.5 μg/kg), 8 × 10−4 μg (10 μg/kg), and 1.2 × 10−3μg (15 μg/kg) was injected intravenously in 5‐μl aliquots of chick Ringer's solution. Additional groups of embryos were treated with the β‐antagonist propranolol, and isoproterenol plus propranolol. Control embryos received 5 μl chick Ringer's solution to assess the hemodynamic effects of a volume injection. We found that isoproterenol caused no change in mean atrial pressure, heart rate, or mean arterial pressure. However, isoproterenol caused a dose‐related decrease in dorsal aortic blood flow and a 2.5‐fold increase in vascular resistance. The effects of isoproterenol were blocked by propranolol, which suggested that the increase in vascular resistance was mediated by β‐receptor stimulation.
Elevated rate of DNA synthesis and its correlation to cAMP‐phosphodiesterase activity during induction of polydactyly in mouse embryos heterozygous for Hemimelia‐extra toe (Hmx)
Authors: Knudsen Thomas B. , Elmer William A. , Kochhar Devendra M.
Published: June 2005

The induction of polydactyly in mouse embryos heterozygous for Hemimelia‐extra toe (Hmx) is associated with aberrant outgrowth of the developing autopod on day 12 of gestation. We have quantitated the rate of DNA synthesis and the activity of cAMP‐phosphodiesterase (PDE) that is characteristic of the prospective polydactylous region. Mid‐stage 18 hind‐limb buds were labeled with [3H]dThd either in situ using whole embryo culture, or as isolated preaxial autopod fragments cultured on a membrane substratum. The mean specific activities of incorporation were compared for normal (+/+) and mutant (Hmx/+) genotypes. A significant (P ≤ 0.01) 19% increase, peculiar to the prospective polydactylous region, was measured after 4 hours in embryo culture. The same increment was detected after 4 hours in organ culture, but was amplified linearly to 55% when incubation was extended to 20 hours. During this period, continuous exposure to 1.0 mM IBMX (3‐isobutyl‐1‐methyl xanthine), an inhibitor of cAMP‐PDE activity, “slowed down” the rate of DNA synthesis to untreated +/+ proportions. When cAMP‐PDE activity was assayed in uncultured autopods, a significant (P ≤ 0.01) 18% increase was detected within the prospective polydactylous region specifically on stage 18 of gestation. This is the developmental phase during which polydactylous outgrowth is induced in situ. Thus, uncontrolled cAMP‐PDE activity may, in part, provoke the enhanced rate of cell proliferation.
Uptake and binding of tritium from [chloroethyl 3H] cyclophosphamide by rat embryos in vitro
Authors: Mirkes Philip E. , Greenaway Jean C.
Published: June 2005

Day 10 rat embryos were exposed in vitro to [chloroethyl 3H] cyclophosphamide (3H‐CP) at 4 μg/ml over a 24‐hour period and the uptake and binding of labeled drug were monitored autoradiographically and biochemically. Autoradiographic analysis revealed that embryos exposed to 3H‐CP and a complete activating system exhibited radioactivity distributed throughout the embryo. Subsequent analysis indicated that the distribution of autoradiographic grains on a per cell basis ranged from 7.7 in surface ectoderm to 13.4 in the neuroepithelium. No correlation was found between the sensitivity of various embryonic tissues to the cytotoxic effects of CP and the number of grains per cell. Direct radiochemical analysis of the amount of tritium taken up and bound by embryos under bioactivating conditions (3H‐CP + S‐9 + cofactors) confirmed the autoradiographic analysis. Autoradiographic and radiochemical analyses demonstrate that embryos exposed under bioactivating conditions take up and bind approximately three times more tritium than embryos exposed under nonactivating conditions (3H‐CP + S‐9 without cofactors). Additional studies have demonstrated that uptake and binding of tritium from bioactivated 3H‐CP only are linear over the first 10 hours of incubation with no detectable increases thereafter.
Chromosomal abnormalities in the Kaiser‐Permanente birth defects study, with special reference to contraceptive use around the time of conception
Authors: Harlap S. , Shiono P. H. , Ramcharan S. , Golbus M. , Bachman R. , Mann J. , Lewis J. P.
Published: June 2005

