tretinoin and Fetal-Death

Acute promyelocytic leukemia (APL) is an uncommon form of acute myeloid leukemia usually associated with disseminated intravascular coagulation (DIC). Pregnancy in patients with APL requires special consideration to maximize the probability of survival of both mother and fetus.. A patient with APL diagnosed during pregnancy who developed DIC is described. Obstetric and oncologic management of this difficult patient is discussed, and a pertinent literature review of pregnancy in APL is presented.. Of 23 pregnancies in patients with APL reported in the literature (including the present patient), 19 yielded live births, including 8 of 12 who received chemotherapy during late pregnancy and all 3 patients who received all-trans-retinoic acid (ATRA) during late pregnancy. Chemotherapy or ATRA induced complete remission in 72% of treated patients.. Proper management of pregnant patients with APL usually results in a live birth and complete remission of the mother's leukemia, despite the potentially devastating consequences of DIC, which is present at diagnosis in most patients.

Topics: Adult; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Disseminated Intravascular Coagulation; Female; Fetal Death; Humans; Leukemia, Promyelocytic, Acute; Pregnancy; Pregnancy Complications, Neoplastic; Pregnancy Outcome; Pregnancy Trimester, Second; Prenatal Care; Remission Induction; Tretinoin

Acute promyelocytic leukemia (APL) manifesting during pregnancy is a very rare but highly challenging gestational complication in part due to its associated profound coagulopathy. We present the case of a 23-year-old Gravida 3 Para 2002 woman admitted to our hospital at 26 weeks of gestation for severe pre-eclampsia with documentation of intrauterine fetal demise (IUFD), thrombocytopenia, and placental abruption. A peripheral blood smear revealed promyelocytes with azure granules, highly concerning for APL. Additional peripheral blood studies confirmed APL. Placental examination also revealed circulating blasts in decidual vessels and scattered blast entrapment in diffuse perivillous fibrinoid deposits, but none in the chorionic villi. Treatment for APL was initiated immediately and she is in complete molecular remission. Our case underscores the importance of close collaboration among obstetric, hematology, and pathology teams in the care of patients with pre-eclampsia, thrombocytopenia, and postpartum coagulopathy. We also describe five additional cases of gestations complicated by hematologic malignancies identified upon a 10-year institutional retrospective review.

Topics: Abruptio Placentae; Antineoplastic Agents; Disseminated Intravascular Coagulation; Female; Fetal Death; Humans; Leukemia, Promyelocytic, Acute; Postpartum Period; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Neoplastic; Retrospective Studies; Treatment Outcome; Tretinoin; Young Adult

Excess exogenous retinoic acid (RA) has been well documented to have teratogenic effects in the limb and craniofacial skeleton. Malformations that have been observed in this context include craniosynostosis, a common developmental defect of the skull that occurs in 1 in 2500 individuals and results from premature fusion of the cranial sutures. Despite these observations, a physiological role for RA during suture formation has not been demonstrated. Here, we present evidence that genetically based alterations in RA signaling interfere with human development. We have identified human null and hypomorphic mutations in the gene encoding the RA-degrading enzyme CYP26B1 that lead to skeletal and craniofacial anomalies, including fusions of long bones, calvarial bone hypoplasia, and craniosynostosis. Analyses of murine embryos exposed to a chemical inhibitor of Cyp26 enzymes and zebrafish lines with mutations in cyp26b1 suggest that the endochondral bone fusions are due to unrestricted chondrogenesis at the presumptive sites of joint formation within cartilaginous templates, whereas craniosynostosis is induced by a defect in osteoblastic differentiation. Ultrastructural analysis, in situ expression studies, and in vitro quantitative RT-PCR experiments of cellular markers of osseous differentiation indicate that the most likely cause for these phenomena is aberrant osteoblast-osteocyte transitioning. This work reveals a physiological role for RA in partitioning skeletal elements and in the maintenance of cranial suture patency.

