bluuebunny/crossref_metadata_2025 huggingface dataset:
Perinatal thymocyte antigen expression and postnatal immune development altered by gestational exposure to tetrachlorodibenzo‐p‐dioxin (TCDD)
Authors: Holladay S. D. , Lindstrom P. , Blaylock B. L. , Comment C. E. , Germolec D. R. , Heindell J. J. , Luster M. I.
Published: June 2005

In utero exposure to the environmental contaminant 2,3,7,8–tetrachlorodibenzo‐p‐dioxin (TCDD) was found to alter expression of murine thymocyte fetal cell‐surface markers. Pregnant mice were treated (via gavage) with 0, 1.5, or 3.0 μ TCDD/kg/day in corn oil on gestational days (gd) 6–14. Offspring were examined on gd 18 and postnatally on d6, d14, and d21, and at 7, 8, and 10 weeks of age. Severe thymic atrophy and cellular depletion were found both pre‐ and postnatally in TCDD‐exposed mice. Immunocytochemical localization of the Thy 1.2 antigen on gd 18 thymocytes revealed no TCDD‐related changes in cellular distribution. Flow cytometric analysis, however, indicated that the TCDD treatment resulted in a significant decrease in the percentage of CD4+8+ fetal thymocytes, as well as significantly increased CD4−8− and CD4−8+ thymocytes. The increased CD4−8+ population after TCDD was not from induction of Ts cells. At 7–8 weeks postnatally, no differences existed between control and treatment groups in mitogen responses and antibody plaque response. However, altered thymocyte antigen expression was found to correlate with altered postnatal immune function, as evidenced by decreased cytotoxic T lymphocyte response at 8 weeks of age. Taken together, these results indicate that immunosuppression following prenatal exposure to TCDD can be readily detected by qualitative and quantitative changes in the cell surface phenotype of fetal thymocytes. Furthermore, the observed altered distribution suggests that TCDD inhibits normal thymocyte maturational processes.
Reversible effects of triamcinolone and lack of effects with aspirin or L‐656,224 on external genitalia of male Sprague‐Dawley rats exposed in utero
Authors: Wise L. David , Vetter Christine M. , Anderson Charles A. , Antonello Joseph M. , Clark Robert L.
Published: June 2005

Inhibitors of the arachidonic acid cascade were given to pregnant rats during the critical period for morphogenesis of the external genitalia. Groups treated subcutaneously (s.c.) with 0.1 or 0.25 mg/kg/day of triamcinolone acetonide (TA) on gestational days (GD) 14–19 had male fetuses on GD 20 with moderate decreases in absolute anogenital distance (AGD), but gross and histological examinations revealed no alterations to the genital tubercle (i.e., no hypospadias). The s.c. coadministration of arachidonic acid at 100 mg/kg/day had minimal to no effect on AGD in the TA‐exposed groups. No effect on AGD was observed in male fetuses from groups administered aspirin orally at 150 mg/kg/day, and only a 6% decrease was observed in the 300‐mg/kg/day group. Neither TA nor aspirin adversely affected AGD of female fetuses. In another study, TA was administered on GD 11–19 at dose levels of 0.05 and 0.1 mg/kg/day, and dams were allowed to deliver. High‐dose male offspring examined on postcoitum day (PCD) 23, had moderate decreases in AGD. In both studies with TA, there were also significant decreases in offspring weights. The contribution of the decreased weight to the decrease in absolute AGD was examined by a variety of methods (ratio of AGD to cube root of weight or biparietal distance, comparison to weight‐matched controls, and covariance analysis). We conclude that TA caused a specific decrease in AGD on GD 20 that was largely reversed by PCD 23. When examined as adults (8 weeks old), the external genitalia of TA‐exposed offspring were normal. Thus, the TA‐induced decreases in AGD on GD 20 did not predict irreversible malformation. TA also caused other effects, which included a somewhat flattened genital tubercle and apparently thinned and glossy skin between the tubercle and the anus in both sexes on GD 20 and PCD 23, but not as adults. In addition, there were high pup mortality and high incidences of micrognathia and omphalocele (in the 0.25‐mg/kg/day group only). Aspirin at 75 or 150 mg/kg/day and a specific lipoxygenase inhibitor (L‐656,224) at 1,000 or 2,000 mg/kg/day were also administered from GD 14 to 19, and no offspring effects were observed. Thus, of the three agents that potentially inhibit the arachidonic acid cascade, only triamcinolone produced moderate effects on rat external genitalia that were largely reversible. Compared with previously reported results using B10.A mice (Gupta and Goldman, '86), these data indicate that the Sprague‐Dawley rat is much less sensitive to the effects of aspirin and glucocorticoids on anogenital distance and, therefore, prostaglandins are unlikely to be primary mediators of androgen‐initiated external masculinization in this rat strain.
Aspirin dose‐dependently reduces alcohol‐induced birth defects and prostaglandin E levels in mice
Authors: Randall Carrie L. , Anton Raymond F. , Becker Howard C. , Hale Robert L. , Ekblad Ulla
Published: June 2005

