bluuebunny/crossref_metadata_2025 huggingface dataset:
Study of the mechanisms of BUdR‐induced cleft palate in the mouse
Authors: Bannigan John G. , Cottell David C. , Morris Aisling
Published: June 2005

This study was designed to examine the pathogenesis of bromodeoxyuridine (BUdR)‐induced clefts of the secondary palate in the LACA mouse. Intraperitoneal injections of BUdR (500 mg/kg body weight) were given at various days and combinations of days between E11 and E15 (plug day = E1). Treatment on E11 alone resulted in approximately 22% of fetuses with cleft palate when the latter were examined either on E16 or E19. Treatment on E11 and E12 approximately doubled the above incidence, and treatment on E11, 12 and 13 raised it to 100%. However, no treatment, either single or multiple, caused cleft palate when given later than E11. This suggests that the cellular changes caused by BUdR that lead to cleft palate must be inflicted during E11 and that such damage can be repaired in about 80% of embryos. All fetuses with cleft palate had severe micrognathia on E16 and E19, which skeletal staining showed to be the result of a bilateral sigmoid buckling of Meckel's cartilage. Studies with the scanning electron microscope (SEM) on E15, 16, and 19 suggested strongly that the micrognathia caused a relative macroglossia and hence mechanical interference with palatal shelf reorientation. Histological studies with the light microscope showed that BUdR caused cellular necrosis in many embryonic tissues during the 24 hours after its administration. This necrosis was strikingly more severe in the mandibular rudiment of the first branchial arch than in the maxillary. The latter observation accords well with findings by other workers that cell proliferation is more rapid in the mandibular blastema than in the maxillary. Transmission electron microscope (TEM) studies of the buckled region of Meckel's cartilage failed to reveal any ultrastructural differences from control Meckel's cartilage. Hence BUdR had only interfered with the shape of the cartilage but not with its histiogenesis. We conclude that BUdR, by its cytotoxicity or antidifferentiative effects, interfered with the formation of the anterior end of Meckel's cartilage, initiating a chain of events leading through micrognathia and relative macroglossia to failure of palatal shelf reorientation and cleft palate.
Expression of Veratrum alkaloid teratogenicity in the mouse
Authors: Omnell M. L. , Sim F. R. P. , Keeler R. F. , Harne L. C. , Brown K. S.
Published: June 2005

Jervine, a steroidal alkaloid found as a minor constituent in the teratogenic range plant Veratrum californicum, has produced similar terata in sheep, rabbit, hamster, and chick, although the sensitivity to the alkaloid varies in the different species. Sprague Dawley rats and Swiss Webster mice are relatively insensitive. The aim of this study was to determine the teratogenic potential of jervine in three strains of mice and to ascertain if the response is strain dependent. One strain, Swiss N:GP(S), was retested since a Swiss Webster strain had been found previously to be jervine‐resistant. In addition, we tested C57BL/6J and A/J, which are known to differ in their response to the teratogenic action of steroids and vitamin A. Mice were treated by gavage with single doses of jervine (70, 150, or 300 mg/kg body weight) on either day 8, 9, or 10 of gestation. Jervine was teratogenic to C57BL/6J and A/J mice but not to N:GP(S). The induced terata included cleft lip with or without cleft palate, isolated cleft palate, mandibular micrognathia or agnathia, and limb malformations. Fetal teratogenicity and maternal and fetal toxicity were highly correlated. The prevalence of each defect and fetal death was a function of strain, dose, and time of treatment. Maternal death was higher in C57BL/6J than in A/J mice. Although some of the terata were similar, the response pattern between strains was different from corticosteroids and vitamin A for both sensitive period and the strain dose response. An effect on differentiation of chondrocyte precursors may account for many of the defects, but an earlier lethal effect on differentiation of neural crest cells or precordal mesenchyme may also occur.
Embryonal disposition of salicylate: In vivo‐in vitro comparisons
Authors: Daston George P. , Francis William R. , Baines Donald , Poynter James I. , D'Souza Richard W.
Published: June 2005

The distribution of salicylate to embryonal compartments for in situ and in vitro rat embryos under equivalent exposure conditions, and salicylate disposition in the in vivo mid‐gestation embryo and late gestation fetus, were compared. Pregnant Sprague‐Dawley CD rats were exposed to steady‐state blood levels of salicylate by infusing 14C‐salicylic acid iv for a 24 hour period from gestation day 11.5 to 12.5. Cultured Sprague‐Dawley rat embryos (in medium consisting of 100% male rat serum) were exposed to the steady‐state 14C‐salicylate concentration achieved in maternal serum in vivo for the same 24 hour developmental period. At the end of the exposure period radioactivity in visceral yolk sac, extra‐embryonic fluid and embryos, and in maternal tissues, was measured. The distribution of salicylate to embryonal tissues was statistically comparable in vivo and in vitro, although the embryos in vitro accumulated slightly (but not significantly) less of the chemical. There was considerable binding of salicylate by maternal serum and culture medium proteins: less than 20% of the chemical was free at the 40 μg/ml concentration used in this experiment. Consequently, the salicylate concentration in embryonal compartments appeared to be quite low when compared to the surrounding serum/medium, but was actually equal to or greater than the concentration of unbound salicylate in serum or culture medium. The proportion of free salicylate in serum increased at concentrations higher than 40 μg/ml, resulting in somewhat higher concentrations of salicylate in in vitro embryos and extra‐embryonic fluid (as compared to medium) when cultured in the presence of 200 or 400 μg/ml salicylate. Salicylate pharmacokinetics in the fetus were determined by infusing 14C‐salicylic acid iv into pregnant rats from gestation day 19.5 to 20.5 and concentrations in fetuses and dams on gestation day 20.5 were compared to those from gestation day 12.5 rats. There was significantly more salicylate distributed to gestation day 20.5 fetal tissues than to gestation day 12.5 embryos. This appeared to result from a higher percentage of unbound salicylate in maternal serum in late gestation, but may also be due to other factors such as different placental characteristics or binding within embryo/fetal compartments. In summary, under the conditions of this study the disposition of salicylate to embryonal compartments was statistically comparable in vivo and in vitro. Disposition is influenced considerably by developmental stage and concentration of salicylate.
Induction of malformations in the cynomolgus monkey with 13‐cis retinoic acid
Authors: Hummler Hans , Korte Rainhart , Hendrickx Andrew G.
Published: June 2005