Topics: Animals; Cell Differentiation; Cranial Sutures; Craniosynostoses; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Disease Models, Animal; Female; Fetal Death; Gene Expression Regulation, Developmental; Growth and Development; Humans; Mice; Osteoblasts; Osteogenesis; Polymorphism, Genetic; Pregnancy; Retinoic Acid 4-Hydroxylase; Sequence Homology, Amino Acid; Tretinoin; Zebrafish; Zebrafish Proteins

The cardiac venous pole is a common focus of congenital malformations and atrial arrhythmias, yet little is known about the cellular and molecular mechanisms that regulate its development. The systemic venous return myocardium (sinus node and sinus horns) forms only late in cardiogenesis from a pool of pericardial mesenchymal precursor cells.. To analyze the cellular and molecular mechanisms directing the formation of the fetal sinus horns.. We analyzed embryos deficient for the Wt1 (Wilms tumor 1) gene and observed a failure to form myocardialized sinus horns. Instead, the cardinal veins become embedded laterally in the pleuropericardial membranes that remain tethered to the lateral body wall by the persisting subcoelomic mesenchyme, a finding that correlates with decreased apoptosis in this region. We show by expression analysis and lineage tracing studies that Wt1 is expressed in the subcoelomic mesenchyme surrounding the cardinal veins, but that this Wt1-positive mesenchyme does not contribute cells to the sinus horn myocardium. Expression of the Raldh2 (aldehyde dehydrogenase family 1, subfamily A2) gene was lost from this mesenchyme in Wt1(-/-) embryos. Phenotypic analysis of Raldh2 mutant mice rescued from early cardiac defects by retinoic acid food supply revealed defects of the venous pole and pericardium highly similar to those of Wt1(-/-) mice.. Pericardium and sinus horn formation are coupled and depend on the expansion and correct temporal release of pleuropericardial membranes from the underlying subcoelomic mesenchyme. Wt1 and downstream Raldh2/retinoic acid signaling are crucial regulators of this process. Thus, our results provide novel insight into the genetic and cellular pathways regulating the posterior extension of the mammalian heart and the formation of its coelomic lining.

Topics: Aldehyde Oxidoreductases; Animals; Apoptosis; Cell Lineage; Coronary Sinus; Fetal Death; Gene Expression Regulation, Developmental; Genotype; Gestational Age; Heart Defects, Congenital; Mesoderm; Mice; Mice, Knockout; Mice, Transgenic; Mutation; Pericardium; Phenotype; Pleura; Signal Transduction; Sinoatrial Node; T-Box Domain Proteins; Tretinoin; WT1 Proteins

Prenatal rat embryo exposure to retinoids induces severe malformations in various organs; the most active and teratogenic metabolite is all-trans-retinoic acid (atRA). The mechanisms of this embryopathy are only partly known. In the present study, the influence of glycine on the teratogenicity of atRA was investigated.. Embryos from 5 groups of white rats were studied: Group 1 remained untreated; Group 2 received glycine 2% in drinking water ad libitum from the first gestational day (GD 1); Group 3 was administered vehicle (corn oil); Group 4 was treated with atRA (50 mg/kg of body weight) injected (IP); and Group 5 was treated with atRA (50 mg/kg of body weight IP) plus glycine 2% in drinking water ad libitum from GD 1. atRA was administrated daily from GD 8-10. Dams were killed on the 21st day of pregnancy, and their fetuses were examined to detect external, visceral, and skeletal malformations.. The results show that the atRA-administered dose is not toxic for the dams, and that although fetal death was not observed, it produced abnormalities in the fetuses. Glycine reduced atRA-induced teratogenic effects (external and skeletal defects).. The results indicate that glycine effectively reduces the teratogenic effects of atRA. Thus, glycine might be useful for the prevention of vitamin A teratogenicity.

Topics: Abnormalities, Drug-Induced; Animals; Antineoplastic Agents; Drug Antagonism; Female; Fetal Death; Glycine; Glycine Agents; Maternal-Fetal Exchange; Pregnancy; Rats; Rats, Wistar; Teratogens; Tretinoin