The purpose of the present study was threefold. The first purpose was to determine if aspirin (ASA) decreases alcohol‐induced birth defects in mice in a dose‐dependent fashion. The second purpose was to see if the antagonism of alcohol‐induced birth defects afforded by ASA pretreatment was related to dose‐dependent decreases in prostaglandin E (PGE) levels in uterine/embryo tissue. The third purpose was to determine if ASA pretreatment altered maternal blood alcohol level. In experiments 1 and 2, pregnant C57BL/6J mice were administered ASA (0, 18.75, 37.5, 75, 150, or 300 mg/kg) on gestation day 10. One hour following the subcutaneous injection of ASA, mice received alcohol (5.8 g/kg) or an isocaloric sucrose solution intragastrically. In experiment 1 the incidence of birth defects was assessed in fetuses delivered by caesarean section on gestation day 19. In experiment 2 uterine/embryo tissue samples were collected on gestation day 10 1 hr following alcohol intubation for subsequent PGE analysis. In experiment 3 blood samples were taken at five time points following alcohol intubation from separate groups of alcohol‐treated pregnant mice pretreated with 150 mg/kg ASA or vehicle. The results from the three experiments indicated that 1) ASA dose‐dependently reduced the frequency of alcohol‐induced birth defects in fetuses examined at gestation day 19, (2) ASA decreased the levels of PGE in gestation day 10 uterine/embryo tissue in a similar dose‐dependent fashion, and 3) ASA pretreatment did not significantly influence maternal blood alcohol levels. These results provide additional support for the hypothesis that PGs may play an important role in mediating the teratogenic actions of alcohol.
Limb reduction defects in humans associated with prenatal isotretinoin exposure
Authors: Rizzo Renata , Lammer Edward J. , Parano Enrico , Pavone Lorenzo , Argyle J. Craig
Published: June 2005

Retinoic acid has long been used to induce limb reductions defects in experimental animal studies. No limb malformations, however, have been reported among malformed retinoic acid‐exposed human fetuses from case reports or epidemiologic studies. We report a child and a fetus with limb reduction malformations following maternal use of isotretinoin (13‐cis‐retinoic acid) during the first trimester of pregnancy. The child had a unilaterally absent clavicle and nearly absent scapula, with a short humerus and short, synostotic forearm bones. He also had ventriculomegaly and developmental delay, minor dysmorphic facial features, and a short sternum with a sterno‐umbilical raphe. The fetus had a unilaterally absent thumb with normal proximal bony structures. Other findings included hydrocephalus, craniofacial anomalies, thymic agenesis, supracristal ventricular septal defect, single umbilical artery, anal and vaginal atresia, and urethral agenesis with dysplastic, multicystic kidneys. Although the limb malformations were quite dissimilar, a number of anomalies that are frequently found among isotretinoin‐exposed fetuses/infants were present in both cases. This increases the probability that retinoic acid caused these limb defects, but a causal association cannot be conclusively drawn on the basis of these two retrospective case reports.
Inhibition of isotretinoin teratogenicity by acetylsalicylic acid pretreatment in mice
Authors: Kubow Stan
Published: June 2005

Although isotretinoin (ITR) has been suggested to cause malformations via cytopathic effects on embryonic cells, the molecular mechanisms of ITR cytotoxicity in teratogenesis are not clear. Since ITR undergoes metabolism by prostaglandin synthase to a potentially cytotoxic peroxyl free radical, the possible role of prostaglandin synthase metabolism as a modulator of ITR teratogenicity was evaluated. Craniofacial and limb abnormalities were noted in fetuses on day 18.5 of gestation following administration of ITR to pregnant CD‐1 mice in a three dose regime of 100 mg/kg at 4 hr intervals on day 10.5 of gestation (plug day = day 0.5 of gestation). Mice were also treated with acetylsalicylic acid (ASA), an irreversible inhibitor of the cyclooxygenase component of prostaglandin synthase, at doses of 20 and 60 mg/kg body weight 2 hr prior to each ITR dose. ASA pretreatment of mice receiving ITR treatment showed a dose‐dependent decrease in the overall incidence of malformations, number of defects per fetus, and the incidence of specific craniofacial and limb defects. Equivalent doses of ASA given to control mice did not cause malformations or alter the incidence of resorptions. These results demonstrate that ASA is able to ameliorate the teratogenic effects of ITR observed in fetal mice near term and indicate that prostaglandin metabolism could play a mechanistic role in ITR teratogenicity.
Benign cystic ovarian teratomas with prostatic tissue: A report of two cases
Authors: Uzoaru I. , Akang E. E. U. , Aghadiuno P. U. , Nadimpalli V. R.
Published: June 2005

We report two cases of the rare occurrence of prostatic epithelium in ovarian teratomas with associated transitional epithelium in one of the cases. This association of prostatic tissue with urothelium tends to reinforce the well‐established embryogenetic derivation of the prostate from the urogenital sinus. Local hormonal events may influence the formation of prostatic tissue from female urothelium. The histologic and immunohistological differences between adult prostate as seen in our cases and female paraurethral (Skene's) glands are discussed.
In vitro development of rat embryos undergoing organogenesis in heparin‐plasma
Authors: Kesby Gregory J.
Published: June 2005

This study examines the use of heparin‐plasma as a culture medium for mammalian postimplantation whole‐embryo culture. The growth and differentiation of head‐fold rat embryo explants over 48 hours in a standard serum medium was compared with development of same stage explants over 48 hours in a plasma medium prepared using sodium heparin.

Heparin disrupted the morphological differentiation of embryos, in a concentration‐dependent manner, from 25 μg sodium heparin/ml media (i.e., 5 IU/ml media), with overall embryo growth being adversely affected from a concentration of 200 μg sodium heparin/ml media (i.e., 40 IU/ml media). Defects of cranial neural tube development were the first apparent structural anomalies resulting from culture in heparin media. Forebrain development was grossly abnormal and associated with failure of eye development. As the heparin concentration in media increased, the cephalic neural folds remained widely open and the edges became increasingly everted, although differentiation of the heart, otic primordia, and pharyngeal arch persisted. Similar concentration‐dependent dysmorphogenic effects were seen when embryos were cultured in the standard serum media with added heparin.