The embryotoxic and teratogenic potential of 13‐cis retinoic acid was assessed in the cynomolgus macaque (Macaca fascicularis). A total of 41 animals was orally administered 13‐cis retinoic acid in four sequential experiments. In Exp. 1 three dose levels, 2, 10, and 25 mg/kg, were administered on gestational day (GD) 18–28; 5 mg/kg was administered as an equally divided dose twice daily in Exp. 2 and 3 on GD 21–24 and on GD 25–27, respectively; in Exp. 4 the drug was administered at 2.5 mg/kg once daily from GD 10 to 25 and twice daily (2 × 2.5 mg/kg) on GD 26 and 27. Maternal death and toxicity, manifested as reduction in maternal weight and food consumption, and diarrhea, was observed in Exp. 1 in all three dose groups. No significant maternal toxicity was observed in the treatment groups in Exp. 2, 3, and 4 or in the control group. The primary manifestation of developmental toxicity was embryolethality in Exp. 1 and 2. The incidence of embryonic deaths in Exp. 3 was comparable to the historical controls. No malformations in GD 100 fetuses were observed in Exp. 1, 2, and 3. In Exp. 4, five of seven fetuses (71%) had malformations of both external ears, four of seven fetuses (57%) exhibited hypo‐ or aplasia of the thymus, and two of seven (29%) had malformations (transposition of the great vessels, ventricular septal defect) of the heart. The teratogenic dose for the cynomolgus monkey in the present study was lower than that reported for all other experimental species. Although central nervous system and craniofacial defects were not observed, the incidence of ear and thymus defects was similar to that reported for the human. The cardiovascular defects resembled those reported clinically, but the incidence was lower in the cynomolgus monkey. The similarity in teratogenic sensitivity to humans supports the use of the monkey as a model for developmental toxicity studies of vitamin A‐related compounds.
Effects of pulsed ultrasound and temperature on the development of rat embryos in culture
Authors: Angles J. M. , Walsh D. A. , Li K. , Barnett S. B. , Edwards M. J.
Published: June 2005

Rat embryos in culture were exposed to pulsed ultrasound at SPTA intensity of 1.2 W/cm2 for 5, 15, and 30 min on day 9.5 of development. The whole embryo culture system allowed precise temperature control for directly examining the effects of ultrasound on the developing neural plate. After exposure, embryos were maintained in culture for a further 48 hr. No major morphological abnormalities were observed but a reduction in somite number occurred in the group insonated for 30 min, which was equivalent to a 2 hr delay in embryonic development. Similar delay in growth and “blistering” in the prosencephalon region of some embryos were observed after insonation for 15 min at 40.0°C, an elevation of 1.5°C over the temperature used for controls. Exposure to ultrasound for 15 min at 40°C caused significant reduction in the growth of the head compared with that of control embryos. Heat shock genes for hsps 71/73 and 88 kD were induced after insonation for 30 min at 38.5°C. Insonation did not cause any temperature changes in the culture medium. However, when the temperature of the culture medium was increased during insonation, defective development occurred. The results of these in vitro experiments suggest that ultrasound if resulting in significant hyperthermia could affect the development during early organogenesis of the neural plate and in particular they suggest that the embryo is at greater risk of damage during hyperthermic conditions. These results should provoke discussion of the concept that ultrasound in the febrile patient may present an increased embryonic risk which should be considered when deliberating on the use of diagnostic ultrasound procedures in the pregnant patient.
Trisomy 22 with holoprosencephaly: A clinicopathologic study
Authors: Isada Nelson B. , Bolan Jean C. , Larsen John W. , Kent Stephen G.
Published: June 2005

Trisomy 22 (47, XY, +22) was found at 17 weeks gestation in one fetus of a twin gestation. The karyotypes of both parents and of the other twin were normal. Abnormal prenatal findings included maternal pre‐eclampsia, fetal growth retardation, and progressive intracranial sonolucency of the trisomic fetus. Delivery by cesarean section at 36 weeks gestation yielded a normal healthy female weighing 2,822 grams and a markedly macerated dysmorphic male weighing 642 grams. Holoprosencephaly was found in the trisomic fetus, an unusual feature in trisomy 22. Additional findings in this case are compared to other findings in the literature.
Growth failure in second‐trimester fetuses with trisomy 21
Authors: Fitzsimmons Jack , Droste Sabine , Shepard Thomas H. , Pascoe‐Mason Julie , Fantel Alan
Published: June 2005