The aim of this study was to determine the possible role of the retinoid-mediated signaling pathway in the pathogenesis of anorectal malformations (ARM). The authors investigated whether all-trans retinoic acid (ATRA) affects the expression pattern of Sonic hedgehog (Shh) and Bone morphogenetic protein 4 (BMP4), which play important roles in anorectal morphogenesis in vertebrates.. Pregnant ICR strain mice were fed 100 mg/kg of ATRA on the ninth gestational day (E9). Embryos with or without administration of ATRA were obtained from the uteri between E12 and E16 and were fixed immediately in a 4% paraformaldehyde solution. Frozen sections were evaluated for concentric layers around the endodermal epithelium by H&E and immunohistochemistry using antibodies created specifically to act against Shh and BMP4.. More than 95% of the embryos administered ATRA had ARM; rectoprostatic urethral fistula, rectocloacal fistula, and short tail were the most frequent anomalies in the mouse embryos. On E14, normal mouse embryos had normal rectum and anus in which the epithelium of the anorectum was positive for Shh, and the mesenchyme was positive for BMP4. In the ARM embryos, however, the epithelium of the anorectum was negative for Shh, and the mesenchyme was also negative for BMP4.. In normal hindgut development, Shh from the epithelium induces BMP4 expression in the mesenchyme, which differentiates into the lamina propria and the submucosa. In ARM embryos, expressions of Shh and BMP4 could not be found in those regions of the hindgut. Therefore, these findings indicate that Shh and BMP4, which appear to play a crucial role in organogenesis of the hindgut, were disturbed in the cell signaling pathway between the epithelium and the mesenchyme layers.

Topics: Abnormalities, Multiple; Anal Canal; Animals; Bone Morphogenetic Protein 4; Bone Morphogenetic Proteins; Cell Differentiation; Cloaca; Epithelium; Female; Fetal Death; Gene Expression Regulation, Developmental; Gestational Age; Hedgehog Proteins; Mesoderm; Mice; Mice, Inbred ICR; Morphogenesis; Organ Specificity; Pregnancy; Rectum; Signal Transduction; Tail; Trans-Activators; Tretinoin; Urethra; Urinary Bladder

The cytochrome P450-dependent monooxygenase system catalyzes the metabolism of xenobiotics and endogenous compounds, including hormones and retinoic acid. In order to establish the role of these enzymes in embryogenesis, we have inactivated the system through the deletion of the gene for the electron donor to all microsomal P450 proteins, cytochrome P450 reductase (Cpr). Mouse embryos homozygous for this deletion died in early to middle gestation (approximately 9.5 days postcoitum [dpc]) and exhibited a number of novel phenotypes, including the severe inhibition of vasculogenesis and hematopoiesis. In addition, defects in the brain, limbs, and cell types where CPR was shown to be expressed were observed. Some of the observed abnormalities have been associated with perturbations in retinoic acid homeostasis in later embryogenesis. Consistent with this possibility, embryos at 9.5 dpc had significantly elevated levels of retinoic acid and reduced levels of retinol. Further, some of the observed phenotypes could be either reversed or exacerbated by decreasing or increasing maternal retinoic acid exposure, respectively. Detailed analysis demonstrated a close relationship between the observed phenotype and the expression of genes controlling vasculogenesis. These data demonstrate that the cytochrome P450 system plays a key role in early embryonic development; this process appears to be, at least in part, controlled by regional concentrations of retinoic acid and has profound effects on blood vessel formation.

Topics: Animals; Blood Vessels; Cytochrome P-450 Enzyme System; Embryo, Mammalian; Fetal Death; Fibroblast Growth Factor 8; Fibroblast Growth Factors; Gene Expression Regulation, Developmental; Homeostasis; Mice; Mice, Mutant Strains; Microsomes; NADPH-Ferrihemoprotein Reductase; Phenotype; Receptors, Retinoic Acid; Tretinoin; Vitamin A

