bluuebunny/crossref_metadata_2025 huggingface dataset:
Alcohol‐induced brain growth restrictions (microencephaly) were not affected by concurrent exposure to cocaine during the brain growth spurt
Authors: Chen Wei‐Jung A. , Andersen Kathleen H. , West James R.
Published: June 2005

The prevalence of concomitant use of alcohol and cocaine among drug abusers has raised concern about the possible increased risk of fetal damage. The aim of this study was to assess the interactive effects of alcohol and cocaine on lethality, somatic growth, and brain growth using an animal model system. Sprague‐Dawley rat pups were used as subjects. They were randomly assigned to 1 of the 9 artificially reared groups which varied with respect to the combination treatments of cocaine (0, 40, or 60 mg/kg) and alcohol (0, 3.3, or 4.5 g/kg). All artificially reared pups were given daily cocaine and alcohol treatments during a major part of the brain growth spurt period (postnatal days 4–9). An additional group of suckled control animals raised by their natural dams was included to control for artificial rearing. The results are summarized as follows: (1) Drug‐induced lethality was higher in cocaine‐treated groups when compared with non‐cocaine‐treated groups, and the concurrent administration of high doses of alcohol and cocaine significantly increased the mortality rate. (2) Somatic growth, in terms of body weight, was not affected by alcohol, cocaine, or the combination of both drugs using the artificial rearing technique. (3) Alcohol exposure during this brain growth spurt period significantly reduced whole brain weight, as well as forebrain, cerebellum, and brain stem weights. (4) In contrast to alcohol, cocaine failed to exert a detrimental effect on brain weight measures during this early postnatal period. (5) There were no antagonistic or synergistic effects in inducing brain growth restrictions by concurrent exposure to alcohol and cocaine during the brain growth spurt. The potential involvement of cocaethylene in mediating the observed lethality is discussed. © 1994 Wiley‐Liss, Inc.
Distribution of cellular retinoic acid‐binding proteins I and II in the chick embryo and their relationship to teratogenesis
Authors: Maden M.
Published: June 2005

The distribution of cellular retinoic acid‐binding proteins I and II (CRABP I and II) during the first 6 days of chick development has been investigated using immunoblotting. Since retinoic acid (RA) is teratogenic to some parts of the embryo, stimulatory to other parts, and has no effect on others it may be that the distribution of cytoplasmic proteins such as CRABP I and II plays some role in this differential activity. Neither protein is expressed in the day 2 embryo, but from day 3 onwards both proteins are expressed and CRABP I is in considerable excess over CRABP II. Within the day 4 embryo there is some significant variation in the distribution according to tissue type. Neural tissues, neural crest derivatives, and limb buds most strongly express CRABP I whilst other tissues contain only moderate levels, and heart and epidermis do not express CRABP I at all. CRABP II has a widespread distribution, although at a lower level than CRABP I, with the exception of somites and ectoderm which do not express it at all. In the limb buds, there is a significant variation in CRABP I levels across the anteroposterior axis which suggests that these two CRABPs may have different functions during development. The relationship of these distributions in the embryo to the role of endogenous RA and the teratogenic effects of RA is discussed. © 1994 Wiley‐Liss, Inc.
Developmental toxicity of the HMG‐CoA reductase inhibitor, atorvastatin, in rats and rabbits
Authors: Dostal Lori A. , Schardein James L. , Anderson John A.
Published: June 2005

The developmental toxicity of the 3‐hydroxy‐3‐methylglutaryl‐coenzyme A (HMG‐CoA) reductase inhibitor, atorvastatin, was investigated in pregnant rats and rabbits given daily oral doses during organogenesis. Rats received 0, 10, 100, or 300 mg/kg on days 6–15 of gestation, and rabbits received 0, 10, 50, or 100 mg/kg on days 6–18 of gestation. Maternal and fetal parameters were evaluated on day 20 (rats) or 29 (rabbits) of gestation. Live fetuses were examined for external, visceral, and skeletal malformations and variations. At 300 mg/kg in rats, 1 treatment‐related death occurred on day 12 of gestation, and maternal body weight gain and food consumption were decreased during treatment (43% and 23%, respectively). In addition, 1 animal at 300 mg/kg had total litter resorption. Increased postimplantation loss (not statistically significant) and slightly decreased fetal body weight (statistically significant only in males) were also observed at 300 mg/kg. There were no significant differences between treated and control groups in the incidence of fetal malformations or variations. No maternal or developmental toxicity was observed in rats at 10 or 100 mg/kg. In rabbits, marked maternal toxicity (7 deaths, body weight loss during and after treatment, and decreased food consumption) and abortion occurred at 100 mg/kg. At 50 mg/kg, maternal toxicity (2 deaths and 72% body weight gain suppression) and abortion also occurred. There were no treatment‐related effects on live litter size or sex ratio. At 50 and 100 mg/kg, nonstatistically significant increases in postimplantation loss and decreases in gravid uterine weight were observed, and at 100 mg/kg, decreases in fetal body weight were observed relative to controls. There were no treatment‐related malformations or variations in live fetuses of atorvastatin‐treated rabbits. No maternal or developmental toxicity was observed in rabbits at 10 mg/kg. Thus, these studies demonstrate developmental toxicity at maternally toxic doses of atorvastatin in rats and rabbits, but no evidence of teratogenicity. © 1994 Wiley‐Liss, Inc.
Enhancement of the teratogenicity of all‐trans‐retinoic acid by maternal restraint stress in mice as a function of treatment timing
Authors: Rasco Jane F. , Hood Ronald D.
Published: June 2005

