Teratogenesis

Fetal alcohol spectrum disorder (FASD) is a leading cause of neurodevelopmental disability. Individuals with FASD may exhibit a characteristic facial appearance that has diagnostic utility. The mechanism by which alcohol disrupts craniofacial development is incompletely understood, as are the genetic factors that can modify individual alcohol vulnerability. Using an established avian model, we characterized the cranial transcriptome in response to alcohol to inform the mechanism underlying these cells' vulnerability. Gallus gallus embryos having 3-6 somites were exposed to 52 mM alcohol and the cranial transcriptomes were sequenced thereafter. A total of 3422 genes had significantly differential expression. The KEGG pathways with the greatest enrichment of differentially expressed gene clusters were Ribosome (P = 1.2 x 10-17, 67 genes), Oxidative Phosphorylation (P = 4.8 x 10-12, 60 genes), RNA Polymerase (P = 2.2 x 10-3, 15 genes) and Spliceosome (P = 2.6 x 10-2, 39 genes). The...

Reptiles are ancestral organisms presenting a variety of
shapes, from the elongated vertebral column of the snake to the turtle dorsalized ribs or retractile neck. Body plans are specified by a conserved group of homeobox-containing genes ( Hox genes), which encode transcription factors important in cell fate and vertebral architecture along the anteroposterior axis during embryonic development; thus, dysregulation of these genes may cause congenital malformations, from mild-sublethal to embryonic-lethal. The genetic pool, maternal transfer, and environmental conditions during egg incubation affect development; environmental factors such as temperature, moisture, oxygen, and pollution may alter gene expression by epigenetic mechanisms. Thus, in this review, we present information regarding Hox genes and development in reptiles, including sex determination and teratogenesis. We also present some evidence of epigenetic regulation of Hox genes and the role of the environment in epigenetic modulation of gene expression. So far, the evidence suggests that the molecular instructions encoded by Hox genes to build a snake, a lizard, or a turtle represent the interplay between genome and epigenome after years of evolution, with occasional environmentally induced molecular mistakes leading to abnormal body shapes.

Qui dit nature, au sens de réalité sensible, dit mesure, recherche d’une harmonie entre les parties et le tout. Ainsi en est-il des liens dialectiques unissant l’idée de cosmos et celle de nomos.

Que ce soit dans les montagnes du Zargos ou aux confins de l’Œkoumène, au-delà des colonnes d’Hercules et de Protée, règne tout un ensemble de créatures monstrueuses. Cette tératogénie, partie intégrante de la cosmogonie, apparait face au contre-nature, au « chaos des exceptions sans lois », elles-mêmes issues d’une négativité propre à l’être sensible.

Partant d’une analyse des tératogénies primordiales issues des civilisations anciennes du Proche-Orient ainsi que de la Grèce Antique, nous tenterons de montrer leurs actualisations au cours du Ve siècle, période qui verra la naissance de la démocratie grecque. Actualisation participant au développement de la notion d’anomie, faisant de la tyrannie et de l’impiété des synonymes de monstruosité morale.

Un teratógeno se define como cualquier sustancia química o agente físico (radiaciones) infeccioso o enfermedad materna que mientras ocurre el periodo embrionario o fetal es capaz de alterar de gravedad el crecimiento y desarrollo del embrión y/o feto, y producir una alteración morfológica o funcional en el periodo postnatal. Todos estos agentes que pueden producir una alteración en el desarrollo de los órganos en formación se denominan agentes teratógenos. Los primeros agentes teratógenos se descubrieron durante la década de 1920, año en que se identificó a la radiación ionizante como un agente potencialmente nocivo y dos décadas después se reconocieron los efectos teratogénicos del virus de la rubéola. Este virus puede causarle al embrión complicaciones como microcefalia, sordera, un desarrollo anormal de los músculos, anomalías cardiacas e incluso la posibilidad de un aborto espontáneo si se contrae en el primer trimestre del embarazo. Al inicio de la década de 1960 la Talidomida fue introducida al mercado como un medicamento contra la gripe y su uso se difundió en diferentes países. En 1961 en Alemania, fueron reconocidos los primeros casos de un nuevo síndrome que se caracterizaba por presentar defectos en la formación de los miembros. Estas anomalías se tornaron epidémicas en diferentes países. La droga había sido aprobada para su venta, luego de haber pasado por las pruebas de experimentación en animales, pero no se había identificado su capacidad de producir defectos congénitos en seres humanos. A pesar de que esta sustancia provoca ciertas malformaciones en uno de cada tres fetos expuestos en el primer trimestre del embarazo, se tardó cuatro años en identificar este riesgo. A partir de estos hechos, se empezó a desarrollar la teratología tanto desde un punto de vista de la investigación básica como clínica y epidemiológica. Después de la fertilización del óvulo, puede llevar entre 6 y 9 días para que se produzca la implantación. Una vez que el óvulo fertilizado penetra en el útero, se establece el aporte de sangre entre la madre y el embrión, esto significa que si hay algún agente que se considere teratógeno en la sangre de la madre, a partir de este momento es que puede pasarlo al feto que se encuentra en desarrollo. Se cree que los teratógenos pueden afectar al feto aproximadamente entre 10 y 14 días después de la concepción. Durante el desarrollo del bebé, ciertos órganos se forman en determinados momentos. Si un teratógeno tiene la capacidad de interferir en el cierre del tubo neural, la exposición al teratógeno debe ocurrir en el período determinado, ya que es a partir de cierto momento de la gestación en que el tubo neural comienza a cerrarse. El tubo neural da lugar a la mayor parte del sistema nervioso, anteriormente se ensancha y se diferencia en el encéfalo y los nervios craneales; posteriormente forma la médula espinal y los nervios motores. La mayor parte del