The functional links of specific retinoid receptors to early developmental events in the avian embryo are not known. Before such studies are undertaken, knowledge is required of the spatiotemporal expression patterns of the receptor genes and their regulation by endogenous retinoic acid levels during the early stages of development. Here, we report the expression patterns of mRNAs for RARalpha, RARalpha2, RARbeta2, RARgamma, RARgamma2, RXRalpha, and RARgamma from neurulation to HH10 in the normal and vitamin A-deficient (VAD) quail embryo. The transcripts for all retinoid receptors are detectable at HH5, except for RXRgamma, which is detected at the beginning of HH6. At the 4/5 somite stage of HH8, when retinoid signaling is initiated in the avian embryo, mRNAs of all receptors are present, with very strong and ubiquitous expression patterns for RARalpha, RARalpha2, RARgamma, RARgamma2, and RXRalpha, a persistent expression of RARgamma in the neural tissues, a strong expression of RARbeta2 in lateral plate mesoderm and somites, and an anterior expression of RXRgamma. All retinoid receptors are expressed in the heart primordia. In the VAD quail embryo, the general pattern of retinoid receptor transcript localization is similar to that of the normal, except that the expression of RARalpha2 and RARbeta2 is severely diminished. Administration of retinol or retinoic acid to VAD embryos at or before the 4/5 somite stage rescues the expression of RARalpha2 and RARbeta2 within approximately 45 min and restores normal development. RARbeta2 expression requires the expression of RARalpha2. After neurulation, the expression of all retinoid receptors in the VAD quail embryo becomes independent of vitamin A status and is similar to that of the normal. The mRNA levels and sites of expression of the key enzyme for retinoic acid biosynthesis, Raldh-2, are not affected by vitamin A status; the expression pattern is restricted and does not correspond to that of retinoid receptors at all sites. The general patterns and intensity of retinoid receptor gene expression during early quail development are comparable to those of the mammalian and thus validate the application of results from retinoid-regulated avian development studies to those of the mammalian.

Topics: Aldehyde Oxidoreductases; Animals; Coturnix; Embryo, Nonmammalian; Fetal Death; Gene Expression Regulation, Developmental; Mice; Receptors, Retinoic Acid; Retinal Dehydrogenase; Retinoic Acid Receptor alpha; Retinoic Acid Receptor gamma; Retinoid X Receptors; Transcription Factors; Transcription, Genetic; Tretinoin; Vitamin A Deficiency

NAT1/p97/DAP5 is a newly identified protein that shares homology with the translation initiation factor eIF4G. Studies in vitro and in transfected cells indicated that NAT1 might suppress global translation, thereby repressing cellular proliferation. Here we studied the functions of NAT1 in vivo by disrupting its gene in mice. NAT1(-/-) embryos died during gastrulation, indicating a crucial role for NAT1 in embryogenesis. Undifferentiated NAT1(-/-) embryonic stem cells were normal in morphology, proliferation, global translation and gene expression profile. However, NAT1(-/-) cells exhibited an impaired ability to differentiate: they were resistant to differentiation induced by retinoic acid, and teratomas derived from them consisted of undifferentiated and poorly differentiated tissues. The expression of retinoic acid-responsive genes, such as the cell-cycle inhibitor p21(WAF1), was selectively impaired in NAT1(-/-) cells. Transcription from synthetic retinoic acid-responsive elements was also impaired. These data demonstrated that this translation initiation factor homolog controls specific gene expression pathways required for cellular differentiation.

Topics: Animals; Cell Division; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Embryo, Mammalian; Embryonic and Fetal Development; Embryonic Induction; Fetal Death; Gene Deletion; Gene Expression Regulation, Developmental; Gene Targeting; Genes, Essential; Genes, Reporter; Genotype; Mice; Mice, Knockout; Peptide Initiation Factors; Protein Biosynthesis; Response Elements; Signal Transduction; Stem Cells; Teratoma; Transcription, Genetic; Tretinoin

Normal embryonic development and survival in utero is dependent on an adequate supply of vitamin A. Embryos from vitamin A-deficient (VAD) pregnant rats fed an inadequate amount of all-trans retinoic acid (atRA; 12 microg per g of diet or approximately 230 microg per rat per day) exhibit severe developmental abnormalities of the anterior cardinal vein and hindbrain by embryonic day (E) 12.5 and die shortly thereafter.. In the present study, we sought to determine whether supplementation of VAD-RA supported (12 microg per g of diet) pregnant rats with retinol (ROL) at the late-gastrula (presomite or rat E9.5) or early somite stages (E10.5), or provision of higher levels of atRA throughout this period could prevent abnormalities in the developing cardiovascular and nervous systems.. A newly described defect in the sinuatrial venus valve along with enlarged anterior cardinal veins and nervous system abnormalities and the later death of embryos are prevented by supplementing pregnant animals with ROL on the morning of E9.5. If ROL supplementation is delayed by 1 day (E10.5), most embryos are abnormal and die by E18.5. Supplementation of VAD rats with atRA (250 microg per g of diet) between E8.5 and E10.5 also prevents the cardiovascular and nervous system abnormalities and a significant number of these embryos survive to parturition. Thus, high levels of atRA can obviate the need for ROL between E9.5 and E10.5.. These results support an essential role for retinoid signaling between the late gastrula and early somite stages in the rat embryo for normal morphogenesis of the primitive heart tube and the posterior hindbrain. Further, these results suggest that embryonic death occurring at midgestation in the VAD rat may be linked to the abnormal development of one or both of these embryonic structures.