Growth failure in the Down syndrome is common postnatally, but is thought to be less consistent in fetuses and newborns. We describe the growth of individual organs in 53 second‐trimester abortuses with trisomy 21 and compare the organ weights to organ weights from 432 spontaneously aborted, but otherwise normal control specimens. Using multiple regression analysis, we found body weight to be the most significant predictor of all organ weights in normal fetuses; therefore, this variable was used to generate the regression lines to which the organ weights of trisomic specimens were compared. All trisomic fetal organs were found to be small, with an abnormal karyotype being a significant predictor of low organ weight. However, the effect on individual organs was variable, with some organs differing only minimally from the controls. Placental weights were not affected by fetal trisomy. This study demonstrates the presence of well‐established, although variably severe, growth retardation in second‐trimester fetuses with Down syndrome.
Effect of prenatal N2O exposure on startle reflex reactivity
Authors: Rice Susan A.
Published: June 2005

The teratogenic effect of N2O is of interest because thousands of pregnant women are exposed to this gaseous anesthetic each year. The effects of repeated N2O exposures were investigated for offspring of mice exposed to air or N2O (5%, 15%, or 35%) for 4 hours per day on days 6 through 15 of pregnancy. Ten litters per exposure group were studied. Exposures did not affect reproductive indices, survival, or physical milestones of development. Body weights showed significant exposure effects that could not be isolated to specific exposure groups; however, N2O‐exposed mice tended to weigh more than air‐exposed animals. Brain weights measured on postnatal day (PND) 126 or 127 were not different among exposure groups or between genders. Ability to stay on a rotating rod was not affected by prenatal N2O exposure. Prenatal exposure to N2O resulted in hyporeactivity of the startle reflex in response to acoustic or tactile stimuli. On PND 95 the results were statistically significant for all N2O‐exposed groups compared with the air‐exposed group. On PND 60, although not statistically significant, there was a definite trend toward hyporeactivity for the N2O groups. There was a significant age‐related difference in startle response; control animals were significantly more reactive at 95 than at 60 days of age. Of the N2O‐exposed groups, only the 15% group showed a statistically significant increase in reactivity from 60 to 95 days of age. The risk of behavioral or functional abnormalities for humans following in utero N2O exposure is unknown and cannot be directly extrapolated from the present study. The 4 hour duration of exposure is not unusual for surgical patients, but exposure throughout the period of organogenesis is unusual. Daily exposure to N2O more closely resembles the pattern of occupational exposure, although the concentrations used in this study are much higher than those measured in surgical or dental operatories. The effects of N2O on reactivity observed in mice are worthy of further investigation because both the mechanism of action and the no‐effect exposure for mice and humans has yet to be determined.
Methionine and neural tube closure in cultured rat embryos: Morphological and biochemical analyses
Authors: Coelho Caroline N. D. , Klein Norman W.
Published: June 2005

When headfold‐stage rat embryos were cultured on cow serum, their neural tubes failed to close unless the serum was supplemented with methionine. Methionine deficiency did not appear to affect the ability of the neural epithelium to fuse as a type of fusion was observed between anterior and posterior regions of the open neural tube in methionine‐deficient embryos. Although methionine deficiency reduced the cell density and mitotic indices of cranial mesenchyme and neural epithelial cells, this did not appear to be a factor in failure of the neural tube to close. For example, embryos cultured on diluted cow serum also had fewer mesenchymal cells yet could complete neural tube closure if provided with methionine. Examination of the tips of the neural folds suggested that microfilament contraction could be involved; in the absence of methionine the neural folds failed to turn in. This possibility was supported by the reductions in neurite extension of isolated neural tubes cultured without methionine and by the reductions in microfilament associated methylated amino acids contained in embryo neural tube proteins.
Cyclophosphamide teratogenesis: Evidence for compensatory responses to induced cellular toxicity
Authors: Francis B. Magnus , Rogers John M. , Sulik Kathleen K. , Alles Ajit J. , Elstein Kenneth H. , Zucker Robert M. , Massaro Edward J. , Rosen Mitchell B. , Chernoff Neil
Published: June 2005

Cyclophosphamide (CP) administered ip to pregnant mice on day 10 of gestation (day of plug = day 0) is teratogenic (exencephaly, cleft palate, and limb malformations) at 20 mg/kg and embryolethal at higher doses. In the present study, CP was administered at 1, 5, 10, or 20 mg/kg on day 10 of gestation. Embryos were removed at 8 and 28 hr postdosing, and two embryos from each litter were immediately stained with Nile blue sulfate (NBS) to identify areas of cell death. The remaining embryos were frozen and forelimb buds subsequently removed for flow cytometric (FCM) analysis of the cellular DNA synthetic cycle. Additional litters were examined near term (day 17) for morphological abnormalities; these data were correlated with embryonic toxicity as detected by NBS staining and FCM analysis.

