ABSTRACT Preconceptual exposure of male mice to a mutagen can increase the incidence of malformations in the offspring. In mutagenized spermatogonial stem cells, genetic changes responsible for FI malformations were produced in a manner similar to that involved in the production of specific locus mutations. Irrespective of the kind of mutagens applied, the germ cell stage treated and the strain of mice used, resulting FI malformations showed type distributions that were indistinguishable from the spectrum of those occumng spontaneously. When a teratogen was applied at the organogenic stage, embryos whose sires were preconceptually exposed to a mutagen showed higher susceptibility to induced malformations than those derived from untreated males. Experimental results pertaining to these contentions are summarized and the possible implications are discussed.
ABSTRACT The heat shock response is associated with a characteristic inhibition of normal transcription and translation with enhanced synthesis of a multigene family of Heat Shock Proteins (HSP), a common cellular mechanism to all living organisms including the most primitive species. Elevated body temperature or hyperthermia can result from many agents including fever, hot weather and heavy exercise. In more modern surroundings induced hyperthermia can be achieved by hot baths, saunas, specific drugs, electromagnetic radiation and ultrasound. Hyperthermia during pregnancy has been shown to cause a wide spectrum of effects in all species studied, including humans. The outcome depends on the duration and severity of the heat shock experienced by both the mother and the embryo and the stage of embryonic or fetal development. In severe exposures in utero embryonic death and resorption or abortion are probably the most common outcomes. In less severe exposures major or minor developmental defects can result, with the CNS a major target for its effects. Heat shock can interrupt cell differentiation at critical stages of organogenesis which may lead to apoptosis. All living organisms appear to have developed protective mechanisms collectively known as the heat shock response. Heat shock triggers the abrupt suspension in the normal protein synthesis and the concurrent induction of heat shock genes (hsp) and the synthesis of a set of multi-gene protein families known as the heat shock proteins (HSP). Each hsp has at least two copies, one which appears to function in normal embryonic development (cognate) and another that is stress-induced (inducible) and can result in acquired thermotolerance, offering some protection against further damage. The inducible HSP are usually activated at critical inductive stages of organ development, suggesting they play a major role in cell differentiation. The HSPs appear to protect cells through their chaperone functions by binding to adhesive sites on newly synthesised or heat damaged and partially unfolded structural and functional proteins. This prevents the formation of functionless aggregates. Heat shock transcription factors (HSF) bind to a heat shock element (HSE) and initiate hsp activation. Although this research has defined some pathways indicating how and why heat can cause some defects, a means of preventing them has not yet emerged.
ABSTRACT Midkine (MK) is a 13 kDa heparin-binding growth factor found as a product of a retinoic acid-responsive gene. MK is rich in basic amino acids and cysteine and its sequence is not homologous with any other proteins so far reported, so it is a new family of heparin-binding growth factor. It has been found that MK exerts variety of biological activities such as neurite-promoting, neuronal cell survival and differentiation-inducing activities. MK is strictly expressed during the mouse embryogenesis; among the adult organs, it is detected only in the kidney. MK is also strongly expressed in a number of human carcinomas and specifically localized in senile plaques in the brain of patients with Arzheimer disease. More recently, it has been reported that MK is an important molecule regulating inflammation response and tissue repair. These results demonstrated that the relevance of MK not only in normal development, but also in processes leading to tissue repair or diseases. Increased MK gene expression is a common phenomenon observed in many human carcinomas, therefore MK is of significant interest in cancer biology. As a new growtwdifferentiation factor, many issues including the detailed sites and the precise time of MK expression, the exact cellular source which synthesizes and secretes MK, the signal transducing receptors for MK, the mechanisms underlying those developmentally regulated expression and its potential clinical significance still remain unknown. To elucidate the molecular mechanisms of MK action will lead not only to a deeper understanding of developmental processes, but also to the ultimate obtaining a key to diagnose and treat human carcinomas.
ABSTRACT The purpose of the present study was to assess the type, frequency and stage specificity of axial skeletal anomalies induced by cyclophosphamide (CP). Female Crj:Wistar rats were mated with male rats (vaginal sperm = gestation day 0, GDO). They were then injected intravenously with 5 mgkg of CP in a saline solution on GD7, 8, 9, 10, 11, 12, 13, or 14, or with saline on GD8 for controls. Dams were sacrificed on GD20. Fetuses were stained with alcian blue and alizarin red S. Eighteen types of axial skeletal anomaly were detected, e.g., shifted ventral lamina, cervical rib, cleft arch of the atlas, axis fused to atlas, sternebral misalignment, bipartite sternum, fused ribs, change in pre-sacral vertebral number, supernumerary rib, misdirected transverse process, anteriorly-shifted spinous process, short spinous process, fused vertebral bodies, cartilaginous short rib at Th.7, short or absent rib at Th.12 or 13, dumbbell-shaped vertebral body, wavy rib, and rib cartilage not attached to the sternal cartilage. The present experimental study indicates that: 1) observations of cartilaginous skeletons can provide more information than observations of ossified skeletons; 2) the pattern of CP-induced anomalies along the anterior-posterior axis may depend on the sequence of development progression among structures, spinous process, vertebral arch, vertebral body, rib/transverse process; and 3) in more cranial vertebrae, anteriorly-shifted anomalies, such as anteriorly-shifted ventral lamina and anteriorly-shifted spinous processes, rather than posteriorly-shifted anomalies, may be the primary indicators for detecting developmental toxicity, since CP injection increased the frequencies of these anomalies.