In CD‐1 mice, maternal restraint stress was combined with all‐trans‐retinoic acid (†RA) given during the restraint period (9:00 a.m. to 9:00 p.m.) to determine in what manner and to what degree teratogenesis might be affected by treatment timing within the stress period and to determine the optimum timing for stress‐enhanced production of fetal defects. Eleven groups were treated on gestation day 9 (copulation plug = day 1): group 1, vehicle (corn oil) control (C); group 2, food/water deprived (FWD); group 3, restraint only (R); group 4, †RA plus food/water deprivation (†RA+FWD); groups 5 and 6, †RA at 0 or 4 hr after 9:00 a.m., i.e., †RA(0) and †RA(4), respectively; and groups 7‐11, restraint plus †RA at 0, 2, 4, 8, or 12 hr after 9:00 a.m., (i.e., R+†RA(0), R+†RA(2), R+†RA(4), R+†RA(8), and R+†RA(12), respectively). The †RA dose was 20 mg/kg, PO; mice were restrained in the supine position. FWD mice were deprived for the same 12 hr as the restrained mice. All stated differences were significant (p⩽0.05), based on litter incidences. The incidences of short tails (65%), fused ribs (62%), and fused vertebrae (37%) were elevated in the R+†RA(4) group in comparison with all others, and there appeared to be more exencephalies in R+†RA(2) litters than in any others. The incidence of supernumerary ribs was elevated in the R group in comparison with C and FWD; it was further elevated by †RA at all treatment times. Fetuses from the R+†RA(4) group weighed less than those from all other †RA‐exposed groups; the differences were nonsignificant except for the comparison with †RA+FWD. These results show that timing of teratogen exposure relative to maternal stress can significantly influence the magnitude of effects on the offspring and that this influence is not merely due to the changing developmental susceptibility of the conceptus. © 1995 Wiley‐Liss, Inc.
Heritable oligodactyly occurring only in male rats
Authors: Kaneda Masahiro , Aoyama Hiroaki , Teramoto Shoji
Published: June 2005

Heritable oligodactylism in male rats was discovered in Wistar‐derived rats. In this study, external and skeletal features of the limb anomalies were examined to clarify the type of oligodactyly. External observation revealed absence and hypoplasia (with respective percentage incidence) in digits II (100,0), III (87,13), and IV (23,1) of the forefeet and in digits II (26,34), III (34,11), and V (0,3) of the hindfeet. Fusion was also observed in digits IV and V in the forefeet (4%) and in digits I and II in the hindfeet (15%). Skeletal examination disclosed absence of all three (proximal, middle, and distal ) phalanges in digits II (97%), III (93%), and IV (67%) and of the middle phalanx in digit V (12%) of the forefeet. In the hindfeet, the missing pattern of phalanges in digits II and III was similar to, but less severe than that in the forefeet; the incidence of absence of the three phalanges in digits II and III was 43% and 45%, respectively. Digit V was more affected than that in the forefeet; absence of the middle phalanx was found at 30% Although no absence was found in the bones proximal to the phalanges, hypoplasia and/or fusion were detected with various degree and incidences among carpi/metacarpi and tarsi/metatarsi. Based on these observations, the types of limb anomalies in this mutant rat were classified as oligodactyly of digits II–V in the forefeet and II, III and V in the hindfeet with hypoplasia and/or fusion of the carpi/metacarpi and tarsi/metatarsi. © 1995 Wiley‐Liss, Inc.
Maternal zinc deficiency, but not copper deficiency or diabetes, results in increased embryonic cell death in the rat: Implications for mechanisms underlying abnormal development
Authors: Jankowski Margaret A. , Uriu‐Hare Janet Y. , Rucker Robert B. , Rogers John M. , Keen Carl L.
Published: June 2005

The mechanism underlying the teratogenicity of maternal copper deficiency, zinc deficiency, and diabetes are largely unknown. Here we investigated whether these insults are associated with altered patterns of cell death in gestation day (GD) 11.0 rat embryos. Four weeks prior to mating, rats in the copper‐deficient group (CuD) were fed a copper‐deficient diet supplemented with the chelator, triethylenetetramine, to facilitate the depletion of tissue copper stores. Rats in this group were switched to a triethylenetetramine‐free copper‐deficient diet 1 week prior to mating. Dams in the diabetic and control groups were fed a control (8μg copper, 25 μg zinc/g) diet throughout the study. On GD 3.0, one subset of the control dams was assigned to the zinc‐deficient group (ZnD) and fed a zinc‐deficient diet. A second subset of control dams was assigned to a restricted fed group and fed the control diet in quantities consumed by the zinc‐deficient dams. Litters were taken by cesarean section on GD 11.0 Embryos were examined for gross morphology and assessed for patterns of cell death using Nile blue sulfate. Embryos from the CuD dams were characterized by edematous hindbrain. Embryos from the diabetic group were characterized by delayed development. Altered patterns of cell death were only detected in embryos from the ZnD dams. Within the ZnD group, embryos were either characterized by small size, edematous head region, and control patterns of cell death, or normal size, normal morphology, and increased cell death. These different patterns of morphology and cell death in the embryos of ZnD dams were associated with different patterns of maternal food intake. These results support the concept that abnormal cell death may contribute to zinc deficiency‐induced teratogenesis. © 1995 Wiley‐Liss, Inc.
Symmetrical terminal transverse limb defects: Report of a twenty‐week fetus
Authors: Harmon James V. , Osathanondh Rapin , Holmes Lewis B.
Published: June 2005