Topics: Abnormalities, Multiple; Animal Feed; Animals; Cranial Nerves; Diterpenes; Dose-Response Relationship, Drug; Embryonic and Fetal Development; Female; Fetal Death; Fetal Heart; Fetal Resorption; Gastrula; Genes, Homeobox; Gestational Age; Morphogenesis; Pregnancy; Pregnancy Complications; Rats; Retinyl Esters; Rhombencephalon; Transcription Factors; Tretinoin; Veins; Vitamin A; Vitamin A Deficiency

To elucidate the underlying developmental mechanisms of persistent hyperplastic primary vitreous (PHPV) in humans, we investigated a mouse model for PHPV induced by retinoic acid. We treated C57BL/6NJcl mice at various stages of pregnancy (gestation days 7, 8, 9, 10, 11, or 12) with the teratogen retinoic acid, which affects the migration of neural crest cells. Untreated pregnant mice served as a control group. The eyes of the fetuses were examined histologically on day 18 on gestation. Developmental abnormalities of the vitreous were defined as the presence of excessive mesenchymal tissue in the vitreous cavity. The incidence of developmental abnormalities of the vitreous in all groups, except for those treated on day 12 of pregnancy, significantly exceeded that in the control group (P<0.01). The histological characteristics of the observed vitreous abnormalities in mice resembled those found in PHPV clinically. Retinoic acid-induced abnormalities in mice can serve as an experimental model for PHPV by environmental factors. Results suggest that the critical period for these retinoic acid-induced abnormalities was during days 7 to 11 of gestation, which corresponds to a critical period of 2.5 to 7 weeks of gestation for PHPV in humans.

Topics: Abnormalities, Drug-Induced; Animals; Female; Fetal Death; Gestational Age; Maternal-Fetal Exchange; Mice; Mice, Inbred C57BL; Pregnancy; Prenatal Exposure Delayed Effects; Tretinoin; Vitreous Body

Several hormones and inducers of intracellular messengers, known to affect plasminogen-activator (PA) production in other systems, were investigated for putative effects on bovine embryos. Day 8 embryos were cultured for 5 days in a humidified atmosphere of 5% CO2 in air at 37 degrees C in media containing different concentrations of progesterone, oestradiol, dexamethasone, retinoic acid, dibutyryl cyclic AMP (dbcAMP) and phorbol myristate acetate (PMA). At intervals of 24 h, the medium was recovered for PA analysis and overall embryonic diameter was measured. While none of the hormones and agents tested affected PA production (P > 0.05), dimethyl sulfoxide, which was used to dissolve PMA, inhibited PA production during the first 72 h of culture (P < 0.05). PA production was affected by duration of culture (P < 0.05). Concentrations of plasminogen activator in the media were low during the first 48 h, had increased after 72 and 96 h in culture, and either remained high or decreased slightly toward the end of the culture period. With the exceptions of dbcAMP and PMA, the hormones tested in this study did not affect embryonic size. Dibutyryl cAMP caused a progressive decrease in embryonic diameter. PMA resulted in embryo death at high concentrations but at lower concentrations it enhanced overall embryonic diameter throughout the time of culture (P < 0.05). These results suggest that cultured bovine embryos produce PA in a fixed, time-dependent manner, independent of exogenous hormonal regulation.

Topics: Animals; Bucladesine; Cattle; Cells, Cultured; Dexamethasone; Embryo, Mammalian; Embryonic and Fetal Development; Estradiol; Female; Fetal Death; Hormones; Plasminogen Activators; Pregnancy; Progesterone; Second Messenger Systems; Tetradecanoylphorbol Acetate; Tretinoin