Chromosomal abnormalities were studied in 33,551 abortions and births to women whose contraceptive histories had been recorded at their first antenatal visit in 1975–1977. Chromosome examinations were performed exclusively on clinical grounds. There were 45 de novo abnormalities detected (1.34/1,000); three of them were detected at amniocentesis. Trisomy 21 was observed in 27 cases (0.80/1,000), trisomy 18 in nine (0.27), other trisomies in three (0.09), and translocations or deletions in five (0.15). One case of triploidy and six cases of inherited abnormalities were detected. There were no significant racial variations. No increase in risk for chromosomal abnormalities was found among women who had used oral contraceptives prior to becoming pregnant or among women who experienced oral contraceptive breakthrough pregnancies. Two cases of trisomy 18 were observed among the 814 deliveries following oral contraceptive breakthrough conceptions (2.46/1,000), two cases of trisomy 21 occurred in 338 births following failures of rhythm contraception (5.92/1,000), and no cases of trisomy 21 or 18 among the 1,569 women using spermicides at the time of conception.
Brain manganese, catecholamine turnover, and the development of startle in rats prenatally exposed to manganese
Authors: Kontur Paul J. , Fechter Laurence D.
Published: June 2005

Manganese (Mn) can be neurotoxic when present in high concentrations. Neonatal animals show differential absorption, accumulation, and excretion of Mn relative to adults. If similar kinetic differences exist during gestation, then fetal animals may be susceptible to Mn neurotoxicity. The objective of this study was to examine maternal‐fetal Mn transfer and the susceptibility of prenatal animals to Mn neurotoxicity. This was approached by studying the ability of Mn to cross the placenta and reach the fetal central nervous system using radiotracer and atomic absorption spectroscopy techniques. Manganese is thought to disrupt catecholamine neurotransmission in the central nervous system. This was examined in newborn rats by alphamethyl‐para‐tyrosine induced catecholamine turnover and the development of the acoustic startle response. The results suggest that there are limits on fetal Mn accumulation under conditions of both normal and excessive dietary Mn levels. Manganese accumulation in the fetal brain after exposure to increased dietary Mn does not alter either dopamine or norepinephrine turnover or the development of the acoustic startle response. Excess Mn does not appear to be neurotoxic to fetal rats in spite of its limited accumulation in nervous tissue after gestational exposure.
Canine cryptorchism and subsequent testicular neoplasia: Case‐control study with epidemiologic update
Authors: Hayes Howard M. , Wilson George P. , Pendergrass Thomas W. , Cox Victor S.
Published: June 2005

A retrospective study of 2,912 cryptorchid dogs identified 14 breeds with significantly high risk. Among six distinct closely interrelated breed groups (e.g., toy, miniature, and standard poodles), the risk in the smaller breed was always greater than that in the larger relative, suggesting that genetically influenced maldescent could be, in part, related to physical size or the rate of growth of the involved structures. Testicular tumors were diagnosed in 5.7% of the cryptorchid dogs; half had only Sertoli cell tumors, one‐third had only seminomas. The relative risk for Sertoli cell tumor or seminoma was not directly related to a familial risk for cryptorchism. Using the health experience of a control population composed of male dogs with anal sac disease (N = 4,184), there is an estimated relative risk of 9.2 in cryptorchid dogs to develop a testis tumor (95% confidence interval, 5.9–14.3) and 4.2 in dogs with inguinal hernia (95% confidence interval, 1.8–9.5). Considering that the anatomical development of the genital tract, testis descent, and tunic relationships in dog are very similar to that in man, and that the associations of cryptorchism and inguinal hernia with testis neoplasms are also similar, the dog should be an excellent model system to further investigate the causes of human cryptorchism.
Genetic analysis of spontaneous and induced palatal slit in C57BL/6 mice
Authors: Kusanagi Takao , Miller James R.
Published: June 2005

The results of experiments designed to elucidate the nature of the genetic factors underlying the palatal slit defect in C57BL/6 mice indicate that probably two loci in females and four in males determine the difference in susceptibility to the spontaneous defect between the C57BL/6 and SWV/BcTa strains of mice. Moreover, it appears that these are not the same genes determining the difference between these same strains in palatal slit response to maternal treatment with triamcinolone. Additional evidence is presented to support the view that in the C57BL/6 strain the triamcinolone‐induced palatal slit and cleft palate responses are not correlated.
Hirschsprung disease in a large birth cohort
Authors: Spouge D. , Baird P. A.
Published: June 2005