A minimum heparin concentration of 100 μg sodium heparin/ml media (i.e., 20 IU/ml media) was required to effectively inhibit coagulation of the plasma medium over the 48 hour culture period. Although embryonic growth was not adversely affected at this heparin concentration, morphological differentiation was severely disrupted. Therefore, heparin is not a suitable anticoagulant for the preparation of plasma for use in postimplantation whole‐embryo culture.
Demographic, reproductive, medical, and environmental factors in relation to gastroschisis
Authors: Werler Martha M. , Mitchell Allen A. , Shapiro Samuel
Published: June 2005

To identify risk factors for gastroschisis other than drug use in pregnancy, an analysis of data collected in a case‐control surveillance program of birth defects (1976‐1990) was conducted. Drug use is considered in Werler et al.,Teratology, 45:361‐367, 1992. Maternal demographic, reproductive, and medical factors, and first trimester environmental exposures, were compared between 76 gastroschisis cases and 2,581 malformed controls. A strong inverse association was found for maternal age: relative to women 30 years or older, relative risks for 25‐29, 20‐24, and <20‐year‐old women were 1.7, 5.4, and 16, respectively. Multivariate relative risks (and 95% confidence intervals) for alcohol use were as follows: for 1‐5 drinks per week, 1.6 (0.7‐3.4); for ⩾6 drinks per week, 2.5 (0.9‐6.8); for a maximum of 1‐4 drinks at any one time, 0.8 (0.4‐1.6); and for a maximum of ⩽5 drinks, 2.8 (1.2‐6.5). With the effect of age taken into account, no associations were identified for cigarette smoking, consumption of caffeinated or decaffeinated coffee, unplanned pregnancy, 12 or less years of education, or a parity of two or more. Other medical and reproductive factors, including weight gain, vaginal bleeding, nausea or vomiting, influenza, “other” infection, and history of spontaneous abortion or elective abortion did not increase the risk.
Morphometric analysis of heterozygote dancer mice predisposed to 6‐aminonicotinamide‐induced cleft lip
Authors: Jacobson Debbie , Trasler Daphne G.
Published: June 2005

Mid‐facial development is an extremely complex process involving coordinated events and precise timing. Cleft lip (CL) may result fro the failed fusion of the lateral and medial nasal processes in the developing embryo. It has been postulated that spontaneous CL in the A/J strain of mice may be due to a predisposing face shape (Trasler, '68). This hypothesis was examined in mutant mice susceptible to teratogen‐induced CL. Mice carrying the dancer (Dc) mutation in the heterozygous state rarely develop CL, whereas 90% of homozygotes (Dc/Dc) develop CL. Outcrossed heterozygotes show elevated susceptibility to 6‐aminonicotinamide (6AN)‐induced CL (Trasler et al., '84) and these were used to investigate face shape as a predisposing factor. Dc/+ and + / + males were mated to R stock females, and embryos were collected on day 10/21 hr, when the nasal placodes are approximately at the oblong or crescent stage. Total nasal process areas and volumes, medial and lateral process areas and volumes, and medial jut lengths were measured from histological sections, and comparisons made between the two populations. The results indicate that compared to +/+ control, heads of embryos from the Dc/ + cross have significantly smaller mean total process areas and volumes (P<0.005), mean lateral process areas and volumes (P⩾0.005), mean medial process area and volumes (P⩾0.01), mean maximum head diameter (P⩾0.02), but similarly sized medial juts and crown rump lengths. Correlations between maximum head diameter and process size indicate that the Dc mutation may hinder normal development of the nasal processes. These reduced nasal processes may explain the underlying predisposition to 6AN‐induced CL.
Mouse conceptuses have a limited capacity to elevate the mRNA level of cellular retinoid binding proteins in response to teratogenic doses of retinoic acid
Authors: Harnish Douglas C. , Soprano Kenneth J. , Soprano Dianne Robert
Published: June 2005

In these studies, we wished to determine the effect of teratogenic doses of retinoic acid on the expression of cellular retinoic acid binding protein I (CRABP‐I) mRNA, cellular retinoic acid binding protein II (CRABP‐II) mRNA, cellular retinol binding protein I (CRBP‐I) mRNA, and cellular retinol binding protein II (CRBP‐II) mRNA in mouse conceptuses. Levels of CRABP‐II mRNA and CRBP‐I mRNA were modestly elevated (2.5‐fold and 1.5‐fold, respectively) in 9‐day gestation conceptuses following treatment of dams with 100 mg/kg b.w. of retinoic acid. These levels were elevated by 6 hr following treatment and remained elevated unitl 48 and 24 hr. respectively. Two other retinoids, etretinate and retinoyl β‐glucuronide, also moderately elevated CRABP‐II mRNA and CRBP‐I mRNA levels in conceptuses. In contrast, the levels of CRABP‐I mRNA in the conceptuses remained unaffected by treatment with any of these three retinoids. These results demonstrate that conceptuses have a limited capacity to elevate the cellular retinoid binding proteins mRNA levels and presumably the synthesis of their respective proteins in response to high, teratogenic doses of retinoic acid. As a result, an excess of free retinoic acid becomes available to the nuclear retinoic acid receptors, which may lead to inappropriate gene expression and eventual maldevelopment. © 1992 Wiley‐Liss, Inc.
Inner ear malformations induced by isotretinoin in hamster fetuses
Authors: Burk Dorothy T. , Willhite Calvin C.
Published: June 2005

