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Preview: Teratology


Wiley Online Library : Teratology

Published: 2002-12-01T00:00:00-05:00


Response to Gideon Koren's letter


Annual commentary on human teratogens


Conjoined twins in a monozygotic triplet pregnancy: Prenatal diagnosis and X-inactivation


BackgroundThe etiology of monozygotic twinning is not known. Some investigators have implicated abnormal X-inactivation, which could also be related to the increased female:male ratio in higher order multiple gestations in general, and in monozygotic and conjoined twins (CTS) in particular. CTS are rare, and even more unusual when part of a triplet pregnancy.MethodsDNA polymorphism analysis using 13 markers in the buccal cells of the triplets and the lymphocytes of the parents were used to evaluate zygosity. We investigated the X-inactivation pattern of the triplets by analyzing methylation at the androgen receptor gene.ResultsWe found a female triplet gestation consisting of CTS and a normal singleton. The thoracopagus CTS were joined from the clavicles to the umbilicus. Congenital heart disease was suspected antenatally, but the precise delineation of the heart defects required extensive postnatal evaluation. There was a single placental mass with a thin dividing membrane. Cesarean section was carried out at 32 weeks after the onset of labor. Histologically, the placenta was diamniotic monochorionic. The normal singleton did well after delivery; the CTS died at 35 days from cardiopulmonary collapse. The babies were monozygotic (>99.99% probability). Each baby in this triplet set exhibited a random and symmetric X-inactivation pattern. The degree of X-inactivation skewing fell in the range of 50–65%.ConclusionGenetic or environmental factors other than abnormal X-inactivation must be involved in causing monozygous multiple gestation or CTS. Despite prenatal diagnosis, shared myocardium or cardiac anomalies in CTS often determine the prognosis. Teratology 66:278–281, 2002. © 2002 Wiley-Liss, Inc.

Diprosopus: A unique case and review of the literature


BackgroundWe present a case of partial facial duplication in a male infant.MethodsThe clinical, radiological, and laboratory findings for this patient are described, followed by a review of the literature.ResultsCraniofacial duplication is a rare form of conjoined twinning and presents in a wide spectrum, from dicephalus to diprosopus to partial facial duplication. Many of these cases can be diagnosed prenatally. Prenatal assessment of our patient revealed only agenesis of the corpus callosum.ConclusionsThe pathogenesis is believed to involve duplication of the notochord. Where there are more severe associated anomalies, the prognosis is poor. Partial facial duplication, as in our case, is associated with fewer anomalies, and the prognosis is better. Symmetry and an excess of tissue, rather than deficiency, favor a positive result. Teratology 66:282–287, 2002. © 2002 Wiley-Liss, Inc.

Role of caspases in murine limb bud cell death induced by 4-hydroperoxycyclophosphamide, an activated analog of cyclophosphamide


BackgroundCaspases play a pivotal role in the regulation and execution of apoptosis, an essential process during limb development. Caspase 8 activation is usually downstream of the Fas/FasL death receptors, whereas caspase 9 mediates the mitochondrial signaling pathway of apoptosis. Caspase 3 is an effector caspase. Previous studies have shown that the exposure of embryonic murine limbs in vitro to 4-hydroperoxycyclophosphamide (4-OOHCPA), an activated analog of the anticancer alkylating agent, cyclophosphamide, induced limb malformations and apoptosis. The goal of this study was to determine the role of caspases in mediating apoptosis in this model system.MethodsLimb buds from gestational day 12 CD-1 mice were excised and cultured in roller bottles in a chemically defined medium for up to 6 days in the absence or presence of 4-OOHCPA. Apoptosis was indicated by internucleosomal DNA fragmentation, as detected by TUNEL staining. The profile of caspase activation was characterized by Western blot analysis and immunohistochemistry of control and treated limbs. To determine the consequences to limb morphology of inhibiting caspase activation, DEVD-CHO, a caspase-3 inhibitor, was added to the cultures.ResultsLimbs cultured in the presence of 4-OOHCPA were growth retarded and malformed; apoptosis was increased in the apical ectodermal ridge and interdigital areas. Western blot analysis showed that 4-OOHCPA exposure did not activate procaspases 8 or 9 in limbs. In contrast, procaspase-3 cleavage was increased in a concentration and time-dependent manner after exposure of limbs to 4-OOHCPA. Immunoreactive activated caspase-3 was localized in the interdigital areas and the apical ectodermal ridge region in control limbs; staining in these areas and in the interdigital areas was increased dramatically in limbs exposed to 4-OOHCPA. Inhibition of caspase 3 activation with DEVD-CHO partially protected limbs from insult with 4-OOHCPA.ConclusionCaspase-dependent and caspase-independent pathways of cell death are both important is mediating the abnormal limb development triggered by insult with 4-OOHCPA. Teratology 66:288–299, 2002. © 2002 Wiley-Liss, Inc.