Only the highest dose produced malformations. In marked contrast, a dose‐related increase in the percentage of limb bud cells in the S (DNA synthetic) phase of the cell cycle was detectable at all doses. Inhibition of DNA synthesis was detected at all doses 8 hr post exposure and persisted through 28 hr for doses ≥10 mg/kg. NBS staining indicated increased cell death in the alar plate of the neural tube 28 hr after exposure to 10 mg/kg CP and generally increased cell death in areas of rapid cell proliferation throughout the embryo at 20 mg/kg. The absence of an overt teratogenic response at dose levels that produced significant perturbation of the cell cycle indicates that a measure of embryonic damage can be compensated for or repaired. The implications of these findings for the existence of thresholds in developmental toxicity are discussed.
External genitalia of the rat: Normal development and the histogenesis of 5α‐reductase inhibitor‐induced abnormalities
Authors: Anderson Charles A. , Clark Robert L.
Published: June 2005

The normal histogenesis of the rat genital tubercle and the effect of exposure in utero to the 5α‐reductase inhibitor finasteride (L‐652,931; MK‐0906;Proscar®) on that process were studied. In normal males and females, the genital tubercle was first seen on Day 14.25 of gestation. It contained a urethral plate which extended from the cloaca (and after Day 15.25, from the urogenital sinus) to the tip of the tubercle. On Day 18.25 the glans lamellae, which would separate the glans penis or the clitoris from the prepuce, began to develop in both sexes. Also on Day 18.25 a dense, midline plate of mesenchymal cells was first evident between the urogenital sinus and the rectum in normal males. This plate acted as a wedge, first increasing the separation between the rectum and the urogenital sinus, and subsequently separating the urethral plate from the surface epithelium in the genital tubercle. As a result, by Day 21.25 the urethra in males followed an “S”‐shaped course, extending from the pelvis through the center of the glans penis to an orifice near the tip of the genital tubercle. In females, in which a mesenchymal plate did not develop, the urethral orifice remained at the base of the tubercle, and the clitoris contained the remnants of the urethral plate, extending as an open groove from the urethral orifice to the tip of the tubercle. Finasteride did not affect development of the genital tubercle in females. However, in males exposed to finasteride in utero, there was variable failure of the mesenchymal wedge to develop. As a result, the urethral plate remained in contact with the surface epithelium and eventually opened to form a groove on the ventral surface of the glans penis (hypospadias). Also, the persistence of the urethral plate along the ventral midline in finasteride‐treated male fetuses and its subsequent opening as a groove interfered with development of the glans lamellae, causing displacement of the frenulum distally on the glans penis and the development of a cleft in the prepuce.
Sensitivity, specificity, and positive predictive value of multiple malformations in isotretinoin embryopathy surveillance
Authors: Lynberg Michele C. , Khoury Muin J. , Lammer Edward J. , Waller Kirsten O. , Cordero Jose F. , Erickson J. David
Published: June 2005

Isotretinoin causes serious birth defects in about 25% of babies exposed in the first trimester of pregnancy. Despite warnings about the drug's teratogenicity, cases of isotretinoin embryopathy continue to occur; more than 80 such cases have been reported since 1982. The true magnitude of the problem is unknown, however, and case estimates range to more than 1,000. The need for isotretinoin embryopathy (IE) surveillance is therefore great. Sixty‐one known cases were evaluated to determine the sensitivity (proportion of cases with a given defect pattern) of various defect combinations. Using data from the Metropolitan Atlanta Congenital Defects Program for the period before isotretinoin was available, we evaluated the specificity (proportion of malformed infants without exposure who do not have the pattern of defects) for the various defect combinations. Ear malformations (microtia, anotia, absence or stricture of auditory canal, missing pinnae) have an associated sensitivity of 70.5% and a specificity of 99.5%. Ear defects combined with central nervous system (CNS) defects (microcephalus, hydrocephalus, reduction deformities of the brain) and cardiovascular (CVS) defects (conotruncal defects, aortic arch abnormalities) have an associated sensitivity of 19.7% and a specificity of 100.0%. The case definition of ear defects combined with either CNS or CVS defects maximizes both specificity (99.9%) and sensitivity (45.9%). The investigators are now evaluating the feasibility of using this pattern of defects to monitor for IE within a national monitoring program.
Teratogenic effect of the cholesterol synthesis inhibitor AY 9944 on rat embryos in vitro
Authors: Repetto M. , Maziere J. C. , Citadelle D. , Dupuis R. , Meier M. , Biade S. , Quiec D. , Roux C.
Published: June 2005

AY 9944 [trans‐1,4‐bis(2‐chlorobenzylaminomethyl) cyclohexane dihydrochloride] is an amphiphilic cationic molecule. This chemical is an established inhibitor of cholesterol synthesis and is teratogenic in rats. The mechanisms of this teratogenicity remain to be clarified. This study used cultured rat whole embryos to ascertain whether AY 9944 had a direct effect on embryos, or whether its action was indirect, via the maternal cholesterol metabolism. Four experimental conditions were investigated: (A) controls; (B) 10 day untreated embryos were cultured in serum of treated rats; (C) 10 day untreated embryos were cultured in serum containing added AY 9944 (0–1,000 μg/ml); and (D) 10 day embryos from females treated on day 4 of gestation were cultured in normal serum. In group B there was no growth retardation; some slight nonspecific abnormalities were not significant. In group C, direct addition of AY 9944 to culture medium retarded growth and differentiation in a dosedependent manner. No malformation was observed, but histological examinations showed numerous areas of cell necrosis, especially in the CNS. In group D, not only was growth retardation observed, but also characteristic malformations of AY 9944 teratogenesis, including pituitary agenesis. These results show that AY 9944 teratogenicity is initiated prior to day 10.
Experience of two teratology information services in Europe
Authors: Garbis Johanna M. , Robert Elisabeth , Peters Paul W. J.
Published: June 2005