Inner ear malformations induced in anotic hamster fetuses following maternal treatment with 50 mg/kg isotretinoin (13‐cis‐retinoic acid) on gestational day 8 are described. Computer‐assisted three dimensional reconstruction was used. Two general types of defective vestibulocochlear development were seen. Defects were bilateral and correlated with extent of middle ear deficiency and severity of mandibular defects. In the more severely affected fetuses the inner ear was limited to an epithelial sac with occasional small projections, no apparent innervation and a correspondingly reduced otic capsule. In most of the fetuses examined the inner ear was less severely affected and was characterized by a reduction in the number of semicircular ducts and alterations in the size and shape of the cochlear duct. These defects are similar to those seen in a child with the isotretinoin embryopathy. Pathogenesis may result from a direct effect on otic epithelium or from faulty inductive interactions with the rhombencephalon or with periotic neural crest cells. © 1992 Wiley‐Liss, Inc.
Developmental stages of the CD® (Sprague‐Dawley) rat skeleton after maternal exposure to ethylene glycol
Authors: Marr Melissa C. , Price Catherine J. , Myers Christina B. , Morrissey Richard E.
Published: June 2005

Ethylene glycol (EG), a chemical which causes skeletal malformations in rats, was administered by gavage to sperm positive CD® rats on gestational days (gd) 6 through 15 at doses of 0 or 2,500 mg/kg/day to assess its effects on the pre‐ and postnatal skeletal development. Dams and fetuses/pups were killed on gd 18, 20, postnatal day (pnd) 1, 4, 14, 21, or 63, and offspring were double‐stained for examination of skeletal malformations and degree of ossification of rapidly developing skeletal districts. No difference in gestational day of delivery between controls and the EG‐treated dams was seen. Fetal weights per litter were significantly decreased with EG treatment in both the gd 18 and 20 groups. Pup body weight on pnd 1 was significantly below controls; however, EG had no effect on pup body weight on pnd 4–63. The percentage of fetuses/pups with skeletal malformations per litter was significantly increased after EG exposure for all time points except at pnd 63, with a predominance of axial skeletal defects. The percentages of total ossification, of sternabrae ossified, and of vertabral centra ossified were significantly reduced in the EG groups on gd 20 and on pnd 1–21, but not on gd 18 or on pnd 63. When the ossification data were subjected to statistical analysis with fetal/pup weights as a covariate, the values for EG‐exposed pups on gd 20 were not statistically significantly different from the control values. The reduced ossification values for EG‐exposed pups on pnd 1–21 retained statistical significance even after covariate analysis. There was no effect of dose or body weight on ossification of fore‐ or hindlimb digits. In conclusion, the differences in incidence of skeletal alterations observed prenatally and through pnd 21 were not evident by pnd 63, suggesting that perinatal skeletal abnormalities may not always be permanent. © 1992 Wiley‐Liss, Inc.
Genetic differences in heat‐induced tolerance to cadmium in cultured mouse embryos are not correlated with changes in a 68‐kD heat shock protein
Authors: Kapron‐Brás Carolyn M. , Hales Barbara F.
Published: June 2005

Heat‐induced cross‐tolerance to cadmium was investigated in two inbred strains of mice, BALB/c and SWV, using a whole embryo culture system. Embryos were exposed to a pretreatment of 5 min at 43°C and subsequently to an embryotoxic concentration of cadmium, 1.75 μM. The two types of embryos responded differently to the heat pretreatment, as cross‐tolerance was induced in SWV but not in BALB/c mice. In SWV embryos, prior exposure to 43°C for 5 min essentially eliminated the negative effects of cadmium on embryonic development and growth. However, in BALB/c embryos, no protection was observed. The variation in development of cross‐tolerance in embryos from the two strains of mice was not correlated with differences in the induction of a 68‐kD heat‐shock protein (hsp68). There was a rapid increase in this protein in both strains after the initial heat exposure but no excess induction in the SWV strain that developed tolerance. The induction of hsp68 is therefore not sufficient to elicit cross‐tolerance, and other mechanisms are likely to be important in the protective response of the embryo. © 1992 Wiley‐Liss, Inc.
Developmental toxicity of dichloroacetate in the rat
Authors: Smith M. K. , Randall J. L. , Read E. J. , Stober J. A.
Published: June 2005

