Teratogenic Mechanisms Research Articles

Nanosecond pulsed electric field incorporation technique to predict molecular mechanisms of teratogenicity and developmental toxicity of estradiol-17β on medaka embryos.

Herein, we propose using a nanosecond pulsed electric field (nsPEF) technique to assess teratogenicity and embryonic developmental toxicity of estradiol-17β (E2 ) and predict the molecular mechanisms of teratogenicity and embryonic developmental defects caused by E2 on medaka (Oryzias latipes). The 5hour post-fertilization embryos were exposed to co-treatment with 10μm E2 and nsPEF for 2hours and then continuously cultured under non-E2 and nsPEF conditions until hatching. Results documented that the time to hatching of embryos was significantly delayed in comparison to the control group and that typical abnormal embryo development, such as the delay of blood vessel formation, was observed. For DNA microarray analysis, 6day post-fertilization embryos that had been continuously cultured under the non-E2 and nsPEF condition after 2hour co-treatments were used. DNA microarray analysis identified 542 upregulated genes and one downregulated gene in the 6day post-fertilization embryos. Furthermore, bioinformatic analyses using differentially expressed genes revealed that E2 exposure affected various gene ontology terms, such as response to hormone stimulus. The network analysis also documented that the estrogen receptor α in the mitogen-activated protein kinase signaling pathway may be involved in regulating several transcription factors, such as FOX, AKT1 and epidermal growth factor receptor. These results suggest that our nsPEF technique is a powerful tool for assessing teratogenicity and embryonic developmental toxicity of E2 and predict their molecular mechanisms in medaka embryos.

The avian embryo as a model for fetal alcohol spectrum disorder.

Prenatal alcohol exposure (PAE) remains a leading preventable cause of structural birth defects and permanent neurodevelopmental disability. The chicken (Gallus gallus domesticus) is a powerful embryological research model, and was possibly the first in which the teratogenicity of alcohol was demonstrated. Pharmacologically relevant exposure to alcohol in the range of 20-70 mmol/L (20-80 mg/egg) disrupt the growth of chicken embryos, morphogenesis, and behavior, and the resulting phenotypes strongly parallel those of mammalian models. The avian embryo's direct accessibility has enabled novel insights into the teratogenic mechanisms of alcohol. These include the contribution of IGF1 signaling to growth suppression, the altered flow dynamics that reshape valvuloseptal morphogenesis and mediate its cardiac teratogenicity, and the suppression of Wnt and Shh signals thereby disrupting the migration, expansion, and survival of the neural crest, and underlie its characteristic craniofacial deficits. The genetic diversity within commercial avian strains has enabled the identification of unique loci, such as ribosome biogenesis, that modify vulnerability to alcohol. This venerable research model is equally relevant for the future, as the application of technological advances including CRISPR, optogenetics, and biophotonics to the embryo's ready accessibility creates a unique model in which investigators can manipulate and monitor the embryo in real-time to investigate the effect of alcohol on cell fate.

Congenital Malformations Attributed to Prenatal Exposure to Cyclophosphamide.

Cyclophosphamide (CPA) remains one of the most widely prescribed anticancer drugs. It is also used in the treatment of rheumatoid arthritis, childhood nephrotic syndrome and systemic lupus erythematosus. It is a potent immunosuppressive agent. It is commonly used in blood and bone marrow transplantation. With the growing trend among women postponing childbearing, the number of women who are diagnosed with breast cancer is also increasing thus escalating the chances of exposure of the unborn child to antineoplastic drugs. A review of the literature provides strong evidence for the teratogenic effects on infants prenatally exposed to CPA. Both sporadic case reports and larger case series have demonstrated that babies with cyclophosphamide embryopathy are afflicted with intrauterine growth restriction, small for gestational age, and craniofacial malformations including eye anomalies, cleft/arched palate, hydrocephaly, micrognathia, low set microtia, hearing defects, craniosynostosis, and facial asymmetry. Also observed in these cases are limb defects such as radial, ulnar and tibial hypoplasia, club foot, digital defects of the hand and feet as well as vertebral fusion, brevicolis, and occasional Sprengel's deformity. These anomalies vary in consistency of occurrence and severity of the phenotype across cases and lack the specificity of thalidomide embryopathy or rubella embryopathy. However, they do occur is no longer in doubt. First trimester of pregnancy seems to be particularly susceptible to fetal malformations, although CPA effects on fetuses of later stages of gestation (hearing defects, growth restriction for example) are also reported occasionally. One of the major concerns from a mechanistic point of view is our inability to dissect the teratogenic effects of CPA from those of other drugs administered together with CPA as combination therapy. Animal experiments have been of particular value in that they are able to circumvent the numerous extraneous variables inherent to human case reports. They have also revealed the detrimental effects of CPA on gametes, preimplantation embryos, organogenesis as well as their potential teratogenic mechanisms. Of particular importance are the role of genetic polymorphisms, male mediated teratogenesis, ovarian failure, preimplantation embryo loss, epigenetic modifications, proxidant-antioxidant imbalance, autophagy, apoptosis, microRNAs and postclosure neural tube defects induced by CPA -all of which are areas for further research in CPA teratogenesis.