The incidence of Hirschsprung disease was studied in a series of almost 700,000 consecutive livebirths in British Columbia from 1964–1982, by means of the records of a health surveillance registry that uses multiple sources of ascertainment. The estimated liveborn incidence rate for Hirschsprung disease was 1 in 4,417 livebirths (156 cases out of 689,118 livebirths). Data pertaining to sex ratio, additional anomalies, recurrence, and mortality were also analyzed over the caseload period 1952 to 1983. A total of 29.8% of cases had some additional anomaly–the majority being nonregional anomalies in other systems or more distantly in the gastrointestinal tract. Cardiovascular and gastrointestinal anomalies not a direct consequence of Hirschsprung disease were the most frequent additional anomalies found, occurring in 10 and 12 of 178 cases, respectively. Sensorineural anomalies were also frequent, occurring in 12 of 178 cases. Clinical implications arising from the study regarding the neonatal assessment of infants with these anomalies are discussed.
Characteristics of growth and palatal shelf development in ICR mice after exposure to methylmercury
Authors: Yasuda Yoshiaki , Datu Abdul Razak , Hirata Shuichi , Fujimoto Toyoaki
Published: June 2005

A single dose of 25 mg/kg methylmercuric chloride (MeHg) was given orally to gravid ICR mice. Cleft palate was induced in 100% of the offspring, with the critical treatment period ranging from day 10/8 hours (10/8) to 12/16 of gestation. Dose‐dependent body weight reduction was observed in day 18 fetuses from both the day 10/8 and 12/16 groups. However, fetal weight reduction was greater in the day 12/16 group for all the MeHg treatments investigated. The relative potency of the induction of cleft palate by MeHg was slightly but significantly higher in the fetuses of the day 12/16 group (1.044–1.197‐fold in 95% limits) than in the day 10/8 group. The results showed that when 25 mg/kg of MeHg was given to the fetuses in the day 10/8 group, palatal shelf growth was delayed at a more primitive stage than in the day 12/16 fetuses. Moreover, disharmony of development between the overall fetus and palatal shelf was noticed. Furthermore, in the day 12/16 fetuses, a delay of palatal shelf growth occurred just prior to shelf elevation. Prior to shelf elevation, coordination was probably lost in the development between the fetus and the palatal shelves. Normal palatal closure in ICR fetuses occurs about 1 day and 10 hours earlier (P < 0.05) than in the A/J fetuses (Biddle, '80). Normal palatal shelves in ICR fetuses moved rapidly, with 3.0 to 5.7 hours (in 95% limits) required for all fetuses to achieve elevation, while, in MeHg‐treated groups, palatal shelf elevation did not occur. The results suggest that the cause of the failure in palatal shelf elevation may be understood by examining the disharmonious development of the fetus after exposure to MeHg.
Effects of cadmium on preimplantation mouse embryos in vitro with special reference to their implantation capacity and subsequent development
Authors: Yu H. S. , Tam P. P. L. , Chan S. T. H.
Published: June 2005

A short exposure to 5 or 10 μg/ml cadmium chloride for 24 hours disturbed the in vitro development of four‐cell and morula‐stage embryos of F1 (C57 female × A2G male) mice. Morulae appeared to be less sensitive to cadmium than four‐cell embryos. However, the in vitro development of four‐cell embryos through compaction to morulae was not affected, though most treated embryos degenerated and decompacted later. It was proposed that cadmium toxicity may not be acting through contact effects on the cell surface and cytoskeleton. It probably interferes with the general energy metabolism of the cells. Although 1 μg/ml cadmium did not disturb the subsequent in vitro development beyond the implantation stage, a reduced capacity of implantation in vivo was observed after surgical transfer to recipients. In spite of the effects of cadmium salts on the maternal side, the present results suggest that a direct embryotoxic and teratogenic activity of cadmium cannot be excluded.
Lead exposure on critical days of fetal life affects fertility in the female mouse
Authors: Wide Mariann
Published: June 2005