Dichloroacetic acid (DCA) is a principal by‐product of the chlorine disinfection of water containing humic and fulvic acids, and is also a drug of interest in the therapeutic management of metabolic disorders. The developmental effects of DCA were evaluated in the pregnant Long‐Evans rat. In two separate studies, animals were dosed by oral intubation on gestation days 6–15 (plug = 0) with 0, 900, 1,400 1,900 or 2,400 mg/kg/day and 0, 14, 140, or 400 mg/kg/day. The vehicle control was distilled water. Maternal observations included clinical signs, weight change, and gross evaluation of organ weights and uterine contents at necropsy (day 20). Corpora lutea were counted and uteri stained for implantation sites. Live fetuses were examined for external, skeletal, and soft tissue malformations. Seven dams died during treatment (1,400 mg 1/19, 1,900 mg 2/19, 2,400 mg 4/21), and maternal weight gain was reduced at all except the lowest treatment levels. Liver, spleen, and kidney weights increased in a dose‐related manner. The mean percentage of resorbed implants per litter was significantly elevated at ≥900 mg/kg/day. Live fetuses showed dose‐dependent reductions in weight and length at doses above 140 mg/kg. Statistically significant frequencies of soft tissue malformations ranged from 2.6% (140 mg/kg) to 73% (2,400 mg/kg). These were principally in the cardiovascular system and predominantly comprised defects between the ascending aorta and the right ventricle. Skeletal malformations were not observed in significant numbers in any dose group. We conclude that the no observed adverse effect level (NOAEL) for the developmental toxicity of DCA in the rat was 14 mg/kg/day, a dose level that produced obvious treatment‐related maternal effects. © 1992 Wiley‐Liss, Inc.
Cardiopathic effects of dichloroacetate in the fetal long‐evans rat
Authors: Epstein D. L. , Nolen G. A. , Randall J. L. , Christ S. A. , Read E. J. , Stober J. A. , Smith M. K.
Published: June 2005

Dichloroacetic acid (DCA) is a by‐product of the chlorine disinfection of water and may occur in treated water at levels exceeding 100 μg/L. Previous studies revealed teratogenic effects, particularly heart malformations, at high doses (900–2,400 mg/kg given on days 6–15 of pregnancy). In a series of three studies, groups of 7–10 Long‐Evans rats were dosed with 1,900 mg/kg of DCA on days 6–8, 9–11, or 12–15; with 2,400 mg/kg on days 10, 11, 12, or 13; and with 3,500 mg/kg on days 9, 10, 11, 12, or 13, in an attempt to determine the most sensitive period and further characterize the heart defect. In a fourth study, six dams were treated with 1,900 mg/kg of DCA days 6–15 of pregnancy, and 56 fetuses were harvested for light microscopy of the heart. Eight control fetuses from four litters were also examined. No heart malformations were seen in the groups treated with 1,900 mg/kg DCA days 6–8 but were present in the group treated on days 9–11 and 12–15, with the higher incidence occurring on days 12–15. Single doses of 2,400 mg/kg DCA given on days 10, 11, 12, or 13 resulted in a much lower incidence of cardiac malformations, which occurred only on days 10 and 12. The high dose of DCA (3,500 mg/kg) did not increase the incidence of heart defects but showed that dosing on day 9 as well as on days 10 and 12 would produce the defect. The defects seen were characterized as high interventricular septal defects (H‐IVSD). Light microscopy showed that the defect was caudal to the semilunar valves, with the anterior right wall of the aorta communicating with the right ventricle. Another aspect of the defect is at the level of the semilunar valves, with the right cusp or sinus of Valsalva in communication with the right ventricle. The defects are discussed more fully and methods for further study suggested. © 1992 Wiley‐Liss, Inc.
Standardized residuals as a means for detection of growth alteration in the pathologic human fetus
Authors: Sherwood Richard J. , Robinson Haynes B. , May Richard L. , Meindl Richard S.
Published: June 2005

This paper introduces and discusses the use of standardized residuals as a technique for comparing the growth of normal and pathologic human fetuses. Anthropometric measures, radiographic measures, and organ weights were regressed on known gestational age of second‐ and third‐trimester fetuses. Standardized residuals were calculated for a group of potentially growth‐impaired fetuses. Use of residuals aids in identification of patterns of growth alteration in specific pathologies. Most important, studying the response of developing organ systems to a variety of insults may elucidate mechanisms of growth regulation in the fetus. We emphasize the special quality of the multivariate measures of the core sample of fetuses from the Akron Children's Hospital collection. © 1992 Wiley‐Liss, Inc.
Absence of limbs and gross body wall defects: An epidemiological study of related rare malformation conditions
Authors: Mastroiacovo Pierpaolo , Källén Bengt , Knudsen Lisbeth B. , Lancaster Paul A. L. , Castilla Eduardo E. , Mutchinick Osvaldo , Robert Elisabeth
Published: June 2005

The study is based on almost 10 million births and reports on 215 infants with two unusual malformations: amelia and gross body wall defect. Amelia without body wall defect was present in 116 cases, 67 had body wall defects without amelia, and 32 had both. The total rate was 2.2 per 100,000 births. The infants were divided into five mutually exclusive groups. There were 40 infants (0.4 per 100,000) with agenesis of the body stalk, 18 with amelia and other types of gross body wall defects (0.2 per 100,000), 56 with amelia and malformations other than gross body wall defects (0.6 per 100,000), 41 with amelia (with or without other limb reduction defects) but no nonlimb malformations (0.4 per 100,000), and 60 infants with gross body wall defects of a type other than agenesis of body stalk and without amelia (0.6 per 100,000). A weak trend of decreasing prevalence of these malformations was found during the observation period. Infants with agenesis of the body stalk and infants with amelia combined with other types of gross body wall defects occurred at an increased rate in infants of young women. This maternal age effect is also found with gastroschisis, but not with omphalocele, and may indicate etiological or pathogenetic similarities between gastroschisis and the two former groups of defect. In infants with amelia, additional limb reduction defects could be of any type: transverse, longitudinal, or intercalary. Therefore, amelia may be the end result of different types of disturbances of limb morphogenesis. There was an increased rate of twinning. The relationship with amniotic band syndrome is discussed. © 1992 Wiley‐Liss, Inc.
Association of paternal alcohol use with gestational age and birth weight
Authors: Savitz David A. , Zhang Jun , Schwingl Pamela , John Esther M.
Published: June 2005