Teratology Information Services (TIS) are started in different countries in Europe in order to gather available data on exogenous agents, to evaluate their pertinence to human subjects, and to apply this knowledge to specific cases. Most European centers can only be consulted by medical professionals. The experience of two such services (Lyon, France, and Bilthoven, The Netherlands) is described. Attention is given to the task of TIS, risk evaluation, operational methods, and functioning and future developments.
Effects of chemically induced maternal toxicity on prenatal development in the rat
Authors: Chernoff Neil , Setzer R. Woodrow , Miller Diane B. , Rosen Mitchell B. , Rogers John M.
Published: June 2005

The hypothesis that chemically induced overt maternal toxicity induces a characteristic syndrome of adverse developmental effects in the rat was investigated. Pregnant animals (Sprague‐Dawley strain) were dosed by oral gavage with one of a series of compounds on days 6–15 of gestation. These chemicals were diquat (DIQ), ethylene‐bis‐isothiocyanate (EBIS), toxaphene (TOX), styrene (STY), 2,4‐dichlorophenoxyacetic acid (2,4‐D), 2,4,5‐trichlorophenol (2,4,5‐Tr), triphenyl tin hydroxide (TPTH), and cacodylic acid (CAC). The compounds were chosen because they exhibited little or no developmental toxicity in previous studies. Dosage levels producing maternal weight loss and/ or lethality were determined from preliminary toxicity studies. Significant maternal weight reductions were noted during the course of treatment with all compounds except CAC and 2,4,5‐Tr. Maternal lethality was produced by EBIS, TOX, 2,4,‐D, and 2,4,5‐Tr. The main treatment‐related developmental toxicity noted in litters at term consisted of increased lethality (EBIS, TPTH) and decreased fetal weight (EBIS and CAC). Treatment‐related anomalies were seen in litters treated with 2,4‐D and TOX (supernumerary ribs) and with EBIS and STY (enlarged renal pelvis). No significant developmental effects were produced with DIQ, or 2,4,5‐Tr. This study indicates that overt maternal toxicity as defined by weight loss or mortality is not always associated with the same defined syndrome of adverse developmental effects in the rat.
Genetically determined transient edema found in the WB/ReJ mouse strain in a teratogenic survey with acetazolamide
Authors: Biddle Fred G.
Published: June 2005

A continuing survey of the genetic variability of different mouse strains to acetazolamide teratogenesis demonstrated the WB/ReJ strain expresses a high frequency of induced subcutaneous edema in day 15 fetuses. In treated WB/ReJ fetuses, the probability of expression of edema is independent of the expression of forelimb ectrodactyly and, with the dosage regime, there is no significant increase in acetazolamide‐induced resorption. It was surprising to find a high frequency of spontaneous edema on day 15 in untreated WB/ReJ fetuses. The spontaneous edema is a transient trait with maximum expression (56%) on day 14, and it is resolved by day 17 without apparent consequence to the survival of previously affected fetuses. There is no sex dimorphism in the liability to express the transient edema. Preliminary genetic crosses to investigate the spontaneous edema were made between WB/ReJ and the C57BL/6J strain, which historically had not be observed to express spontaneous edema. A low frequency of spontaneous edema was observed on day 14 in both C57BL/6J and the reciprocal F1 fetuses. The trait is not additive because there is dominance deviation of the BC1 fetuses in the direction of the F1 fetuses. The data were fitted to a threshold model suggesting that the developmental liability to express the difference in transient edema is determined by more than one gene, but the data can be interpreted by a minimum of two loci with duplicate epistasis. The observed differences in frequencies of edema suggest the genetic model can be tested with relatively few test crosses.
Compensatory renal growth in human fetuses with unilateral renal agenesis
Authors: Hartshorne Nikolas , Shepard Thomas , Barr Mason
Published: June 2005

To determine whether compensatory growth of the kidney occurs during fetal life we studied 20 human specimens with a unilateral kidney as an isolated defect. The mean combined kidney weight to body weight ratio × 100 in controls was 0.76 ± 0.14 (SD) and in the solitary kidney cases (after doubling the kidney weight) was 1.26 ± 0.35 (SD). This significant increase leads us to hypothesize that the increased weight may be due to an induced negative feedback system involving a renotropic factor. From histologic studies a uniform increase in all nephron elements was found. Why should a fetus with adequate placental clearance of metabolic wastes need increased renal size?
Anencephaly and maternal common cold
Authors: Kurppa Kari , Holmberg Peter C. , Kuosma Eeva , Aro Timo , Saxén Lauri
Published: June 2005

To study the risk of anencephaly related to common cold during pregnancy, a case‐control study was made. The series comprised 393 Finnish mothers of anencephalic children and their time‐area‐matched controls in the period 1964 through 1982. Seventy mothers of anencephalic infants and 17 controls had reported common cold in the first trimester [adjusted odds ratio 4.5; 95% confidence interval (2.2–9.1)]. Reported common cold in the second trimester was not associated with anencephaly. As suggested by our previous cohort study in the same population, a true viral influenza resembling “common cold” might not explain the observed association.
Developmental regulation of heat shock protein synthesis and HSP 70 RNA accumulation during postimplantation rat embryogenesis
Authors: Mirkes Philip E. , Grace Richard H. , Little Sally A.
Published: June 2005