The detrimental effects of prenatal alcohol exposure on the developing brain include structural brain anomalies as well as cognitive and behavioral deficits. Initial neuroimaging studies of fetal alcohol spectrum disorders (FASD) using magnetic resonance imaging (MRI) confirmed previous autopsy reports of overall reduction in brain volume and central nervous system (CNS) disorganization, with specific structural abnormalities of the corpus callosum, cerebellum, caudate, and hippocampus. Advances in neuroimaging techniques have allowed detection of regional increases in cortical thickness and gray matter volume along with decreased volume and disorganization of white matter in individuals with FASD. In addition, functional imaging studies have found functional and neurochemical differences in those prenatally exposed to alcohol. Behavioral alterations noted in individuals with FASD are consistent with the findings noted in the brain imaging studies. Continued neuroimaging studies are needed to further advance understanding of the neuroteratogenic effects of alcohol.

Adriamycin is teratogenic if given to pregnant rats. A wide range of anomalies involving the gastrointestinal, renal, and cardiovascular systems has been described, similar to the VATER association, yet it is not known if they are identical to the human pattern. The aim of this study was to document the visceral anomalies in rat fetuses exposed to adriamycin and to determine their similarities with the congenital defects in humans with the VATER association. The results revealed a spectrum of very similar anomalies. Furthermore, the characteristics of the tracheo-oesophageal anomalies had a lot of features in common with the human pattern. We conclude that the adriamycin-treated fetal rat is an excellent model for studying the VATER association.

It has been reported that fractionated doses of 13-cis-retinoic acid are disproportionately more embryotoxic in pregnant mice than is the same dose given in a single bolus. Here, we examined limited pharmacokinetic profiles of a single (100 mg/kg dose given to NMRI mice on day 11 of gestation) versus multiple (3 x 100 mg/kg, 4 h apart) doses in an effort to assess the relative contribution to teratogenicity made by the drug and/or its metabolites. The major plasma metabolite of 13-cis-retinoic acid in the mouse was 13-cis-retinoyl-beta-glucuronide, followed by the 4-oxo metabolites and all-trans-retinoic acid. Transfer to the mouse embryo was very efficient for all-trans-retinoic acid, whereas, it was tenfold less efficient for 13-cis-retinoic acid and 100-fold less efficient for 13-cis-retinoyl-beta-glucuronide. The isomer all-trans-retinoic acid was found in the placenta at concentrations two- to three-fold higher than in the plasma, suggesting placental accumulation as well as placental cis/trans isomerization. Since 13-cis-retinoyl-beta-glucuronide and 13-cis- and all-trans-retinoic acid were detected in the embryo after this multiple dosing schedule, any of the three or their combinations may have been involved in the induction of malformations, but all-trans-retinoic acid, a well-known potent teratogen detected at concentrations of between 590 and 80 ng/g for 10 critical hours during gestation, could have been the major component.

BACKGROUND: Triadimefon is an antifungal derived from triazole. In in vitro whole-rodent embryo cultures, triazole-derivatives showed specific teratogenic effects at the branchial apparatus. The aim of the present work was to test in vivo triadimefon (FON), in order to verify a relationship between triazole exposure, embryonic abnormalities, and/or fetal malformations. METHODS: Pregnant CD-1 mice were treated with 0–300 mg/kg FON by gavage on day 8 post coitum (p.c.) at 10:00 AM, and sacrificed on day 8 p.c. at 1:00 PM, on day 9 p.c. at 10:00 AM, on day 10 p.c. at 10:00 AM, and at term of gestation (day 18 p.c.). At midgestation, the embryos were processed for specific immunostainings to visualize the hindbrain segmentation (day 8 p.c.) and the neural crest cell migration (days 8 and 9 p.c.). Fetuses explanted at term were all processed for skeletal examination after double-staining of osseous and cartilaginous tissues. RESULTS: At midgestation, the immunostaining of rhombomeres 3 and 5 showed a light scattering of the immunostained areas; the neural crest cell migration was unaffected, but their localization at the branchial arch level was abnormal. At term, several severe malformations were observed at the craniofacial and at the axial skeletal level. Ectopic cartilage was observed at the upper jaw. CONCLUSIONS: Triadimefon is teratogenic. The observed craniofacial malformations could be explained by an alteration of the rhombomeric organization and neural crest migration to the branchial arches; the axial abnormalities could be explained by the abnormal segmental identity specification. Birth Defects Res B 74:185–195, 2005. © 2005 Wiley-Liss, Inc.