Female mice were exposed to lead in utero by intravenous injection of lead chloride into the mothers at different stages of pregnancy. At a mature age the mice exposed as fetuses (F1 generation) conceived at a normal rate, but the litter size and fetal survival varied significantly. Small litters and increased numbers of fetal deaths were observed in mice exposed to lead on day 8 of intrauterine life. The live fetuses in this group were normal with respect to weight and morphological appearance. Serum levels of estradiol and progesterone, measured on day 17 of pregnancy, did not differ significantly between F1 mice of a control, unexposed group and of the group exposed to lead on day 8 of intrauterine life. Ovarian follicle counts revealed a significantly smaller number of primordial follicles in the latter group. It is suggested that the exposure to lead at a time of early organogenesis caused the observed fertility decrease by interfering with the development of the female germ cells.
Cadmium‐induced forelimb ectrodactyly: A proposed mechanism of teratogenesis
Authors: Feuston Maureen H. , Scott William J.
Published: June 2005

We have attempted to elucidate the mechanism of cadmium teratogenesis utilizing inbred mouse strains sensitive (C57BL/6J) or resistant (SWV) to the embryotoxic effect of this common heavy metal contaminant. Carbonic anhydrase activity of whole‐embryo homogenates was moderately depressed in C57BL/6J mice compared to a slight and transient decrease in the resistant SWV mice. Embryonic erythrocytes were similarly examined, and the cadmium did not have any effect on carbonic anhydrase activity in either strain. Likewise, histochemical examination of carbonic anhydrase activity did not reveal any effect of cadmium in the embryos of their strain.

Generally, the zinc concentration of embryos was not affected by cadmium administration. However, increased levels of zinc were observed in cadmiumexposed yolk sacs of both strains suggesting that cadmium produces an adverse effect on yolk sac function. Untreated C57BL/6J units (embryo plus surrounding extraembryonic membranes), embryos, and yolk sacs had much lower hemoglobin concentrations than those observed in untreated SWV units, embryos, and yolk sacs. Additionally, cadmium exposure significantly decreased C57BL/6J embryonic hemoglobin levels on gestation day 10 (PM) and increased C57BL/6J yolk sac hemoglobin levels on gestation days 10 (AM) and 10 (PM). No difference in hemoglobin concentration was observed between untreated and cadmium‐treated SWV embryos or yolk sacs. We propose that cadmium induces forelimb ectrodactyly by creating an acidotic embryonic environment and that the primary site at which cadmium exerts its teratogenic effect might be the yolk sac.
A comparison of hydrocortisone and triamcinolone inhibition of scale and feather development
Authors: Fisher Cynthia J. , Sawyer Roger H.
Published: June 2005

Hydrocortisone (30–40 μg on day 10) and triamcinolone (10–20 ng on day 7–8) both inhibit or alter morphogenesis of scales and feathers. However, there are marked temporal and region‐specific differences in the effects induced by these two glucocorticoids. Triamcinolone (TAC) is most teratogenic on day 7 or 8, inhibiting formation of spurs and feathers and inducing club feather formation. Hydrocortisone is most teratogenic later in development, on day 10. Unique hydrocortisone‐induced responses are complete inhibition of scutellate scale formation, bent feathers, and apteria around the external auditory meatus. Altered synthesis of keratin polypeptides follows inhibition of scale morphogenesis by hydrocortisone and TAC. These in vivo data suggest that heterogeneity of glucocorticoid binding occurs in embryonic chick metatarsal skin. Survival data indicate that TAC is 2,000 times more embryotoxic than hydrocortisone.
Yolk sac failure in embryopathy due to hyperglycemia: Ultrastructural analysis of yolk sac differentiation associated with embryopathy in rat conceptuses under hyperglycemic conditions
Authors: Pinter Emese , Reece E. Albert , Leranth Csaba Z. , Sanyal Mrinal K. , Hobbins John C. , Mahoney Maurice J. , Naftolin Frederick
Published: June 2005