The embryotoxic and teratogenic potential of all-trans retinoic acid was assessed following exposure prior to and during early organogenesis in the cynomolgus monkey (Macaca fascicularis). Sixteen pregnant females were orally administered all-trans retinoic acid (Tretinoin, Hoffmann-La Roche) once daily from GD 10-20 and twice daily from GD 21-24 at three different dosages, 5 (n = 9), 10 (n = 6) and 20 mg/kg (n = 1). Adverse clinical signs resembling hypervitaminosis A were observed in one animal at 5 mg/kg, in three animals at 10 mg/kg, and in the animal treated with 20 mg/kg all-trans retinoic acid. Maternal weight loss was observed in the 10- and 20-mg/kg groups. A dose-dependent increase in embryolethality was observed, with 22% (2/9), 50% (3/6), and 100% (1/1) occurring at 5, 10, and 20 mg/kg, respectively. The majority of embryonic deaths occurred between GD 16 and 20; the incidence of these early losses was higher than in historical and concurrent controls. No malformations, but a single growth-retarded fetus, was observed in the 5-mg/kg group. Craniofacial malformations, consisting of external ear defects, mandibular hypoplasia, cleft palate, and temporal bone abnormalities, were seen in three viable fetuses in the 10-mg/kg group. Skeletal variations were common to the majority (70%, 7/10) of viable fetuses in both dose groups and were increased relative to historical controls (32%, 25/77). Unlike previous studies with 13-cis-retinoic acid during the pre- and early organogenic stages of development (Hummler et al., Teratology 42:263-272, 1990), no thymic hypo- or aplasia or heart anomalies were observed, which may be attributable to the slightly longer 13-cis retinoic acid treatment period, i.e., GD 10-27. However, external ear and temporal bone defects were common to both all-trans and 13-cis retinoic acid. The similarity observed in the malformation syndrome induced by both all-trans and 13-cis retinoic acid in the cynomolgus monkey and 13-cis retinoic acid embryopathy in humans supports this macaque species as a model for further developmental toxicity studies of vitamin A-related compounds.

Topics: Abnormalities, Drug-Induced; Animals; Embryo, Mammalian; Female; Fetal Death; Macaca fascicularis; Male; Pregnancy; Teratogens; Tretinoin; Weight Gain

Treatment of pregnant Sprague-Dawley rats with etretinate or retinoic acid on pregnancy Day 8.5-9.0 resulted in craniofacial malformations in 100% of the embryos. A morphological investigation of the maxillofacial malformations was undertaken. Retinoid-exposed embryos showed a reduced skull base, flattened and elongated occiput and micrognathia. The malar bones were reduced or missing. Meckel's cartilage was delayed in differentiation as was the mandibular bone. The fusion between different facial processes was disturbed which resulted in facial and palatal clefts. Disturbance of the development of the hypophysis was combined with persisting Rathke's pouch. Aplasia of incisor and molar tooth buds was seen as was aplasia of salivary gland ducts. The facial artery was hyperplastic.

Topics: Abnormalities, Drug-Induced; Animals; Etretinate; Facial Bones; Fetal Death; Fetal Resorption; Gestational Age; Mandible; Microscopy, Electron, Scanning; Neural Tube Defects; Rats; Rats, Inbred Strains; Skull; Tooth Abnormalities; Tretinoin

Treatment of pregnant Sprague-Dawley rats with retinoic acid or etretinate pregnancy day 8.5 to 9.0 resulted in craniofacial defects in 100% of the embryos. A morphologic investigation of the malformations occurring in the ear was performed. Outer ears were missing, microtic, low-placed, and dorsally situated. External acoustic meatus was short or absent. Middle ear structures were delayed in differentiation, middle ear ossicle primordia were hypoplastic and malformed, the stapedial artery and facial nerve were hypoplastic, and their relation to the stapes was variable. In the inner ear, the otic capsule was thick, the cochlea had fewer turns and the semicircular ducts showed poor differentiation.

Topics: Abnormalities, Drug-Induced; Animals; Ear; Ear, External; Ear, Inner; Ear, Middle; Etretinate; Female; Fetal Death; Fetus; Pregnancy; Rats; Rats, Inbred Strains; Tretinoin

The effects of retinoic acid (RA) on the manifestation and nature of neural tube defects (NTD) in heterozygous embryos of mutant mice carrying the gene loop-tail (Lp) and in normal (+/+) littermates and embryos from normal homozygous matings were compared with NTD that occur in untreated abnormal homozygous (Lp/Lp) embryos. A single intraperitoneal dose (5 mg/kg) of RA administered at 9 AM or 3 PM on day 8 of gestation induced NTD in +/+ as well as Lp/+ embryos removed on day 12 of gestation. All of the NTD were confined to the brain and consisted of exencephaly involving the diencephalon, mesencephalon, and metencephalon. In neither phenotype (Lp/+; +/+) was the massive exencephaly and myeloschisis characteristic of untreated Lp/Lp embryos produced; thus, it is possible that the teratogenic mechanisms of RA-induced defects and of Lp-induced defects may differ.