A 20‐Week gestation hydropic Thai fetus is reported who had symmetrical absence of each hand and forefoot with persistence of digit‐like nubbins on each limb. The histologic studies showed there was calcified acellular material in the digit‐like nubbins, consistent with infarcted blood vessels, and cartilaginous structures that represent possibly the distal metacarpal articulating surface. The red blood cell indices of both parents were consistent with their being heterozygous for a hemoglobinopathy, such as α‐thalas‐semia, which is common in Thais. The infarcted blood vessels could be the result of thrombosis of the digital arteries in the fetus due to a hemoglobinopathy such as hemoglobin Bart's, just as rabbit fetuses homozygous forbrachydactylyhave transverse terminal digit amputations following digital vessel occlusions due to macrocytic anemia. This was the only child with symmetrical absence of the hands and feet identified among 123, 489 liveborn and stillborn infants surveyed for major malformations. © 1995 Wiley‐Liss, Inc.
Placental transfer and developmental effects of 9‐cisretinoic acid in mice
Authors: Kochhar Devendra M. , Jiang Heng , Penner John D. , Heyman Richard A.
Published: June 2005

9‐cisretinoic acid (RA) is a naturally occurring isomer of all‐transRA. While both isomers can bind with high affinity and activate RA receptors, only 9‐cisRA is the specific ligand for the retinoid X receptors. 9cisRA has also been shown to be much more potent than all‐transRA in inducing digit duplication in the chick embryo wing bud. To gain further insight into its mechanisms, here we investigated the teratogenic activity in pregnant mice of 9‐cisRA and compared it with those of all‐transRA and 13‐cisRA. Using frequency and severity of limb reduction defects as well as palatal clefts in the resultant fetuses as indicators, we found that orally administered 9‐cisRA was one‐half as potent a teratogen as all‐transRA. That 9‐cisRA was intrinsically less active than all‐transRA was deduced by comparing the inhibitory activities of the two retinoids in the limb bud mesenchymal cell micromass cultures using chondrogenesis as an end‐point. Since placental transfer ofcisisomers of RA is generally poor, we monitored the identities and amounts of retinoids in the embryo after administration of 9‐cisRA to the mother. We found that 9‐cisRA undergoes extensive metabolism and isomerization during absorption resulting in a number of metabolites in the maternal circulation within 30 min after administration. Although some of these metabolites remain to be identified, the most abundant RA isomers in the plasma coeluted with 13‐cisRA. The major isomer in the embryo, however, was all‐transRA, which exceeded the embryonic levels of 9‐cisRA and other retinoids in the 13‐cisRA fraction during the 3 hr period of monitoring. We conclude that orally administered 9‐cisRA is a weaker teratogen in mice than all‐transRA and suggest that its isomerization may be an important contributory factor to its teratogenicity. The individual role played by either of the receptor pathways in teratogenesis is unclear and needs further study. © 1995 Wiley‐Liss, Inc.
Anti‐interferon immunoglobulins can improve the trisomy 16 mouse phenotype
Authors: Maroun Leonard E.
Published: June 2005

Mouse trisomy 16 is a well‐studied model for human chromosome 21 trisomy (Down's syndrome). The late stage trisomy 16 mouse fetus exhibits significant growth retardation, inappropriately opened eyes, and convex rather than concave back curvature. The interferons (α β and γ)have potent growth retarding activity, and sensitivity to these cytokines is controlled by genes that map to mouse chromosome 16 and human chromosome 21. In experiments designed to determine if the interferons induce or aggravate the trisomy phenotype, mice pregnant with trisomy 16 fetuses were injected with a combination of anti‐α,‐β and‐γ interferon lgG. This maternal anti‐ interferon treatment was found to provide measurable benefit to the development and growth of the trisomic fetuses with significant return‐ forward‐ normal values observed for overall fetal growth, eye opening, and back curvature.© 1995 Wiley‐Liss, Inc.
Detection of genotype‐environment interaction in case‐control studies of birth defects: How big a sample size?
Authors: Khoury Muin J. , Beaty Terri H. , Hwang Shih‐Jen
Published: June 2005

Detecting interactions between risk factors in case‐control studies of birth defects and other conditions usually requires increasing the sample size beyond that needed to detect marginal effects. A special case of such interaction is genotype‐environment interaction in which the effects of an exposure on disease risk are modified by genetic susceptibility. When case‐control studies are designed to detect marginal effects of an exposure (i. e., in the whole population), under many plausible interaction schemes, no additional case and control subjects are needed to detect genotype‐environment interaction. On the contrary, inclusion of genotypic information generally can improve the statistical power of the original study. Using the example of oral clefts, maternal cigarette smoking, and genetic variation at the transforming growth factor alpha gene, we illustrate sample size and power issues in designing case‐control studies when prior information is available on both the marginal effects of the exposure and the genetic factor.© 1995 Wiley‐Liss, Inc.