ABSTRACT The mesenchyme in the truncal ridge and aortico-pulmonary (A-P) septum in the developing heart expresses tenascin (TN), a component of extracellular matrices. We observed immunohistochemically the localization of TN with reference to fibronectin (FN) distribution in rat embryonic hearts at gestation days 12, 13 and 14 and compared the results with those in his-diamine-induced cardiovascular anomalies. In control rat embryonic hearts, TN was distributed in the dorsal mesocardium and the distal part of the truncal ridge at gestation day 12, and in part of the conal and truncal ridges, A-P septum and proximal wall of aortic arch arteries at gestation days 13 and 14. The conotruncal regions with TN expression may correspond to the areas where cardiac neural crest cells migrate in the heart. In bis-diamine-treated rat hearts showing conotruncal anomalies, TN was localized in incompletely fused and hypoplastic conotruncal ridges, but the intensity and area of staining were decreased suggesting a decreased neural crest cell migration. FN was diffusely distributed in both the normal and anomalous embryonic hearts, including atrioventricular cushion tissue in addition to the region expressing TN. TN was densely distributed in the fusing area of the conal and truncal ridges in comparison to FN, suggesting that TN may be mainly expressed during the time of fusion of conal and truncal ridges to form the A-P septum in the embryonic heart. In conclusion, his-diamine may cause the poor development of neural crest derived tissue, subsequently bringing about hypoplasia of the A-P septum and truncal and conal ridges.
ABSTRACT Mice with short and knotty tails arose as a spontaneous mutant in an ICR strain, and they have been named knotty-tail mouse (gene symbol; knt). They also have a minor anomaly of the cervical vertebrae, especially in the axis. In this study, the cervical vertebrae of knotty-tail (knt/knt) mice were investigated by morphological and morphometric examinations during the prenatal and postnatal period. From the observation of double-stained preparations of kntknt mice, morphological changes of cervical vertebrae were confined to the vertebral arch of the axis, which was asymmetrical and hypoplastic. From the morphometric analyses, outside of the axis, minor anomalies (i.e., broadened cervical vertebrae in the transverse direction, shortened and broadened ventral tuberculum of the atlas, thickened ventral lamina of 6th cervical vertebra) were maintained in the cervical vertebrae of knt/knt mice. Morphological deformity, reflecting an adult osseous anomaly, had been already formed in the cartilaginous axis prenatally. In the papain- digested preparations of kntknt mice, a bony invagination into the canal was detected in the axis, and the morphometric analyses on axis revealed that the growth of spinous process was apparently disturbed in comparison with that of ICR mice.
ABSTRACT We observed an unusual case of a woman who had received a gonadotropin- releasing hormone (GnRH) agonist (GnRH-a), leuprolide acetate, during the first trimester and early in the second trimester of pregnancy. Nevertheless, the pregnancy was uncomplicated and a healthy male infant (2,670 g) was born after spontaneous labor at the 38th week of gestation. The infant suffered no malformations or respiratory complication and he achieved normal growth. Although GnRH-a is known to induce pregnancy loss, the drug does not appear to be teratogenic. Accordingly, a pregnancy that occurs during GnRH-a therapy and progresses normally should not be terminated for fear of its teratogenic effects.
ABSTRACT The oral surface of the mouse palate has eight or nine pairs of transverse ridges, or rugae. We have reported that various teratogens induce abnormal patterns of palatal rugae in mice. In the present note, we show examples of palatal ruga anomalies induced by several teratogens in mouse fetuses near term. Defined variant patterns are supernumerary, division, lateral or medial bifurcation, short, maldirection, cross, modified cross, lateral or medial fusion, lateral or medial bifurcation, median fusion, median division, and numerical reduction. In some cases naming of observed variants may be difficult, but differential diagnosis between variations in the ”normal” range and “anomalous” variants seems rather easy.
Abstract: This note presents current state and background of the homepage of Congenital Anomalies, the online version of the official Journal of the Japanese Teratology Society, and also introduce some of the teratology-related web sites, in the hope that the usage of these and the other Internet tools will contribute greatly toward the advancement of teratology studies. Due to the cross-disciplinary concepts and principles in the field of teratology, no single web site can provide exhaustive coverage of teratology. Nevertheless, there is indeed a great deal of useful information for a teratologist available on the Web. Proper usage of the Internet by exchanging and sharing valuable information can yield the mutual understanding and better collaboration, which in turn is indispensable for the overall measures of congenital anomalies.