Thalidomide induces apoptosis in undifferentiated human induced pluripotent stem cells.

Thalidomide, which was formerly available commercially to control the symptoms of morning sickness, is a strong teratogen that causes fetal abnormalities. However, the mechanism of thalidomide teratogenicity is not fully understood; thalidomide toxicity is not apparent in rodents, and the use of human embryos is ethically and technically untenable. In this study, we designed an experimental system featuring human-induced pluripotent stem cells (hiPSCs) to investigate the effects of thalidomide. These cells exhibit the same characteristics as those of epiblasts originating from implanted fertilized ova, which give rise to the fetus. Therefore, theoretically, thalidomide exposure during hiPSC differentiation is equivalent to that in the human fetus. We examined the effects of thalidomide on undifferentiated hiPSCs and early-differentiated hiPSCs cultured in media containing bone morphogenetic protein-4, which correspond, respectively, to epiblast (future fetus) and trophoblast (future extra-embryonic tissue). We found that only the number of undifferentiated cells was reduced. In undifferentiated cells, application of thalidomide increased the number of apoptotic and dead cells at day 2 but not day 4. Application of thalidomide did not affect the cell cycle. Furthermore, immunostaining and flow cytometric analysis revealed that thalidomide exposure had no effect on the expression of specific markers of undifferentiated and early trophectodermal differentiated cells. These results suggest that the effect of thalidomide was successfully detected in our experimental system and that thalidomide eliminated a subpopulation of undifferentiated hiPSCs. This study may help to elucidate the mechanisms underlying thalidomide teratogenicity and reveal potential strategies for safely prescribing this drug to pregnant women.

The Dihydroxy Metabolite of the Teratogen Thalidomide Causes Oxidative DNA Damage.

Thalidomide [α-(N-phthalimido)glutarimide] (1) is a sedative and antiemetic drug originally introduced into the clinic in the 1950s for the treatment of morning sickness. Although marketed as entirely safe, more than 10 000 babies were born with severe birth defects. Thalidomide was banned and subsequently approved for the treatment of multiple myeloma and complications associated with leprosy. Although known for more than 5 decades, the mechanism of teratogenicity remains to be conclusively understood. Various theories have been proposed in the literature including DNA damage and ROS and inhibition of angiogenesis and cereblon. All of the theories have their merits and limitations. Although the recently proposed cereblon theory has gained wide acceptance, it fails to explain the metabolism and low-dose requirement reported by a number of groups. Recently, we have provided convincing structural evidence in support of the presence of arene oxide and the quinone-reactive intermediates. However, the ability of these reactive intermediates to impart toxicity/teratogenicity needs investigation. Herein we report that the oxidative metabolite of thalidomide, dihydroxythalidomide, is responsible for generating ROS and causing DNA damage. We show, using cell lines, the formation of comet (DNA damage) and ROS. Using DNA-cleavage assays, we also show that catalase, radical scavengers, and desferal are capable of inhibiting DNA damage. A mechanism of teratogenicity is proposed that not only explains the DNA-damaging property but also the metabolism, low concentration, and species-specificity requirements of thalidomide.

FARMACOCINÉTICA E MECANISMOS DE TERATOGENICIDADE DOS MEDICAMENTOS NA GESTAÇÃO: UMA REVISÃO DA LITERATURA.

As alterações fisiológicas que ocorrem no organismo feminino durante o período gestacional é assunto bastante explorado pelos pesquisadores e encontra-se bem elucidado pela literatura; porém a temática relativa à farmacocinética e os mecanismos de teratogenicidade dos fármacos neste organismo em processo de alterações fisiológicas ainda encontra-se pouco explorado. O objetivo desta pesquisa foi revisar e contribuir para ampliar o conhecimento científico acerca da farmacocinética e dos mecanismos de teratogenicidade dos fármacos na gestação.

POSSIBLE TERATOGENIC EFFECTS OF ANTIEPILEPTICS IN ALBINO RATS: COMPARATIVE STUDY BETWEEN OLD AND NEW GENERATIONS: PART II