This article is a US Government work and, as such, is in the public domain in the United States of America

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Evaluation of the reproductive and developmental toxicity of the AT1‐selective angiotensin II receptor antagonist Losartan in rats
Authors: Spence S. G. , Cukierski M. A. , Manson J. M. , Robertson R. T. , Eydelloth R. S.
Published: June 2005

Losartan, an AT1‐selective angiotensin ll receptor antagonist, was evaluated in female rats for effects on fertility reproduction, and perinatal and postnatal development. In a range‐finding study, pregnant rats were treated orally from gestation days 6–17 (GD 6–17) with doses of 25, 75, 150, 225, and 300 mg Losartan/kg/day. There were treatment‐related decreases in maternal body weight gain, slight treatment‐related decreases in hemoglobin concentration, and slight treatment‐related increases in serum urea nitrogen in the 225 and 300 mg/kg/day groups. In a fertility study, female rats were treated for 15 days prior to mating, during mating, and GD 0–19 with doses of 25, 100, and 300 mg Losartan/kg/day. The initial dose of 300 mg/kg/day was lowered to 200 mg/kg/day at the start of mating due to excessive body weight loss during the premating treatment interval. There were no treatment‐related effects on reproductive performance, mating, or fertility indices in the F0 generation. There was no evidence of treatment‐related or dose‐related fetal malformationsHowever, decreased F1 pup body weights were observed in all drug‐treated groups. In the 100 and 300/200 mg/kg/day groups there were treatment‐related increases in F1 pup mortality and alterations in the pattern of postweaning body weight gains. There was also a delay in developmental signs in the 100 and 300/200 mg/kg/day groups, which were likely secondary to the decreased weight of the pups in these groups. In a development toxicity study, pregnent rat were administered 50, 100, and 200 mg Lasartan/kg/day on GD 6–17 There was no evidence of developmental toxicity in any dose group. Maternal toxicity was evident in the 200 mg/kg/day group as a treatment‐related decrease in body weight gain during gestation. In a late‐gestation/location study pregnant rats were administered 10, 25, and 100 mg Losartan/kg/day on GD 15 through lactation day (LD 20). There were treatment‐related decreases in maternal body weight gain during gestation and lactation in the 100 mg/kg/day groups. Decreased pup weight were noted in all dose groups, and pre‐ and postweaning pup deaths were observed in the high dose group which were comparable to those observed in the female fertility study. The lack of fetal body weight effects at 100 mg Losartan/kg/day in the developmental toxicity study, with treatment ending on GD 17, indicates that adverse effects observed in the F1 generation in the fertility and late‐gestation/lactation studies were due to exposure during late gestation and/or lactation. Similarities between the developmental and reproductive toxicity of Losarton and angiotensin‐converting enzyme inhibitors are discussed. © 1995 Wiley‐Liss, Inc.
Clusterin expression during programmed and teratogen‐induced cell death in the postimplantation rat embryo
Authors: Little Sally A. , Mirkes Philip E.
Published: June 2005

Clusterin appears to play a role in multiple cellular processes including reproductive cell function, lipid transport, complement regulation, and endocrine secretion. In addition, clusterin has been shown to be associated with both developmental and induced cell death. We have used immunohistochemistry and in situ hybridization to study the relationship between clusterin expression, normal programmed cell death (PCD) in the developing rat limb bud, and abnormal cell death induced by hyperthermia in day 11 rat embryos. Immunohistochemical localization of clusterin in day 14‐16 limb buds showed that the most intense immunostaining was associated with the condensing mesenchyme of the developing digit, a tissue exhibiting low levels of PCD. Moreover, areas of digital cell death, confined to future interphalangeal spaces, were devoid of clusterin immunostaining. Clusterin immunostaining was also observed in the interdigital mesenchyme and partially overlapped the cell death that occurs in this tissue during the early development of the digits. Although clusterin immunostaining overlaps areas of interdigital cell death, most apoptotic cells in the interdigital mesenchyme and underlying the surface ectoderm were not associated with clusterin immunostaining. We also examined the expression of clusterin in day 11 rat embryos exposed to 43°C, an exposure that induces extensive cell death primarily in the developing neuroepithelium. In control embryos cultured at 37°C, clusterin mRNA and protein were expressed at high levels in the heart, a tissue that is completely resistant to the cytotoxic effects of hyperthermia. Within 2.5 hr after an exposure of 43°C, clusterin mRNA showed a dramatic induction in the prosencephalic mesenchyme and only a modest induction in the prosencephalic neuroepithelium. Although less dramatic, clusterin immunostaining was also induced in the prosencephalic mesenchyme, a tissue that is relatively resistant to the cytotoxic effects of hyperthermia. Our results suggest that clusterin is not associated with either PCD or hyperthermia‐induced cell death. Nonetheless, our results suggest that clusterin plays some role in the differentiation of digital cartilage/bone and possibly in the protection of specific embryonic cell types (heart, mesenchyme) from hyperthermia‐induced cell death. © 1995 Wiley‐Liss, Inc.
Induction of hsp72 in heat‐treated rat embryos: A tissue‐specific response
Authors: Fisher Benjamin R. , Heredia Dinorah J. , Brown Kenneth M.
Published: June 2005