Exposure of postimplantation rat embryos on days 9, 10, 11, and 12 of gestation to an in vitro heat shock of 43°C for 30 min results in the induction of heat shock proteins (HSPs) in day 9 and 10 embryos, a severely attenuated response in day 11 embryos, and no detectable response in day 12 embryos. The heat shock response in day 9 embryos (presomite stage) is characterized by the synthesis of HSPs with molecular weights of 28–78 kDa. In heat shocked day 10 embryos, two additional HSPs are induced (34 and 82 kDa). In addition, two HSPs present on day 9 are absent on day 10. In day 11 heat shocked embryos, only three HSPs (31, 39, and 69 kDa) are induced, while in day 12 embryos no detectable HSPs are induced. Northern blot analysis of HSP 70 RNA levels indicates that the accumulation of this RNA, but not actin RNA, varies depending on developmental stage at the time of exposure to heat as well as the duration of the heat shock. Day 9 embryos exhibit the most pronounced accumulation of HSP 70 RNA while embryos on days 10–12 exhibit an increasingly attenuated accumulation of HSP 70 RNA, particularly after the more acute exposures (43°C for 30 or 60 min). Thus, the ability to synthesize HSP 70 and to accumulate HSP 70 RNA changes dramatically as rat embryos develop from day 9 to day 12 (presomite to 31–35 somite stages).
Visceroatrial heterotaxy syndrome in the NOD mouse with special reference to atrial situs
Authors: Morishima Masae , Ando Masahiko , Takao Atuyoshi
Published: June 2005

Following the onset of diabetes mellitus (DM) in the NOD mouse, diabetic dams have many offspring with severe anomalies, especially with visceroatrial heterotaxy syndrome. The purpose of the present study is to analyze this syndrome with special reference to atrial situs. The fetuses from a colony of NOD mice in our laboratory were divided into two study groups: Group A included fetuses from dams before the onset of DM and group B included fetuses from dams with overt DM before day 8 of pregnancy. The fetuses which had cardiac anomalies with viscero‐atrial heterotaxy were classified into four subtypes according to the atrial morphology, i.e., “incomplete situs solitus” (or solitus‐like), “incomplete situs inversus” (inversus‐like), right isomerism, and left isomerism. Group A (671 fetuses) included only one case with right isomerism (0.15%) and four cases with left isomerism (0.6%). Group B (158 fetuses) had 57 fetuses with heterotaxy syndrome (36.1%), including 20 cases with solitus‐like, 6 with inversus‐like, 30 with right isomerism, and one with left isomerism. A tendency for right isomerism to occur was found in fetuses with solitus‐like and inversus‐like anomalies. These results show that the maternal DM in this mouse had an influence upon the morphological mechanism determining right isomerism of visceroatrial heterotaxy syndrome. Thus this syndrome in the NOD mouse is equivalent to asplenia in humans, and it may be useful in elucidating the mechanism of the human syndrome.
Pathogenesis of ethanol‐induced limb reduction defects in mice
Authors: Kotch L. E. , Dehart D. B. , Alles A. J. , Chernoff N. , Sulik K. K.
Published: June 2005

Acute administration of dosages of 2.5, 2.8, or 2.9 g/kg of ethanol to pregnant C57BL/6J mice on gestational day 9¼ resulted in major malformations of the forelimb including postaxial ectrodactyly, preaxial syndactyly, and reduction defects involving intermediate digits. The incidence and severity of these defects was positively correlated with dosage. Sidedness of the defects was also dose‐dependent. In affected embryos, excessive amounts of cell death were notable within 5–9 hr of treatment initiation in selected cell populations. Cell death was primarily distributed in two regions of the developing limb bud—a ventrodistal ectodermal cell population (apical ectodermal ridge) and a proximal mesenchymal cell population. The patterns of cell death observed appear to be pathogenically related to the limb defects noted at later stages. In particular, it would appear that the deficiencies in the apical ectodermal ridge resulting from ethanol‐induced cell death can account for virtually all the subsequent limb defects. © 1992 Wiley‐Liss, Inc.
Maternal zinc and fetal neural tube defects
Authors: Milunsky Aubrey , Morris J. Steven , Jick Hershel , Rothman Kenneth J. , Ulcickas Marianne , Jick Susan S. , Shoukimas Polly , Willett Walter
Published: June 2005

Among the factors implicated in the heterogeneous etiology of neural tube defects (NTDs) is the trace element zinc (Zn). In a case‐control study, we collected midtrimester maternal toenail samples for multiple trace element analyses, including Zn, which were assayed by neutron activation analysis. We studied 17 women with NTD offspring and 1,787 controls. The crude OR for NTD comparing Zn values >normal range to normal Zn values was 3.2 (95% CI 1.1,9.7). These results were not materially affected when adjustment was made for folic acid supplementation. An overall increased risk for NTD associated with increasing toenail Zn was also evident. A matched subset of 17 cases and 73 controls yielded a crude OR of 3.1 (95% CI 0.9,10.3) when cases with elevated Zn (≥120 ppm) were compared to those with normal Zn. Matched analyses controlling for folic acid supplements, family history of NTD, assay batch, age of mother and year of delivery yielded an OR of 5.0 (95% CI 1.1,21.6). This study reveals an association between increased toenail Zn in the second trimester of pregnancy and the risk of having a child with an NTD. Whether Zn sequestration has resulted in relative Zn deficiency at the site of neural tube closure remains uncertain. © 1992 Wiley‐Liss, Inc.
Serotonin as a regulator of craniofacial morphogenesis: Site specific malformations following exposure to serotonin uptake inhibitors
Authors: Shuey Dana L. , Sadler Thomas W. , Lauder Jean M.
Published: June 2005