Diabetes mellitus in pregnancy is associated with an increased incidence of various congenital anomalies that occur during organogenesis. Because a well functioning yolk sac is crucial to embryonic growth and development during this period, we performed an ultrastructural study of the effects of excess glucose (total glucose 750 mg/dl, osmolality 305 mOsm/kg) on pregnancy day 10 (Witschi stage 13) rat conceptuses cultured for 48 hr in heat‐inactivated male rat serum with and without added d‐ or l‐glucose. Embryos exposed to excess d‐glucose demonstrated decreased conceptus size (P < 0.001), and gross malformations in a dose‐related fashion. The visceral yolk sac capillaries and vitelline vessels of conceptuses in excess d‐glucose were sparse, patchy, and nonuniformly located. Ultrastructurally, the visceral yolk sac endodermal cells had reduced numbers of rough endoplasmic reticulum, ribosomes, and mitochondria. These obvious defects in yolk sac structure suggest that hyperglycemia during organogenesis has a primary deleterious effect on yolk sac function with resultant embryopathy.
Scalp neoplasm associated with cranium bifidum in a 24‐week human fetus
Authors: Barr Mason , Heidelberger Kathleen P. , Dorovini‐Zis Katerina
Published: June 2005

Prenatal ultrasonography at 24 weeks disclosed a fetus with a large mass protruding from the occiput. The mass was an invasive, undifferentiated mesenchymal neoplasm of the scalp associated with a defect in the occipital bone (cranium bifidum). The tumor may have derived from neural crest at the site of rhombencephalic closure. The tumor itself would seem to be a sporadic event, but the cranium bifidum may imply a recurrence risk of 2–3% for future pregnancies.
Perinatal cannabinoid exposure: Effects on hepatic cytochrome P‐450 and plasma protein levels in male mice
Authors: Dalterio S. , Thomford P. J. , Michael S. D. , DeAngelo L. , Mayfield D.
Published: June 2005

Maternal exposure to the major psychoactive Δ9‐tetrahydrocannabinol (THC), or to the nonpsychoactive cannabinol (CBN) or cannabidiol (CBD) on day 12 of gestation, or on day 1 postpartum, affected the concentrations of hepatic cytochromes P‐450 in adult male offspring. Levels of P‐450 were significantly increased in adult males prenatally exposed to cannabinoids, but were reduced after postnatal exposure. The response to exogenous testosterone was also differentially affected by perinatal cannbinoid exposure, with reduced plasma androgen in males prenatally to THC or CBN. There was a concomitant decrease in plasma albumin and increased γ‐globulin in adult males postnatally exposed to CBN. Beta‐globulin levels were also significantly increased in adult males exposed to cannabichromine (CBC) on day 1 postpartum. Cannabinoid exposure during perinatal periods of development exert effects on hepatic function, plasma androgen levels, and on the immune system. These effects may reflect the ability of perinatal cannabinoid exposure to interfere with androgen‐mediated processes of differentiation.
Renal functional teratogenesis resulting from adriamycin exposure
Authors: Kavlock Robert J. , Rogers Ellen H. , Rehnberg Blair F.
Published: June 2005

Pregnant Sprague‐Dawley rats were exposed to adriamycin and offspring were evaluated for renal functional competence. Exposure consisted of 0, 1.0 or 1.5 mg/kg/day by intraperitoneal injection on either gestational days 7–10 or 10–12. The exposed offspring were evaluated for 1) growth and viability; 2) serum concentrations and renal clearances of creatinine, urea, glucose, sodium, potassium, chloride, and total osmotic particles; 3) the ability to excrete an osmotically concentrated urine following fluid deprivation; 4) the ability to excrete an osmotically dilute urine following isotonic volume expansion; and 5) the ability to secrete hydrogen ions following administration of a fixed acid. Exposure during days 7–10 of gestation produced greater evidence of overt developmental toxicity than did exposure during days 10–12 of gestation. The reverse was true, however, for the effects of adriamycin on renal function, as the majority of effects on these measures were found in the high dose pups exposed during days 10–12 of gestation. The application of the renal function tests did not lower the observed effect level for adriamycin‐induced developmental toxicity, but it did provide confirmatory information on the nature of the effect, on the magnitude of the effect in the exposed population, and on the possible morphological site of observed functional lesion. For reasons discussed in the text, a combination of the basal clearance test and the renal concentrating test appears to provide the most efficient means for detecting the presence of prenatally induced functional alterations of the kidneys.
Syngeneic spleen cell immunization induces high mortality among progeny in mice
Authors: Pechan Peter A.
Published: June 2005