Previous studies have demonstrated that heat exposure on gestation day 10 (GD10) resulted in disrupted somite development in rat embryos 24 hr after exposure and in thoracic skeletal malformations in neonatal rats examined 3 days postpartum. The production of abnormal somites was correlated with the location of skeletal elements that developed from the affected somites. Heat has also been shown to induce changes in genetic expression whereby new proteins are synthesized and the expression of constituent proteins may be repressed. In the present study, heat‐induced alterations in proteins synthesis during rat organogenesis that may be associated with previously observed malformation was investigated. GD10 rat embryos were expose in utero to a heat treatment previously demostrated to produce skeletal malformations; maternal core temperature was raised and maintained at 42‐42.4°C for 5 min. In addition, explanted GD10 embryos were cultured in vitro and exposed to temperatures of 42‐42.5°C for 15 min. At various times postexposure, embryos were labeled with 35S‐methionine and processed for SDS‐PAGE. In both in vivo and in vitro heat‐treated embryos, a transient enhanced de nove synthesis of 70‐ and 90‐kD proteins was observed 1‐8 hr after exposure. Actinomycin D studies were conducted to determine whether transcription of new mRNA was required for the enhanced synthesis of the 70‐ and 90‐kD proteins was observed 1‐8 hr after exposure. Actinomycin D studies were conducted to determine whether transcription of new mRNA was required for the enhanced synthesis of the 70 ‐and 90‐kD proteins in heat‐treated embryos. Results from these studies demonstrated that the expression of these proteins was transcriptionally regulated. The 70‐kD protein was identified, using Western blot analysis, as a eukaryotic inducible stress protein (hsp72), and the presence of this protein was detected between 2 and 27 hr postreatment. Immunohistochemical results indicated that following heat shock, hsp72 accumulates in the neuroectodermal tissues of the embryos. The data demonstrate that although heat‐induced expression and accumulation of the hsp72 precedes aberrant somite morphology, the lack of hsp72 accumulation in the somite mesoderm may explain the sensitivity of this tissue to heat. © 1995 Wiley‐Liss, Inc.
Ethanol‐induced teratogenesis: Free radical damage as a possible mechanism
Authors: Kotch Lori E. , Chen Shao‐Yu , Sulik Kathleen K.
Published: June 2005

To investigate the possibility of a free radical mechanism for ethanol‐induced teratogenesis, gestational day 8 mouse embryos were exposed for 6 hr in whole embryo culture to a teratogenic dosage of ethanol alone (500mg%) or in conjunction with an antioxidant, superoxide dismutase (SOD; 300 U/ml). For subsequent analysis, some embryos were examined at the end of this 6‐hr period, while others were removed to control medium and cultured for an additional time period. Ethanol exposure resulted in increased superoxide anion generation and increased lipid peroxidation (as noted 6 hr after initial ethanol exposure) and in excessive cell death (as noted 12 hr after initial exposure) in the embryos. Following a total of 36 hr in culture, a high incidence of malformation, including failure of the anterior neural tube to close in 63% of the ethanol‐exposed embryos, was noted. The ethanol‐induced superoxide anion generation, lipid peroxidation, excessive cell death, and dysmorphogenesis were diminished in embryos co‐treated with SOD, suggesting that the teratogenicity of ethanol is mediated, at least in part, by free radical damage. © 1995 Wiley‐Liss, Inc.
Severe limb defects and craniofacial anomalies in a fetus conceived during acitretin therapy
Authors: De Die‐Smulders Christine E. M. , Sturkenboom Mirjam C. J. M. , Veraart Joep , Van Katwijk Cees , Sastrowijoto Prapto , van der Linden Ed
Published: June 2005

We describe a 20‐week‐old fetus with multiple congenital anomalies exposed to acitretin in the first trimester of pregnancy. Acitretin and its ethylester etretinate are both vitamin A congeners; drugs of this group are well‐known teratogenic agents. Since the marketing of acitretin only one report on human teratogenicity associated with acitretin has been published. The present male fetus showed severe symmetric anomalies of upper and lower limbs, craniofacial anomalies, ear anomalies, and an atrioventricular septal defect (ASD). Although the craniofacial anomalies resemble the abnormalities described in classical “retinoic acid embryopathy,” limb anomalies were seldomly reported after maternal use of vitamin A congeners. However, in laboratory animals limb defects were frequently observed after retinoid exposure in utero. This case emphasizes again that extreme care and precaution are needed before prescribing a potentially teratogenic drug to a fertile woman. © 1995 Wiley‐Liss, Inc.
In vitro assessment of the effect of methanol and the metabolite, formic acid, on embryonic development of the rat
Authors: Brown‐Woodman Patricia D. C. , Huq Fazlul , Hayes Louise , Herlihy Carolyn , Picker Kelvin , Webster William S.
Published: June 2005

Inhalation studies in rats have indicated that methanol is embryotoxic at levels that are only mildly maternally toxic. In the present study, the embryotoxicity of methanol and its metabolite, formic acid, was evaluated using rat embryo culture. The results showed that both methanol and formic acid have a concentration‐dependent embryotoxic effect on the developing rat embryo in vitro. The no‐effect concentration of methanol was 211.7 μmol/ml culture medium, while embryotoxicity was observed at 286.5 μmol/ml. The no‐effect concentration of formic acid was 3.74 μmol/ml, while a concentration of 18.66 μmol/ml was associated with severe embryotoxicity. When embryos were grown in sera containing 18.66 μmol sodium formate/ml or in sera adjusted with hydrochloric acid to pH values similar to those achieved with formic acid, the results indicated that both low pH and formate contributed to the observed embryotoxicity of formic acid. When the levels of methanol found to be embryotoxic in the present study is compared to blood levels in the human following controlled industrial exposure there appears to be a large margin of safety. However, plasma methanol levels are only one aspect of methanol toxicity in the human. Of greater significance is the formate level and the associated acidosis. However, it appears that embryotoxicity due to low pH ro high formate levels would only occur after very severe methanol intoxication. Based on these in vitro studies, current industrial safety limits would appear to provide protection for the developing embryo. © 1995 Wiley‐Liss, Inc.
Pharmacokinetics of teratogenic antibodies administered to rats
Authors: Fawcett Lynda B. , Beckman David A. , Fawcett Paul T. , Brent Robert L. , Lloyd John B.
Published: June 2005