The majority of epileptic disorders are not self-limiting over time, and therefore require a long-lasting and often even lifelong antiepileptic drug (AED) treatment. In women with epilepsy the influence of their disease on the possibility and course of pregnancies, as well as the potential impact of the AED treatment on mother and child, are crucial questions. This review addresses the clinically relevant knowledge concerning the impact of the disease itself and the AED treatment on fertility pregnancy, delivery, the postpartum period, and teratogenicity. Some of the new AEDs appear to have a favorable profile due to a lack of clinically relevant interactions and promising teratogenic profiles. However, the finding of decreases in lamotrigine serum concentrations during hormonal contraception and pregnancy is an instructive example, showing that ongoing studies are urgently needed to further investigate still-unanswered questions. Several prospective multinational surveys are curren...

Some 2000 species of cyanobacteria (blue-green algae) occur globally in aquatic habitats. They are able to survive under a wide range of environmental conditions and some produce potent toxins. Toxin production is correlated with periods of rapid growth (blooms) and 25%–70% of blooms may be toxic. Anatoxin-a is an alkoloid neurotoxin that acts as a potent neuro-muscular blocking agent at the nicotinic receptor. Acute toxicity, following consumption of contaminated water, is characterized by rapid onset of paralysis, tremors, convulsions and death. Human exposures may occur from recreational water activities and dietary supplements, but are primarily through drinking water. The current studies were conducted to examine the effect of in utero exposure on postnatal viability, growth and neurodevelopment, to evaluate the potential of in vitro embryotoxicity, and to explore the synergistic relationship between anatoxin-a and the algal toxin microcystin-LR by the oral route. The results of preliminary studies on amphibian toxicity are also reported. Time-pregnant mice received 125 or 200 µg kg−1 anatoxin-a by intraperitoneal injection on gestation days (GD) 8–12 or 13–17. Pup viability and weight were monitored over a 6-day period. Maternal toxicity (decreased motor activity) was observed at 200 µg kg−1 in both treatment periods. There were no significant treatment-related effects on pup viability or weight on postnatal day (PND) 1 or 6. The GD 13–17 pups were evaluated on PND 6, 12 and 20 for standard markers of neurodevelopmental maturation (righting reflex, negative geotaxis and hanging grip time). No significant postnatal neurotoxicity was observed. In vitro developmental toxicity was evaluated in GD 8 mouse embryos exposed to 0.1–25 µm anatoxin-a for 26–28 h. Perturbations in mouse yolk sac vasculature were noted from the 1.0 µm concentration in the absence of significant embryonic dysmorphology. Potential algal toxin synergism was tested in mice receiving either 0, 500 or 1000 µg kg−1 microcystin-LR by gavage and ∼50 min later receiving either 0, 500, 1000 or 2500 µg kg−1 anatoxin-a by the same route. No deaths occurred at any dose and no definitive signs of intoxication were observed. Stages 17 and 25 toad embryos (Bufo arenarum) were exposed to 0.03–30.0 mg l−1 of anatoxin-a for 10 days. Adverse effects included a dose-dependent transient narcosis, edema and loss of equilibrium. Most notable was the occurrence of 100% mortality at the high dose in both groups 6–13 days post-exposure. The observed delay between initial exposure and death is highly unusual for anatoxin-a. Published in 2005 by John Wiley & Sons, Ltd.

Caudal dysgenesis/sirenomelia is a malformation complex for which the pathogenesis is controversial. This report describes the particular vulnerability of specific caudal structures to Ochratoxin A (OA), a fungal toxin, as the basis for caudal dysgenesis in an avian model. The experimental procedure involved injection of 1 microgram of OA into the air sac of eggs that had been incubated for 48 hours prior to treatment (i.e., embryos that had reached Hamburger and Hamilton stage 9-10 (6-10 somite pairs) [Hamburger and Hamilton (1951) Dev. Dyn. 195:231-272] by the time of treatment). Six to twelve hours following OA injection, excessive cell death, as shown by vital staining and routine histology, was evident in selected cell populations, including cells of the caudal-most mesoderm (the mesoderm that apparently forms the external genitalia and median infraumbilical region), the tail bud, and the neural tube caudal to the wing buds (corresponding to the level of the presomitic mesoderm). The notochord was not severely affected, although there were degenerative changes in the presomitic mesoderm. Except for positional abnormalities, development of the lateral plate mesoderm from which the leg buds are derived appeared relatively normal in most of the treated embryos. Six days post-treatment, varying degrees of caudal dysgenesis, presenting in severely affected specimens as sirenomelia, were observed in approximately 30% of the surviving treated embryos. The potential basis for the differential vulnerability of the affected cell populations and, therefore, the cellular basis for the genesis of caudal dysgenesis/sirenomelia in this model are discussed.