Paternal alcohol use has been associated with a number of adverse reproductive outcomes in laboratory animals and there is one epidemiologic report of a detrimental effect on infant birth weight. To expand the epidemiologic evidence, data from the Child Health and Development Studies were analyzed. Data collected from the onset of prenatal care in 10,232 women enrolled in the Kaiser Foundation Health Plan and residing in the San Francisco East Bay area between June 1959 and September 1966 were available, including information on the mother's report of paternal alcohol consumption and a number of potential confounders. Pregnancy outcomes included preterm delivery (<37 weeks completed gestation), moderately low birth weight (1,501–2,500 g), very low birth weight (≤1,500 g), small‐for‐gestational‐age (<10th percentile of weight for gestational age), and mean birth weight. Paternal alcohol use, analyzed in intervals from 0 to 2.0 or more drinks per day, showed no association with any of the outcomes of interest. Adjusted prevalence odds ratios ranged from 0.7 to 1.5, with no indication of a monotonic dose‐response gradient. Mean birth weight was also virtually unrelated to paternal alcohol use. Compared with the earlier report, this population had a very modest level of alcohol consumption. Nonetheless, within the range that was studied there appears to be no association between paternal alcohol use and birth outcome. © 1992 Wiley‐Liss, Inc.
Omphalocele and gastroschisis: A collaborative study of five Italian congenital malformation registries
Authors: Calzolari E. , Volpato S. , Bianchi F. , Cianciulli D. , Tenconi R. , Clementi M. , Calabro A. , Lungarotti S. , Mastroiacovo P. P. , Botto L. , Spagnolo A. , Milan M.
Published: June 2005

During 1984–1989, 116 cases of omphalocele and 42 cases of gastroschisis were detected among 736,760 consecutive births in the area covered by five Italian congenital malformation registries. The prevalence rate was 1.6 per 10,000 for omphalocele and 0.6 per 10,000 for gastroschisis. Three additional cases were detected among spontaneous abortions, giving a total of 117 cases of omphalocele and 44 of gastroschisis. No variations in prevalence rates were observed among registries. A cluster of omphalocele was found in 1989 in Firenze. All cases were sporadic except for one infant with two sibs with Beck‐with–Wiedemann syndrome. A predominance of male infants was observed for both defects. This study confirms the very young maternal age for isolated gastroschisis as compared to that for omphalocele and controls. Birth weight and the percentage of small‐for‐date is different among isolated gastroschisis, omphalocele and controls. Associated anomalies occurred in 45 cases of omphalocele and 11 cases of gastroschisis. Our data confirm the association of omphalocele with trisomies 13 and 18. Twelve cases of omphalocele and gastroschisis with associated limb defects were classified as limb body wall complex. The possible differences in etiopathology between omphalocele and gastroschisis, both isolated and associated, are discussed. © 1993 Wiley‐Liss, Inc.
Evaluation of the bioeffects of prenatal ultrasound exposure in the cynomolgus macaque (Macaca fascicularis): III. Developmental and hematologic studies
Authors: Tarantal A. F. , O'Brien W. D. , Hendrickx A. G.
Published: June 2005

The multiple applications of diagnostic ultrasound in obstetrics have resulted in a continued rise in the prenatal population exposed each year. Although human epidemiologic and experimental studies with various animal models have not consistently documented any significant, reproducible findings related to clinically relevant exposures, technologic changes in scanning equipment and gaps in our knowledge regarding the interaction(s) of ultrasound with tissues emphasize the need to pursue safety issues. Studies with nonhuman primates have provided information on the potential for pre and postnatal effects on offspring exposed repeatedly during gestation (ATL MK 600, 7.5 MHz, ISPTA = 27 m W/cm2; ISPPA = 85 W/cm2; Estimated power = 12 m W—scanned for 10 min 5 times weekly gestational day [GD] 20–35; 3 times weekly GD 36–60; once weekly for 20 min GD 60–150). These studies have indicated transient effects on body weight, white blood cell counts (WBCs), and muscle tone postnatally. In an effort to confirm these findings and focus on hematologic changes, a second series of studies was initiated using the same exposure conditions (N = 22; 11 exposed, 11 sham controls). Data derived from both studies were combined and confirmed transient reductions in body weights for infants up through 4 months of age (P ⩽ 0.03); no statistically significant differences in muscle tone were noted. Similar to the original findings, WBCs were transiently reduced on days 3 (P ⩽ 0.02) and 21 (P ⩽ 0.05); prenatal sampling indicated a significant difference between the groups on GD 140 (P ⩽ 0.04). No direct effects were evident in bone marrow aspirates collected on postnatal days 3, 9, and 21 ± 1. Although animals were able to compensate for these observed changes and remained unaffected by their occurrence, additional studies will be required to further our understanding of this phenomenon. © 1993 Wiley‐Liss, Inc.
Developmental toxicity of caffeine in the larvae of Xenopus laevis
Authors: Sakamoto Michiko K. , Mima Shin , Kihara Takahide , Matsuo Takuya , Yasuda Yoshiko , Tanimura Takashi
Published: June 2005