The serum levels of total and visceral yolk sac (VYS)‐reactive sheep IgG have been determined following injection of a teratogenic sheep anti‐VYS antiserum. After intravenous injection, levels of VYS‐reactive IgG fell rapidly, with 75% of the amount in the injection removed in the first 5 min, and 90% by 60 min. By contrast, 90% or more of the total sheep IgG was still present at these times. A similar difference in clearance was seen after intraperitoneal injection, although the serum levels also reflected the presence of a pool of antiserum in the peritoneum and the simultaneous influx and efflux of IgG into and from the circulation. The clearance pattern was similar in pregnant and nonpregnant rats; it is concluded that antibodies against VYS‐specific antigens comprise a very small fraction of VYS‐reactive antibodies in the antiserum. ELISA and Western blot analysis indicated extensive cross‐specificity with antigens present in rat tissues other than the VYS. Similar teratogenic effects were observed after intravenous or introperitoneal injection of the antiserum at 8.5 days of gestation; we conclude that the proximal effect likely begins within the period immediately after the injection. The results are also considered within the context of published reports that the VYS shows structural and functional damage for several days after intraperitoneal administration of antiserum at 8.5 days. © 1995 Wiley‐Liss, Inc.
Comparison of two approaches to analyzing correlated binary data in developmental toxicity studies
Authors: Have Thomas R. Ten , Hartzel Tracy
Published: June 2005

Recently developed statistical methodology is presented for analyzing correlated developmental toxicity data where multiple measures are obtained on individual units such as rat pups. Of particular interest is the assessment of the homogeneity of effects from chemical exposure across different outcomes such as malformation types or non‐ossification of forepaw digits. Such contrasts are referred to as within‐cluster effects, as they represent differences between observations within a cluster (e.g., pup). Between‐cluster effects correspond to comparison of observations from different clusters, e.g., pups exposed to varied doses of chemicals or carcinogens. Two classes of statistical models are available for estimation of these distinct types of effects: (1) cluster‐specific models in which regression adjustments are made for cluster effects, and hence all parameters are interpreted as within‐cluster effects; and (2) population‐averaged models in which no explicit adjustments are made for cluster, and thus all parameters are interpreted as group differences without regard to whether they represent between‐ or within‐cluster effects. Many models in the developmental toxicity literature are population‐averaged logistic regression models ignoring variation among clusters which may be significant under strong influences of genetic and environmental factors. Under such conditions, confidence interval‐based inference for effect homogeneity will depend upon the class of models. These issues are illustrated with data from two developmental toxicity studies: (1) a National Toxicology Program study of the effects of in utero exposure to di(2ethylhexyl)phthalate among three malformation outcomes in mouse pups; and (2) a study conducted by Hartsfield to investigate the effects of anticonvulsant phenytoin on the risk of non‐ossification among digits of the left and right forepaws in rat pups. © 1995 Wiley‐Liss, Inc.
Functional involvement of Pax‐1 in somite development: Somite dysmorphogenesis in chick embryos treated with Pax‐1 paired‐box antisense oligodeoxynucleotide
Authors: Smith Carol A. , Tuan Rocky S.
Published: June 2005

The metameric pattern of the vertebrate axial skeleton, defined by structures such as the vertebral bodies and ribs, is a result of segmentation events that occur during embryogenesis. The key event in axial segmentation is somite formation. This study examines the role of Pax‐1, a member of the paired‐box containing Pax gene family, in chick somite development. To investigate whether misexpression of Pax‐1 during somite development is functionally related to abnormal axial patterning, antisense methodologies were used to perturb Pax‐1 expression. An antisense, phosphorothioate‐modified oligodeoxynucleotide (ODN) was designed based on the mouse Pax‐1 paired‐box sequence, and was either injected into or directly applied topically to early, somitic stage chick embryos. Abnormalities in somite structure and pattern were subsequently observed and scored, including loss of somites (18% of injected embryos, 35% of embryos treated by topical application), fusion of somites (25% of injected, 6% with topical application), and shortened body axis (0% of injected, 11% with topical application). Control embryos receiving sense ODN or non‐sense ODN (a scrambled sequence with base composition identical to the antisense ODN) showed substantially fewer somite anomalies, indicating that the effects were sequence‐specific. These developmental abnormalities were analyzed using standard histological methods. Whole mount in situ hybridization was carried out to analyze the three‐dimensional pattern of Pax‐1 expression in whole embryos. In control, untreated embryos, the expression was localized to the entire epithelial somite, and as the somite matured, the expression was limited to its ventromedial region. With Pax‐1 antisense ODN treatment, embryos with fused somites retained expression over the entire fused somite, and embryos that had complete loss of somites had greatly reduced expression of Pax‐1 transcript. The results presented here provide strong evidence that Pax‐1 is functionally important during somitogenesis and morphogenesis of the vertebral column. The spatial pattern of gene expression appears to delineate different populations of cells in the developing embryo (i.e., somite from somite, sclerotome from dermomyotome), and is consistent with the hypothesis that Pax‐1 is involved in forming or maintaining boundaries at specific times and locations during development. © 1996 Wiley‐Liss, Inc.
Effects of spatial crowding on social behavior in a chimpanzee colony
Authors: Nieuwenhuijsen Kees , de Waal Frans B. M.
Published: June 2005