Effect of sera from women with systemic lupus erythematosus or antiphospholipid syndrome and recurrent abortions on human placental explants in culture


BackgroundSystemic lupus erythematosus (SLE) with or without evidence of antiphospholipid antibodies (aPA) and antiphospholipid syndrome (APS) is associated with a high rate of spontaneous abortions. The placenta is thought to be the site of pathological damage in many of these abortions. To test this hypothesis, we studied the effects of sera obtained from women with SLE with or without treatment on human placental explants in culture.MethodsWe cultured 5.5- to 7.5-week-old human placental explants in a culture medium containing F-12 DMEM and 10% FCS or in 90% human serum obtained from nonpregnant women with SLE prior to or after treatment. Culture was carried out for 96 hr. At the end of the culture period, we studied the secretion of the placental hormones estrogen (E2), progesterone (PGN), and human chorionic gonadotropin (hCG). In addition, we studied the proliferation rate (using PCNA staining) and the rate of apoptosis (using ApoTag) of the trophoblastic cells.ResultsPlacentae grew better in normal human serum than in a chemically defined medium of F-12 DMEM and 10% FCS. Enhanced growth and higher secretion rates for hCG and estradiol (E2) were manifested in placentae cultured in control sera with no change in PGN secretion. Secretion rates of hCG and PGN (but not of E2 in the treated group) by placental explants were similar to that of controls. However, the serum levels prior to culture were not measured. Further, explants in serum from untreated women with SLE produced a significant decrease in the proliferation rate of the trophoblastic cells and an increase of apoptosis. Treatment significantly reduced the apoptotic rate and increased cell proliferation, but the cell proliferation rate was still lower than that noted in controls.ConclusionsWe conclude that sera from women with SLE may directly damage the developing placenta reducing proliferation and enhancing apoptosis. Successful treatment of the women reduces that damage. Teratology 66:300–308, 2002. © 2002 Wiley-Liss, Inc.

Dose and litter allocations in the design of teratological studies for detecting hormesis


BackgroundHormesis is being recognized in the field of toxicology due to the stimulating effects of some toxic compounds at low exposure levels. Therefore, it is desirable that experimental designs for toxicological studies be flexible enough to aid in the detection of hormetic effects. Current designs may still not have enough power to do this.MethodsA simulation study was conducted to determine teratological study designs that would yield more power over standard designs in detecting hormesis. Developmental toxicity endpoints of interest are the number of dead/resorbed or malformed fetuses in a litter. The simulation designs mimic teratological experiments in terms of sample size and number of dose levels. Modified designs with even dose spacing at low levels and reallocated litters are investigated to determine the power of hormetic detection.ResultsDesigns with reallocated litters (with more litters at low exposure levels than at high levels) and even dose spacing have more power than those with equal litters per group and uneven dose spacing.ConclusionsThrough appropriate modifications of current experimental designs, such as reallocation of litters and even dose spacing, we can better detect hormetic effects. Teratology 66:309–314, 2002. © 2002 Wiley-Liss, Inc.

A new rapid radiological procedure for routine teratological use in bone ossification assessment: A supplement for staining methods


BackgroundPresently, bone ossification is assessed by the study of single-stained fetal bones (alizarin red-S) or double-stained bones and cartilaginous structures (alcian blue followed by alizarin red-S). Both methods, especially double-staining, are labor-intensive, time-consuming, and provide qualitative information regarding skeleton ossification. Quantitative evaluation of ossification is more difficult and is usually based on determination of calcium and other minerals in the bone by means of atomic absorption spectrometry. Here we introduce a simple new method that allows quantitative determination of skeleton ossification before routine staining examination.MethodsFetuses delivered by laparotomy on the 16th and 21st day of gestation as well as 1-day-old rat pups were examined. The fetuses and pups were prenatally subcutaneously exposed to sodium valproate or to physiological saline. Lateral, prone, and supine digital radiograms of each fetus were taken using the Digora-Soredex digital radiography system and the Planmeca Intra intraoral X-ray machine. According to the best visualization, the data concerning vertebra were analyzed. All the fetuses were then routinely double-stained using alcian blue and alizarin red-S.ResultsMalformations of axial skeleton (rib, sternum, and thoracic and sacral vertebra) were found in valproate-treated groups. Unlike cartilage malformations, the bone changes were detected in similar frequency in radiological and staining methods. Differences in densities according to the degree of ossification in the vertebral arches and bodies at different levels of the vertebral column, between drug-treated and negative control groups were noted.ConclusionsThe preliminary results suggest that digital radiography examination is a useful method in determining delaying of skeleton ossification not detectable by other methods. It balances qualitative and quantitative aspects of the presently used methods and is also simple, objective, fast, and relatively inexpensive. Teratology 66:315–325, 2002. © 2002 Wiley-Liss, Inc.