To examine the developmental toxicity of caffeine, Xenopus larvae just after hatching, were continuously exposed to 100–2,000 mg/L caffeine for 48 hours. Caffeine interfered with development of Xenopus larvae at a concentration of 100 mg/L and above in a concentration‐dependent manner. Characteristic external abnormalities, such as shortened body with wavy fins, were observed, the severity of which was clearly concentration dependent. These larvae were frequently accompanied by abnormal body flexure and edema in the fin. Light microscopy revealed that exposure to caffeine induced severe damage in the myotome and neural tube, and at higher concentrations, the epidermal tissue was also affected. Myoblasts showed wide intercellular spaces, and their cytoplasm lost uniform staining. Ultrastructural studies of myoblasts revealed distinct myofibril disorganization and degeneration, and mitochondrial alterations. In the neural tube, cells at the dorsal part of tube showed wide intercellular spaces and some of them were segregated to the peripheral region. Furthermore, vacuole‐like structures of various sizes appeared in the white matter. The outer layer of epithelial cells in the epidermis were vacuolated and swollen. With regard to the pathogenesis of myofibril damage, caffeine appeared to cause a disturbance of intracellular calcium regulation, by releasing calcium ions from the sarcoplasmic reticulum, and the mitochondrial changes observed in myotomal cells were considered to be reflective of this increased intracellular calcium ion levels. It is speculated that caffeine interferes with cell adhesion in the myotome and neural tube by affecting calcium ion regulation. © 1993 Wiley‐Liss, Inc.
Preovulatory administration of clomiphene citrate to mice causes fetal growth retardation and neural tube defects (exencephaly) by an indirect maternal effect
Authors: Dziadek Marie
Published: June 2005

Clomiphene citrate was administered to female mice at different doses and different times prior to ovulation, in the preimplantation period after ovulation, and after implantation. Pregnancy outcome was determined on day 15 of gestation, when the number of implantations and resorptions were calculated relative to the number of ovulations, and fetuses were assessed for size and stage of development and morphological abnormalities. Preovulatory administration of clomiphene citrate caused decreased implantation rates and growth retardation of surviving fetuses, the degree of the effect being dependent on the dose and the time of drug injection relative to ovulation. The implantation rate was lowest, and the degree of fetal growth retardation highest, when clomiphene citrate was administered immediately before ovulation. An increased incidence of exencephaly was found in the fetuses of females injected with clomiphene citrate prior to ovulation. Transfer of blastocysts from treated mice to untreated fosters showed the effect of clomiphene citrate on implantation and fetal growth to be predominantly mediated through the female reproductive tract, rather than a direct effect on the embryo itself. Administration of clomiphene citrate in the preimplantational period resulted in complete inhibition of implantation, while the only effect when administration was after implantation was a slight reduction in fetal weight. These results indicate that preovulatory clomiphene citrate impairs uterine function, which has an indirect effect on the growth and development of the postimplantation embryo. © 1993 Wiley‐Liss, Inc.
Dose‐response models for developmental malformations
Authors: Gaylor David W. , Chen James J.
Published: June 2005

An empirical dose‐response model can generally be found for bioassay data, which provides a mathematical relationship between the incidence of a developmental malformation and dose of a toxicant in the experimental dose range. If biological principles and data can be used in the formulation of the dose‐response model, the estimation of the incidence of malformations outside of the experimental dose range may be improved. In this paper, exponential growth of morphological structures in rodents during gestation is assumed. Further, it is assumed that some structural malformations are the result of reduced or delayed growth and the incidence of structurally normal fetuses is proportional to fetal weight raised to a power. When the exponential growth rate constant is reduced by dose raised to a power, a Weibull dose‐response function is obtained. When the exponential growth rate constant is modeled by a polynomial function of dose, a polynomial‐exponential dose‐response model is obtained. The Weibull and the polynomial‐exponential model, restricted to degrees from one up to the number of dosed groups, were fit to a database of bioassay data assembled from Teratology Vol. 1 (1968) to Vol. 42 (1990). In general the two models gave similar results and often gave exactly the same fit. The linear term appeared in the polynomial‐exponential model in about one‐fourth of the cases and was not related to the background incidence. Published 1993 by Wiley‐Liss, Inc.
Ataxia and a cerebellar defect in the exencephaly‐prone SELH/Bc mouse stock
Authors: Juriloff D. M. , Harris M. J. , Harrod M. L. , Gunn T. M. , Miller J. E.
Published: June 2005

SELH/Bc inbred mice have an abnormal mechanism of anterior neural tube closure and 10–20% of embryos have a lethal neural tube closure defect, exencephaly. Our previous studies have focused on this multifactorial threshold trait. However, SELH mice are also characterized by another trait that also shows non‐Mendelian transmission ratios, an ataxia recognized in juvenile and adult mice. Here we report our first genetic and morphological studies of the ataxia trait. Recent pedigree records for the SELH colony showed that 7% of the 467 weaned progeny from normal breeding pairs were ataxic; 17 of the 20 pairs produced ataxic progeny. This result was statistically consistent with the hypothesis that all SELH mice have the ataxic genotype, which is expressed in only 7% of them. Genetic studies of an outcross to a normal strain and the subsequent F2 and testcross of the F2 were also done. The results were consistent with a one or two gene locus cause of liability to ataxia in SELH mice. The genetic correlation between exencephaly production and ataxia production for a sample of nine F2 males was 0.35, as expected if both traits are caused by the same genes, but was not statistically significant. In another approach, we examined the morphology of brains from normal and ataxic adult SELH mice. All 20 brains from non‐ataxic SELH mice were morphologically normal. In all 18 brains from ataxic SELH mice the cerebellum was abnormal, lacking the vermis, and characterized by a midline fissure. This phenotype in mice has previously been known in Mendelian mutants at the Wnt‐1 locus. Our observations in SELH mice suggest that these cerebellar defects can also show multifactorial threshold patterns of occurrence. Because the site of origin of the cerebellum is the site of maximal delay in neural tube closure in SELH mice, the exencephaly and ataxia may share a common genetic etiology. © 1993 Wiley‐Liss, Inc.
Effects of Retinoic acid on cartilage differentiation in a chondrogenic cell line
Authors: Lau W. F. , Tertinegg I. , Heersche J. N. M.
Published: June 2005