Among mammals there is usually an increased frequency of aggressive interactions when population density increases. Conducted at the Arnhem Zoo, the present study examined the effects of spatial crowding on social behavior. Observations were carried out during three winter and two summer periods, using six distinct behavioral categories as dependent variables. The hypothesis that the behavior of individual chimpanzees would be intensified under crowded conditions was examined. Only absolute grooming changes supported the “density‐intensity” hypothesis. Aggression data exhibited only a slight increase. Apparently, advanced mammalian forms, such as chimpanzees and human beings, are able to cope with crowding‐induced stress by engaging in alternatives to overt aggression.
The control of progression order in a captive herd of sable antelope (Hippotragus niger)
Authors: Stine Wm. Wren , Howell Leonard L. , Murdock Gwendolyn K. , Newland M. Christopher , Conradsen Linda , Maple Terry L.
Published: June 2005

A small herd of captive sable antelope (Hippotragus niger) was observed repeatedly while progressing through a gate connecting a pasture to a corral. The ordinal position of each herd member was recorded during each progression. These data were analyzed quantitatively with respect to three models of progression order control and one of random ordering. An end point‐control model, stating that the oldest female of a progression occupies the first position while the remainder of the animals randomly distribute themselves within the progression, accounts for the data. These results are related to both protection and resource learning theories of progression order. The terminology used in the study of leadership and ordinal progressions is discussed as well.
Studies on Asian elephant reproduction at the Washington Park Zoo
Authors: Schmidt Michael J.
Published: June 2005

Studies of Asian elephant reproduction at the Washington Park Zoo in the areas of the estrous cycle, semen collection, bull elephant management and health care, pregnancy, and pheromones have yielded sufficient information to attempt repeated artificial insemination (AI) at the time of ovulation. While no pregnancy has been achieved to date, with the information now at hand AI can be expected to become a practical technique for breeding elephants in captivity.
Behavioral effects of a change in the physical environment: A pilot study of captive chimpanzees
Authors: Clarke A. Susan , Juno Charles J. , Maple Terry L.
Published: June 2005

A small group of chimpanzees was studied before and after their translocation from a laboratory environment to a naturalistic man‐made island. After 22 weeks of island living, stereotyped and self‐directed behavior was dramatically reduced. Social behavior did not improve on the island, but the animals were more active and manipulative in the enriched setting. Naturalistic environments are clearly conducive to normal behavior patterns.
Association between burst‐pulse sounds and aggressive behavior in captive Atlantic bottlenosed dolphins (Tursiops truncatus)
Authors: Overstrom Neal A.
Published: June 2005

A specific display observed during agonistic behavior among captive Atlantic bottlenosed dolphins (Tursiops truncatus) was examined. The primary component of the display was an open‐mouthed posture accompanied by violent vertical head motions and the emission of pulse‐type vocalizations. Jaw‐clap behavior produced during the display was quantified for use as an index of aggressive motivation. By aurally monitoring the animals' vocalizations it was found that the level of aggressive response between the participants of the interactions increased with the production and subsequent duration of burst‐pulse sounds. The possibility of burstpulse sounds resulting in auditory or tactile discomfort when directed toward conspecifics is discussed.
Mass propagation techniques currently being used in the spawning and rearing of marine fish species
Authors: Frakes Thomas A. , Hoff Frank H.
Published: June 2005

Propagation techniques for marine fish species, applicable to public aquariums, are reviewed based on work with ornamental tropicals and foodfish species. Adult conditioning, spawning procedures, incubation of eggs, larval rearing, larval food culture, and facilities are discussed with specific references to techniques used at Instant Ocean Hatcheries, Inc, for Anemonefish (Amphiprion spp) culture in synthetic seawater.
The breeding of captive wild species by artificial methods
Authors: Seager S. W. J.
Published: June 2005

The growing interest in many zoos, wildlife parks and game ranches in the captive breeding of wild species has brought about much interest and research in developing and testing artificial methods of breeding. Much of this work has been concentrated in endangered species. The author outlines the relevance and utilization of such techniques and reviews successful attempts in this area and elaborates on future potential ones. A brief review is given of successful artificial methods of breeding domestic species and how this may be applied to non‐domestic ones. Areas that are covered are semen collection, semen freezing, induction of estrus, artificial insemination, embryo transfer including interspecies transfer and embryo surgery. It is acknowledged that it is highly unlikely that an artificial program could save a species from extinction but such methods could greatly assist a comprehensive natural breeding program.
Development of a masterplan for captive propagation of Siberian tigers in North American Zoos
Authors: Seal U. S. , Foose T.
Published: June 2005

The status of the Siberian tiger in the wild is endangered. A captive propagation program has been initiated by the American Association of Zoological Parks and Aquariums (AAZPA). A Species Survival Plan (SSP) has been prepared and 50 institutions have agreed to participate. The goals of the SSP include management for longterm survival with retention of maximum genetic diversity.
Breeding condors in captivity for release into the wild
Authors: Bruning Donald
Published: June 2005