Timing of prenatal care initiation and risk of congenital malformations


BackgroundAlthough previous studies provide some evidence that timing of prenatal care initiation is associated with risks of congenital malformation, the issue has not previously been examined in depth. This study uses data from a large population-based registry to explore the association of timing of prenatal care initiation with risks of selected congenital malformation phenotypes.MethodsData on cases were grouped according to four-digit malformation codes of the International Classification of Diseases, Ninth Revision (ICD-9). A randomly selected group of 10,000 nonmalformed deliveries served as the comparison group. Information on month of initiation of prenatal care (categorized as during months 1–3 of gestation, months 4–7, or after month 7) and other maternal characteristics were derived from vital statistics data.ResultsAmong the 176 four-digit ICD groupings, 67 had an adjusted odds ratio for at least one of the two prenatal care categories that was either ≤ 0.67 or ≥ 1.50. Later prenatal care initiation was associated with risk ≥ 1.50 for most groups. Later care was associated with risk ≤ 0.67 for only two groups, and the effects were imprecise. Statistical interaction between parity and prenatal care was indicated for 13 groups (P < 0.10). Risks among women with no previous pregnancy tended to increase with later prenatal care initiation; risks among parous women tended to be somewhat weaker. In general, associations applied to a wide range of malformation groups.ConclusionsThis is the first large-scale study of the association of timing of prenatal care initiation and congenital malformation risks. Further defining the phenomena that surround prenatal care as a marker may help clarify the etiologies of a variety of malformations. Teratology 66:326–330, 2002. © 2002 Wiley-Liss, Inc.

Quantification and localization of expression of the retinoic acid receptor-β and -γ mRNA isoforms during neurulation in mouse embryos with or without spina bifida


BackgroundPrevious studies observed that retinoic acid receptor-gamma (RARγ) is expressed in the open caudal neuroepithelium but that RARβ is expressed in the closed neural tube. Furthermore, retinoic acid (RA) induces RARβ expression, a molecular event associated with neural tube closure, but treatment with RA at the appropriate gestation time causes failure of neural tube closure. Since there are four isoforms of RARβ, perhaps the isoforms expressed in the closed neural tube and induced by RA are different. To investigate the hypothesis that the switch from RARγ to RARβ is mechanistically linked to neural tube closure, this study determined the concentrations and distributions of RARβ and RARγ isoforms in mouse embryos with RA-induced neural tube defects and in splotch (Sp) mutant embryos with spina bifida.MethodsAbsolute concentrations of RARβ and RARγ isoforms were determined throughout primary neurulation (gestational day 8.5–10.0) in treated or untreated C57BL/6J mouse whole embryos by ribonuclease protection analysis. Treatment consisted of an oral dose of 100 mg/kg of all-trans-RA on gestational day 8.5. Spatial distributions of RARβ and RARγ were examined in RA-treated and Sp mutant embryos by in situ hybridization.ResultsRARβ2, γ1, and γ2 were expressed in untreated embryos and were induced 4.5-, 1.6-, and 4.0-fold, respectively, 4 hr after treatment with RA. In embryos with RA-induced spina bifida, RARβ2 was expressed in the closed neural tube while RARγ1 and RARγ2 were expressed in the open caudal neuroepithelium. In splotch mice with spina bifida, the boundary between RARβ and RARγ did not correspond to the site of neural tube closure.ConclusionsIn RA-treated embryos, the relationship between RARβ expression in the closed and RARγ in the open caudal neuroepithelium was not altered. However, in splotch embryos with spina bifida, the juncture between RARβ and RARγ expression remained in the same anatomical position in the neuroepithelium irrespective of the neural tube closure status and suggests that the switch from RARγ to RARβ expression in the closing caudal neuroepithelium may not be causally linked to neural tube closure in the splotch mutant. Teratology 66:331–343, 2002. © 2002 Wiley-Liss, Inc.

Aqiba Bokhari, Susan Connolly, Brent A. Coull, Elizabeth A. Harvey, Lewis B. Holmes. Effects on toes from prenatal exposure to anticonvulsants. Teratology 122–126


The original article to which this Erratum refers was published in Teratology (2002) 66(3) 122–126.