During craniofacial development in the mouse embryo (days 9–12 of gestation; plug day = day 1), transient expression of serotonin (5‐HT) uptake in epithelial structures of this region correlates with critical morphogenetic events (Lauder et al., '88; Shuey, '91; Shuey et al., '89, '92). The purpose of the present investigation was to assess the possible functional significance of these uptake sites by examination of patterns of dysmorphology following exposure of embryos to selective 5‐HT uptake inhibitors. Exposure of mouse embryos in whole embryo culture to sertraline, at a concentration (10 μM) which produced no evidence of general embryotoxicity, caused craniofacial malformations consistent with direct action at 5‐HT uptake sites. Two other 5‐HT uptake inhibitors, fluoxetine and amitriptyline, produced similar defects. The critical period of sertraline exposure occurred on days 10–11. The observed craniofacial defects were associated with decreased proliferation and extensive cell death in mesenchyme located 5–6 cell layers deep from the overlying epithelium. In contrast, the subepithelial mesenchymal layers showed normal or elevated levels of proliferation. From these results it appears that inhibition of 5‐HT uptake into craniofacial epithelia may produce developmental defects by interference with serotonergic regulation of epithelial–mesenchymal interactions important for normal craniofacial morphogenesis. © 1992 Wiley‐Liss, Inc.
Reproduction of the mongoose lemur (Lemur mongoz) in captivity
Authors: Schaaf C. D. , Stuart M. D.
Published: June 2005

Responses to questionnaires sent to 20 institutions holding Lemur mongoz did not reveal which aspects of management or husbandry could account for reproductive failure in the captive population, but allowed some qualitative comparisons with data compiled for captive and wild animals. In general, reproduction has occurred initially among wild‐caught specimens before tapering off, and rarely occurs in the captive F1 generation. Data compiled by the International Species Inventory System and the International Zoo Yearbook revealed an aging captive population with no recent reproduction. No aspect of group composition, activity patterns, seasonal light regime, reproductive cycles, or diet could be linked to the lack of reproduction; and among lemurs subjected to the same conditions, some were known to reproduce while others did not. Lack of knowledge about this species and the threat of extinction for both captive and wild populations make an investigation of reproductive biology imperative. Recommendations for a research program are given.
Breeding of the cotton‐top tamarin Saguinus oedipus oedipus: A comparison with the common marmoset
Authors: Evans Siân
Published: June 2005

A colony experienced in the successful breeding of thecommon marmoset acquired 15 cotton‐top tamarins for breeding purposes over a period of 2 yrs. Data are presented on the breeding of the cotton‐top and compared with the breeding of the common marmoset. The tamarins did not breed as successfully as the common marmosets. There were several reasons for this: Cotton‐tops took longer to produce young on initial pairing, had a longer birth interval, and showed a high incidence of suspected infanticide and parental neglect. These factors are thought to be largely responsible for the relatively low reproductive potential of the cotton‐top in captivity.
An electrified enclosure of 650 m2 designed for rearing baboons (Papio papio)
Authors: Fabre Jean‐Claude , Pallaud Berthille , Fady Jean‐Claude
Published: June 2005

A system for an electrified enclosure designed for baboons is described. Live wires were alternated with grounded wires in order to increase the likelihood of electric shock if an animal tried to escape. A sinusoidal current of 50‐Hz frequency, 650‐V voltage, and 10 mA was used and proved to be quite efficient and not dangerous. In order to make the apparatus more reliable the electric main sources were connected to an automatic control system which monitored irregularities in the supply and switches to an emergency circuit if necessary.
The millenium ark: How long a voyage, how many staterooms, how many passengers?
Authors: Soulé Michael , Gilpin Michael , Conway William , Foose Tom
Published: June 2005

Barring holocausts, demographic forecasts suggest a “demographic winter” lasting 500–1,000 years and eliminating most habitat for wildlife in the tropics. About 2,000 species of large, terrestrial animals may have to be captively bred if they are to be saved from extinction by the mushrooming human population. Improvements in biotechnology may facilitate the task of protecting these species, but it probably will be decades at least before cryotechnology per se is a viable alternative to captive breeding for most species of endangered wildlife. We suggest that a principle goal of captive breeding be the maintenance of 90% of the genetic variation in the source (wild) population over a period of 200 years. Tables are provided that permit the estimation of the ultimate minimum size of the captive group, given knowledge of the exponential growth rate of the group, and the number of founders. In most cases, founder groups will have to be above 20 (effective) individuals.
Selection in captive populations
Authors: Frankham R. , Hemmer H. , Ryder O. A. , Cothran E. G. , Soulé M. E. , Murray N. D. , Snyder M.
Published: June 2005

We have briefly reviewed types of genetic variation and selection in the wild as contrasted with selection in captive populations, along with the objectives of captive breeding programs, before recommending selection procedures for the genetic management of captive populations.

Although some inadvertent selection for tameness and adaptation to captive environments is inevitable in captive populations, any selection that is actively applied to captive populations should have clearly defined objectives.