Recognizing the decline of the South American Condor in some parts of its range and the highly endangered status of the California condor, the New York Zoological Society developed a captive‐breeding program for South American condors. This program was designed to produce techniques applicable to hand‐rearing of either species of condor. Once condors were successfully reared in captivity, it became imperative to develop techniques to ensure that captive‐reared condor chicks could be released into the wild, could survive there, and could interact naturally with other wild condors. Captive‐bred hand‐reared condor chicks were taken to Northwestern Peru and successfully released into the wild.
Several examinations on the reproductive status of lowland gorillas (Gorilla g. gorilla) at Hannover Zoo
Authors: Böer Michael
Published: June 2005

There as been no reproduction within the Hannover Zoo's gorilla group, although several adult females and a silverback male have been living together for a prolonged period. Therefore, the sexual cycle of three adult females was examined by means of total urinary estrogen excretion, measurement of the urogenital cleft length, ovulation detection with the help of the Subhuman‐Primate‐Pregnancy Test (SPPT), measurement of basal body temperature, semiquantitative blood tests to detect menstruation, and observation of sexual behavior. Fertility status of the silverback male was examined by means of behavioral observation, rectal probe ejaculation (RPE), and testicular biopsy. Sexual cyclicity was demonstrable in two females, whereas the third had an irregular occurrence of estrogen peaks and her menstruation and sexual behavior did not show normal cyclicity. The male's infertility was characterized by absence of any sexual behavior, azoospermia in repeated RPE, unsuccessful treatment with clomiphene, and atrophy of seminiferous tubules in the extirpated tissue.

Several factors, such as vitamin E deficiency, humoral dysregulation, testicular hypoxy, and spermatogenic arrest, caused through stress due to inadequate shelter systems, are discussed hypothetically in regard to their possible etiological relevance with respect to infertility in this species.

In many cases infertility in the gorilla male is presumably based on a polyfactoral etiology. Analysis of urinary hormone levels in parallel with behavioral studies is still to be tested as a practical method of gaining information on the puberty development of adolescent males and on the fertility status of adult males under zoo conditions.
Housing conditions and breeding success of chimpanzees at the primate center TNO
Authors: Goosen C. , Schrama A. , Brinkhof H. , Schonk J. , van Hoek L. A.
Published: June 2005

Results of rearing and breeding chimpanzees at the Primate Center TNO are presented. The colony was built up from 1964 to 1971 by the acquisition of mostly young chimpanzees; thereafter, it was increased by local breeding. The ages at which the animals became reproductive were between 6 and 11 years for the males and between 7 and 15 years for the females. Seventy‐six percent of the pregnancies (N = 132) were carried to full term and 87% of these were live births. Fifty‐five percent of the babies were nursed by their mothers for 2–10 months. The next pregnancy after an abortion occurred on the average after 7 months; after a carriage to term, this occurred after 11.9 months. The difference was not influenced by the duration of the weaning period. Animals of 2 years or more that had been weaned within a month were more likely to show body rocking than animals weaned later. Cases of disturbed social or reproductive behavior were rare; the first locally bred animals have become reproductively active.
Electroejaculation in chimpanzees and gorillas and artificial insemination in chimpanzees
Authors: Bader H.
Published: June 2005

Electroejaculation was performed in 3 chimpanzees, 1 pygmy chimpanzee, and 2 gorillas with an instrument that delivers a modified sine wave current with a frequency of 24 Hz. The current stimuli were applied by a rectal probe with longitudinal electrodes. The electrical parameters varied from 6 to 12 V and from 30 to 40 mA for response of erection and lay between 8 and 18 V and between 40 and 145 mA during semen emission. Eleven chimpanzee semen samples showed the following data (x ± SD): total volume 1.9 ± 1.3 ml, volume of the liquid fraction 0.3 ± 0.2 ml, spermatozoa per ejaculate 743 ± 376 × 106, sperm motility 52.7 ± 9.6%, morphologically abnormal spermatozoa 12.2 ± 7.5%. From an adult gorilla, three semen samples were collected, in each case without spermatozoa. The electrostimulation of a 6‐year‐old gorilla led to an erection, but not to semen emission. Three female chimpanzees were inseminated with fresh or frozen semen, each of them within three different estrous cycles. None of these inseminations led to a pregnancy.
An integrative approach to environmental engineering in zoos
Authors: Quick Debra L. Forthman
Published: June 2005

Zoos have shifted recently from the historical tendency to display as many species as possible to an emphasis on improved education and captive propagation. Many enlightened zoo administrations attempt to achieve these goals through creation of exhibits that mimic animals' natural physical and social environments, as extrapolated from field studies. An adjunct is the increased use of technology as a tool in environmental engineering, the term used herein to refer to the design of habitats for captive animals. Recently there has been discussion about the degree of technological control that is appropriate in zoo displays. One progressive group has proposed that natural resources and technology should only be used to enhance displays passively. Their efforts are concentrated on simulation of natural physical and social environments. Another group has suggested that technology should play an active role in the design of captive environments. They attempt to modify displays so that captive animals participate actively to obtain food. This paper first reviews the literature of both groups and suggests an integration of their views. The second section illustrates how both methods may be used to solve problems zoos face with animals during reproduction, development, and adulthood.