Topics: Animals; Diencephalon; Female; Fetal Death; Injections, Intraperitoneal; Maternal-Fetal Exchange; Mice; Mice, Mutant Strains; Neural Tube Defects; Pregnancy; Tretinoin

The allelic loci splotch (Sp) and splotch-delayed (Spd) cause neural tube defects (NTDs) in mice homozygous for either of these genes. The polymorphic enzyme isocitrate dehydrogenase (Idh-1) in conjunction with a recombination suppressor was used as a genetic marker to identify embryos homozygous for these alleles. A split dose of all-trans retinoic acid (RA) totalling 5.0 mg/kg administered on gestation day 9/15 and 9/18 (days/h) significantly reduced the frequencies of NTD and of mutant genotypes in marked Spd embryos examined on day 16 without significantly increasing the resorption frequency. There was a nonsignificant decrease in the frequencies of NTD and mutant genotypes in embryos examined on day 11 of gestation. Thus, retinoic acid treatment was associated with selective mortality of the homozygous Spd mutants. No evidence of selective mortality was observed in RA-treated Sp embryos.

Topics: Alleles; Animals; Crosses, Genetic; Embryo, Mammalian; Female; Fetal Death; Heterozygote; Homozygote; Isocitrate Dehydrogenase; Male; Mice; Mice, Mutant Strains; Mutation; Neural Tube Defects; Pregnancy; Teratogens; Tretinoin

Reproduction and teratology studies were performed with etretin, the free acid analog of the retinoid etretinate. The lowest teratogenic dose of etretin in mice, rats and rabbits was 3, 15 and 0.6 mg/kg, respectively. In all three species, the lowest dose which was embryolethal, fetolethal or reduced the survivability of the pups during lactation was 2-3 times higher than the above doses. In rats, the lowest effective dose of etretin was 3 mg/kg in both the study for fertility and general reproductive performance and the peri- and postnatal study. The main adverse effect in these two experiments was a reduced survival of the F1-generation.

Topics: Abnormalities, Drug-Induced; Acitretin; Administration, Oral; Animals; Dose-Response Relationship, Drug; Embryo, Mammalian; Female; Fetal Death; Mice; Pregnancy; Pregnancy, Animal; Rabbits; Rats; Reproduction; Teratogens; Tretinoin

Retinoic acid, an analogue of vitamin A, is known to be teratogenic in laboratory animals and has recently been implicated in a few clinical case reports. To study the human teratogenicity of this agent, we investigated 154 human pregnancies with fetal exposure to isotretinoin, a retinoid prescribed for severe recalcitrant cystic acne. The outcomes were 95 elective abortions, 26 infants without major malformations, 12 spontaneous abortions, and 21 malformed infants. A subset of 36 of the 154 pregnancies was observed prospectively. The outcomes in this cohort were 8 spontaneous abortions, 23 normal infants, and 5 malformed infants. Exposure to isotretinoin was associated with an unusually high relative risk for a group of selected major malformations (relative risk = 25.6; 95 per cent confidence interval, 11.4 to 57.5). Among the 21 malformed infants we found a characteristic pattern of malformation involving craniofacial, cardiac, thymic, and central nervous system structures. The malformations included microtia/anotia (15 infants), micrognathia (6), cleft palate (3), conotruncal heart defects and aortic-arch abnormalities (8), thymic defects (7), retinal or optic-nerve abnormalities (4), and central nervous system malformations (18). The pattern of malformation closely resembled that produced in animal studies of retinoid teratogenesis. It is possible that a major mechanism of isotretinoin teratogenesis is a deleterious effect on cephalic neural-crest cell activity that results in the observed craniofacial, cardiac, and thymic malformations.