Much of the apparent disagreement about genetic management of captive populations probably stems from the varying objectives of different captive breeding programs. Objectives differ depending on whether the populations are: (1) common species for display, (2) endangered species for long‐term conservation, (3) rare species being multiplied for immediate release back into the wild, or (4) rare species not yet capable of self‐sustaining reproduction in captivity.

For all categories of populations we recommend selection to keep the genetic load under control.

Populations in category 1 can be selected for adaptation to captive breeding, ease of handling, and for classic species phenotype.

Populations in categories 2 and 3 should have no deliberate selection applied to them, apart from that to control the genetic load, so that the probability of successful release back into the wild is maximized.

Populations in category 4 may require selection for captive breeding success until they attain self‐sustaining status. Once this has been achieved they should be managed as under category 2.

The special cases of species that have been subjected to introgression are discussed. The multidisciplinary nature of captive population management is stressed.
Pedigree analysis by computer simulation
Authors: MacCluer Jean W. , VandeBerg John L. , Read Bruce , Ryder Oliver A.
Published: June 2005

Computer simulation is a valuable tool in the genetic management of captive populations. It can be used to assess the extent of genetic variability in a colony, to predict the risk of future loss of variability, or to identify likely ancestral sources of traits of interest. “Gene dropping” is a simulation procedure in which hypothetical alleles are assigned to each colony founder, and a genotype is created for each descendant by Mendelian segregation of parental alleles. The gene dropping method is applied to analyses of four populations: (1) a colony of small South American marsupials, Monodelphis domestica; (2) Speke's gazelles, Gazella spekei; (3) Przewalski's horses, Equus przewalskii; and (4) American Standardbred horses.
Genetic effects of a maximal harvest schedule
Authors: Dyke Bennett , Gage Timothy B. , Mamelka Paul M.
Published: June 2005

A mathematical method of maximizing the reproductive efficiency of captive populations is evaluated for its efficacy in very small breeding groups and for its effect on the loss of genetic variability. The evaluation consists of comparing reproductive performance of simulated populations having demographic characteristics similar to a small troop of rhesus kept at the Vilas Park Zoo in Madison, WI, under two age‐specific removal strategies. It was found that a “maximal harvest schedule” (in which a portion of the animals reaching age 1, and all animals age 19, were removed) resulted in a higher rate of reproduction than did a “random harvest schedule” that removed a fixed proportion of all age classes. Little or no difference between the two removal strategies was found in between‐locus variance calculated for 40 simulated genetic loci. From these results we conclude that a maximal harvest strategy may be an effective way to increase reproductive efficiency in small captive populations, and that such a strategy per se may not accelerate the loss of genetic variability.
Visitor behavior in the National Zoo's reptile house
Authors: Marcellini Dale L. , Jenssen Thomas A.
Published: June 2005

Visitor behavior was evaluated in the National Zoo's reptile house. Nearly 600 visitors were tracked; time spent in the house and time spent looking at exhibits were noted. These parameters were investigated by sex, age, and type of visitor grouping. The most looked‐at exhibits were determined. For 573 visitors, the mean time in the reptile house was 14.7 minutes. Only about 8 minutes was spent looking at exhibits, and this time was strikingly similar for age, sex, and group type. Time spent looking at exhibits was negatively correlated with visitor density. Amphibians and lizards were looked at for less time than snakes and turtles. Crocodilians were looked at longer than the other taxonomic groups, while larger animals in all groups were looked at longer than smaller ones. This study and other similar studies imply that the public does not respond to exhibits with the expected interest and enthusiasm. It is hoped that with a better understanding of the public through research, zoo staff can improve visitor interest in the exhibits.
Training zoo biology in tropical countries: A report on a method and progress
Authors: Wemmer Chris , Pickett Charles , Teare J. Andrew
Published: June 2005

In 1987 the National Zoological Park inaugurated a Zoo Biology training program for developing country zoos, particularly those in the tropics where the threats to biological diversity are greatest. The program last 2 to 4 weeks, is targeted to mid‐level zoo managers, and aspires to improve the care and management of wildlife in zoos through in situ training. A host zoo in the foreign country is responsible for selecting and inviting trainees from other zoos in the country or region. Training activities include daily lectures, demonstrations, quizzes, problem solving exercises, and class projects. In addition, the class participates in creating an animal inventory for the host zoo, and endemic species are identified for studbook compilation and captive propagation projects. Most mid‐level zoo managers in tropical developing countries are college‐educated men in their thirties, and have on average less than 10 years of zoo experience. We evaluate our program, and discuss the problems confronting tropical zoos in the developing world. Finally, we suggest ways that zoos in developed countries can influence tropical conservation through training and education.
Behavior research in zoos: Past, present, and future
Authors: Kleiman Devra G.
Published: June 2005

This paper reviews the historical emphases in zoo behavioral research and the contribution of these studies to animal management and to advancement in the behavioral sciences. Some examples are provided from research conducted at the National Zoological Park and elsewhere. The potential for doing behavior studies of excellence in zoos and aquariums has become more complicated in recent years by 1) changes in the aims and objectives of modern zoological parks, especially the increasing emphasis on conservation, 2) changes in focus in the science of animal behavior itself, and 3) the tendency of trained behaviorists to assume positions as curators and directors without time for research. These issues represent challenges to be overcome so that zoos can continue to be important sites for the study of animal behavior and contribute to the science of animal management and conservation, as well as the advancement of theory in biology. © 1992 Wiley‐Liss, Inc.