Syngeneic spleen cell immunization of C57BL/6J females prior to syngeneic matings resulted in significant perinatal and postnatal mortality and increased abnormality among progeny. Thus female recipients of transplants and transfusions from major histocompatibility complex (MHC) compatible donors might effect some risk to their progeny.
The natural history of gastroschisis during fetal life: Development of the fibrous coating on the bowel loops
Authors: Tibboel D. , Vermey‐Keers C. , Klück P. , Gaillard J. L. J. , Koppenberg J. , Molenaar J. C.
Published: June 2005

Patients with gastroschisis have a paraumbilical defect of the anterior abdominal wall through which bowel loops protrude. These bowel loops are edematous and covered by a fibrous coating. The moment of occurrence of gastroschisis as well as the development of the fibrous coating are unknown. This prompted an investigation of 26 human embryos and fetuses with gastroschisis at various developmental stages (crown‐rump length 25–240 mm) and two stillborn fetuses (gestational age 30 weeks) with gastroschisis, as well as resected material from ten newborns (gestational age 33–40 weeks) operated for gastroschisis. Progressive changes of the serosa were only noted after the 30th week of gestation and consisted of an amniotic fluid peritonitis and progressive fibrosis. The changes are in agreement with experimental data and correlate with changes in the composition of amniotic fluid. The findings prove that gastroschisis is a very early occurrence, while the fibrous coating is a late development.
An epidemiological study on the effect of N, N′‐methylene‐bis‐(2‐amino‐1,3,4‐thiadiazole) (MATDA) on outcomes of pregnancy
Authors: De‐Kun Li , Qi‐Dong Zhou , Xing‐Bo Qin , Rong‐Min Sun , Xi‐Lan Zhu , He‐Jian Cheng , Cheng‐Su Wang , Jian‐Ping He , Chao Qian , Shou‐Zhen Xue , Xue‐Qi Gu
Published: June 2005

A retrospective cohort study on the effect of the suspected teratogenic pesticide N, N′ ‐methylene‐bis‐(2‐amino‐1,3,4‐thiadiazole) (MATDA) on outcomes of pregnancy was conducted. The exposed group (6,173 pregnancies) was composed of childbearing women who, during their gestation, consumed rice harvested from a field where MATDA had been applied. The control I group (10,145) came from an adjacent county where MATDA had never been used; the control II group (3,326) consisted of women who had been pregnant previous to the introduction of this pesticide in the same region as the exposed group. The validity of the survey was verified by comparability and data checking studies. After adjustment for the calendar year, maternal age, and pregnancy order, no significant differences were found in rates of spontaneous abortion, fetal death and stillbirth, birth defects, as well as in sex ratio and birth weight between the study groups. The same result was found in the comparison of individual categories of malformation. The rates of the birth defects were 23.84, 21.49, and 22.78 per 1,000 live births for the exposed, internal, and external control groups, respectively. No dose‐response relationship was revealed. The results were consistent with previous reports and indicated the difference between animal experiments and human exposures. Although MATDA is teratogenic in animals, it is clear that the pesticide does not adversely effect outcomes of pregnancy in humans as currently applied.
Prevention of caffeine‐induced limb malformations by maternal adrenalectomy
Authors: Moriguchi Masahide , Scott William J.
Published: June 2005

Caffeine at high doses is a known rodent teratogen and induces limb malformations along with cleft palate in various strains of rats and mice. Fujii and Nishimura ('74) postulated that caffeine was teratogenic by virtue of catecholamine release from maternal or embryonic tissue. We tested this hypothesis by surgically removing the maternal adrenal gland on day 6 of pregnancy and then administering 175 mg/kg of caffeine intraperitoneally at 1600 h day 11 and 900 h day 12. The teratogenic effects of caffeine in adrenal‐ectomized versus nonadrenalectomized AKR mice were assessed in day 18 fetuses. Thirty percent of the surviving offspring were malformed in caffeinetreated, nonadrenalectomized dams compared to 7% of the offspring from adrenalectomized dams. Therefore we believe caffeine teratogenesis is initiated by release of catecholamines from the maternal adrenal gland.