Previously we have isolated the monopotential chondrogenic cell line RCJ 3.1 C5.18 from the multipotential mesenchymal cell line RCJ 3.1 [Grigoriadis et al.: Endocrinology, 125:2103–2110, 1989]. When cultured for approximately 20 days under appropriate conditions, these cells form cartilage nodules. In the present investigation, we have used this cell line to study the effects of all‐trans retinoic acid (RA) on chondroblast differentiation, cartilage formation, and cartilage degradation. Continuous exposure of cultures to RA (0.01–100 nM) inhibited chondroblast differentiation and glycosaminoglycan (GAG) accumulation in a dose‐dependent manner, without comparable effects on cell growth. Pulse treatment with RA for various 4 day periods during a 17–24 day culture period established that RA inhibited differentiation of chondroprogenitors at all periods tested. These effects were reversible, except for part of the effect on early chondroprogenitors. Treatment with RA on days 13–17 in 17 day cultures not only resulted in cessation of cartilage formation, but also in disappearance of pre‐existing cartilage nodules. We demonstrated that this was associated with RA‐induced downregulation of GAG synthesis and increased degradation of cartilage proteoglycans. Hence, the inhibitory effects of RA on cartilage formation consist of inhibition of chondroblast differentiation, inhibition of GAG synthesis by differentiated chondroblasts, and stimulation of cartilage proteoglycan degradation by differentiated chondroblasts and/or chondrocytes. These results indicate that the clonal monopotential chondrogenic cell line RCJ 3.1 C5.18 forms a good model system to study the effects of retinoids on cartilage differentiation, formation, and degradation. © 1993 Wiley‐Liss, Inc.
Serotonin and cardiac morphogenesis in the mouse embryo
Authors: Yavarone M. S. , Shuey D. L. , Tamir H. , Sadler T. W. , Lauder J. M.
Published: June 2005

The possible involvement of the neurotransmitter serotonin (5‐HT) and its binding protein (SBP) in cardiac morphogenesis was studied using mouse whole embryo culture (together with immunocytochemistry or 3H‐thymidine autoradiography) and a cell migration assay. Embryos were cultured before and during the period of endocardial cushion formation, embryonic (E) days 9–12, in the presence of 5‐HT, the monoamine oxidase (MAO) inhibitor nialamide, or an uptake inhibitor (fluoxetine or sertraline). For the migration assay, cells from the outflow tracts of E12 embryos were dissociated and placed in a chemotaxis chamber together with different concentrations of 5‐HT. E9 embryos cultured in the presence of 10 μM 5‐HT and nialamide exhibited intense 5‐HT immunoreactivity (5‐HT IR) throughout the myocardium. This staining was greatly diminished by fluoxetine, sertraline, or the absence of nialamide. As morphogenesis proceeded, myocardial staining in embryos exposed to 5‐HT became restricted to developing endocardial cushion forming regions and was more completely blocked by uptake inhibitors. No evidence for 5‐HT synthesis by myocardium was found at any age studied using the precursor L‐tryptophan. SBP was present in endocardial cushions in cultured and uncultured embryos. 3H‐thymidine autoradiography demonstrated that both fluoxetine and sertraline inhibited proliferation of cardiac mesenchyme, endocardium, and myocardium. These effects were most pronounced when exposure began at E9 (prior to cushion formation). Dose‐dependent effects of 5‐HT on migration of outflow tract cells were also observed. Taken together, these results suggest that 5‐HT may play a role in cardiac morphogenesis during endocardial cushion formation. © 1993 Wiley‐Liss, Inc.
Embryonic development of the mammalian caudal Neural Tube
Authors: Nievelstein R. A. J. , Hartwig N. G. , Vermeij‐Keers C. , Valk J.
Published: June 2005

In the literature, some controversy still exists about the embryonic developmental processes involved in the formation of the caudal neural tube. Therefore, a three‐dimensional and histological study concerning the normal development of the caudal neural tube was performed on both mouse and human embryos. Three developmental processes can be distinguished in caudal neural tube development: caudal neuropore closure, secondary neurulation, and degeneration and differentiation of the secondary neural tube. Caudal neuropore closure occurs at the level of somite 32–34 in both species. Therefore, primary neurulation leads to the formation of all spinal cord segments and ganglia. Secondary neurulation involves cell deposition from a cluster of neurectodermal cells at the caudal end of the closed neural tube, directly around a lumen, the lumen always in contact with the lumen of the primary neural tube. This process leads only to the formation of the primordia of the filum terminale and ventriculus terminalis and, possibly, part of the conus medullaris. Secondary neurulation is followed by a period characterized by degeneration and differentiation of the secondary neural tube. Its lumen and neural tissue will disappear, whereas part of the secondary neurectodermal cells differentiate to a fibrous layer comparable and continuous with the marginal layer of the primary neural tube. This fibrous layer represents the future filum terminale. The embryological processes indicated above can be helpful in the interpretation of congenital anomalies affecting the caudal spinal cord and spine. © 1993 Wiley‐Liss, Inc.