Topics: Abnormalities, Drug-Induced; Abortion, Spontaneous; Acne Vulgaris; Adolescent; Adult; Female; Fetal Death; Heart Defects, Congenital; Humans; Infant, Newborn; Isotretinoin; Male; Pregnancy; Pregnancy Trimester, First; Prospective Studies; Retrospective Studies; Risk; Tretinoin

Retinoic acid (25 mg/kg) administered by gavage to rats at 216 hours of gestation killed almost all conceptuses by 288 hours and all by full term. The embryolethal dose50 was 12.3 mg/kg. Embryos died from damage to the allantois leading to agenesis or hypogenesis of the chorioallantoic placenta. Suppression of cell division in, disturbed fluid entry into, and impaired normal vascularization of the allantois underlay the abnormality, the predominant element depending principally on when exposure occurred. Hydremia (Br. J. Exp. Pathol., 57:525-541, '76) affected over 50% of the sacs. Relating data from the literature to resorption patterns suggested that 25 mg/kg of retinoic acid raised a lethotoxic level (approximately 2 micrograms/ml) of retinoate in the plasma for about 5 hours. This, together with asynchronous development, was used to help explain why groups of embryos responded to the teratogen for 18 hours longer than single embryos and why exposure 18 hours before the allantois on average appears, killed some young. Comparison showed that retinoic acid was 4.8 times as embryolethal as retinol. Otherwise, each behaved qualitatively similarly, suggesting that either retinol acts through retinoic acid or via a common path entered independently by each. Placental agenesis is well documented in Soviet literature. It is almost unknown in Western teratology even though it is probably the most important cause of embryonal death following teratogenic procedures around the time of placentation.

Topics: Allantois; Animals; Blood; Body Fluids; Dose-Response Relationship, Drug; Embryo Loss; Embryo, Mammalian; Female; Fetal Death; Gestational Age; Placenta; Pregnancy; Rats; Rats, Inbred Strains; Tretinoin

Caffeine and retinoic acid were examined for effects upon limb morphogenesis and upon creatine kinase (CK) as a measure of limb myogenesis. Caffeine at 200 mg/kg, i.p., on E11 produced a low level of forelimb (1.2%) and hindlimb (2.0%) defects. Retinoic acid, at 50 mg/kg given orally as an oily suspension, induced a high level of reduction deformities. Hindlimbs (100%) were affected more than forelimbs (88%). Limbs (E16) were examined for CK isoenzymes using DEAE-Sephacel column chromatography. Untreated limbs had 88.04% skeletal muscle (MM), 6.98% hybrid (MB) and 5.08% brain (BB) CK isoenzyme. Caffeine had no effect. However, retinoic acid increased MM-CK to 92.67%, and decreased BB-CK to 2.24%. This is the first evidence that suggests that retinoic acid may modify the phenotypic expression of developing muscle.

Topics: Animals; Caffeine; Chromatography, DEAE-Cellulose; Creatine Kinase; Electrophoresis, Cellulose Acetate; Extremities; Female; Fetal Death; Isoenzymes; Maternal-Fetal Exchange; Mice; Mice, Inbred ICR; Muscles; Pregnancy; Teratogens; Tretinoin

Fifteen pregnant Macaca mulatta were treated with doses of 20 or 40 mg of retinoic acid between 19--45 or 17--45 days of gestation, respectively, for 4--8 consecutive days. Based on gross examination, ten malformed infants, including one stillbirth and one abortus, four normal infants, and one resorption were produced. The most critical sensitive period was between days 24--35 of gestation, and the malformations primarily involved the craniofacial skeleton. Ten treated infants and eight age-matched controls were cephalometrically analyzed using craniometric points as closely correlated as possible with those in humans in order to define the craniofacial malformations induced prenatally by retinoic acid. Although all ten animals had detectable linear and angular deviations from the controls, four had cephalometric patterns which appeared to be of similar developmental origin.

Topics: Abnormalities, Drug-Induced; Animals; Animals, Newborn; Cephalometry; Facial Bones; Female; Fetal Death; Macaca; Macaca mulatta; Monkey Diseases; Pregnancy; Radiography; Skull; Tretinoin

Topics: Alcohols; Animals; Diet; Female; Fetal Death; Histology; Placenta; Pregnancy; Pregnancy, Animal; Rats; Reproduction; Research; Tretinoin; Vitamin A; Vitamin A Deficiency