All antiepileptic drugs (AEDs) are either known or suspected of being teratogenic. The possible teratogenic mechanism is likely to be multiple even for the same drug. Treatment of females with epilepsy in the childbearing period raises questions due to interactions between epilepsy, antiepileptic drugs (AEDs) and different forms of reproductive life. The use of AEDs in these females is a balance between seizure control and adverse effects of these drugs, which are both potentially harmful to the developing fetus, neurological development, growth and subsequent pediatric progress, which presents unique challenges to both the clinicians and their patients. Recently, number of commercially available AEDs has steadily increased. This work is a randomized single blind control trial that aims to study the possible teratogenic effects of AEDs by comparing carbamazepine (old generation) with lamotrigine (new generation) in order to detect the drug that can be used safely by epileptic pregnant females. Pregnant female albino rats (120 in number) were used. They were randomly classified into six groups (2 control and 4 treated groups) each contained 20 pregnant rats. Animals were killed on the 20th day of gestation, dissected and fetuses were exposed and randomly classified into two subgroups: The first (1/3 of fetuses) were eviscerated and preserved in 95% ethyl alcohol for skeletal staining, using Alizarin red stain. Examination included: bones of axial skeleton (skull, vertebral column, sternum and ribs) and appendicular skeleton (clavicle, scapula, forelimbs and hind limbs). The second (2/3) were fixed in Bouin’ s solution for visceral examination. Examination of the axial skeleton: craniofacial bones showed highly significant reduction in complete ossification centers (OCs) of all treated groups in comparison with the control with no significant difference between lamotrigine and carbamazepine in therapeutic doses. Other parts of axial skeleton were not affected in therapeutic treated groups. Appendicular skeleton, except metacarpal OCs, showed no difference from control in therapeutic doses. There was a highly significant reduction in complete metacarpal OCs of both doses of carbamazepine and ¼ LD50 of lamotrigine, in comparison with the control, but there was a highly significant increase in both doses of lamotrigine in comparison with corresponding doses of carbamazepine. Similarly, there was a highly significant reduction in complete metatarsal OCs in both ¼ LD50 doses in comparison with the control. No significant difference was recorded in complete metatarsal OCs of therapeutic dose of lamotrigine and a highly significant increase in ¼ LD50 dose in comparison with corresponding doses of carbamazepine.Visceral findings: no abnormalities were detected among fetuses in therapeutic doses of treated groups. Fetuses of ¼ LD50 treated groups showed internal abnormalities in heads cross sections, while other levels showed no difference from control. Conclusion: lamotrigine in therapeutic dose can be used safely by epileptic pregnant females.

Arrested Development: Infantile Hemangioma and the Stem Cell Teratogenic Hypothesis.

Early-life programming is defined by the adaptive changes made by the fetus in response to an adverse in utero environment. Infantile hemangioma (IH), a vascular anomaly, is the most common tumor of infancy. Here we take IH as the tumor model to propose the stem cell teratogenic hypothesis of tumorigenesis and the potential involvement of the immune system. Teratogenic agents include chemicals, heavy metals, pathogens, and ionizing radiation. To investigate the etiology and pathogenesis of IH, we hypothesized that they result from a teratogenic mechanism. Immature, incompletely differentiated, dysregulated progenitor cells (multipotential stem cells) are arrested in development with vasculogenic, angiogenic, and tumorigenic potential due to exposure to teratogenic agents such as extrinsic factors that disrupt intrinsic factors via molecular mimicry. During the critical period of immunological tolerance, environmental exposure to immunotoxic agents may harness the teratogenic potential in the developing embryo or fetus and modify the early-life programming algorithm by altering normal fetal development, causing malformations, and inducing tumorigenesis. Specifically, exposure to environmental agents may interfere with physiological signaling pathways and contribute to the generation of IH, by several mechanisms. An adverse in utero environment no longer serves as a sustainable environment for proper embryogenesis and normal development. Targeted disruption of stem cells by extrinsic factors can alter the genetic program. This article offers new perspectives to stimulate discussion, explore novel experimental approaches (such as immunotoxicity/vasculotoxicity assays and novel isogenic models), and to address the questions raised to convert the hypotheses into nontoxic, noninvasive treatments.

The Molecular Mechanisms of Thalidomide Teratogenicity and Implications for Modern Medicine.

Thalidomide is a teratogen that affects many organs but primarily induces limb truncations like phocomelia. Rodents are thalidomide resistant. In the 1950s, this has led to misinterpretations of animal tests and to the fatal assumption that the drug was safe for pregnant women to use against morning sickness. The result was one of the biggest scandals in medical history: 10.000 and more infants with birth defects in Europe. Nonetheless, thalidomide still has its place in modern medicine as it has strong therapeutic potential: it has been approved by the FDA for multiple myeloma and erythema nodosum leprosum, and its anti-inflammatory, immunomodulatory and antiangiogenic activities are considered in many other refractory diseases. The aim is to develop derivatives that are not teratogenic but maintain the therapeutic potential. This requires detailed knowledge about the underlying molecular mechanisms. Much progress has been made in deciphering the teratogenic mechanisms in the last decade. Here, we summarize these mechanisms, explain thalidomide resistance of rodents, and discuss possible mechanisms that could explain why the drug primarily targets the developing limb in the embryo. We also summarize the most important therapeutic mechanisms. Finally, we discuss which therapeutic and teratogenic mechanisms do and do not overlap, and if there is a chance for the development of non-teratogenic thalidomide derivatives with therapeutic potential.

Ethanol itself is a holoprosencephaly-inducing teratogen.

Ethanol is a teratogen, inducing a variety of structural defects in developing humans and animals that are exposed in utero. Mechanisms of ethanol teratogenicity in specific defects are not well understood. Oxidative metabolism of ethanol by alcohol dehydrogenase or cytochrome P450 2E1 has been implicated in some of ethanol’s teratogenic effects, either via production of acetaldehyde or competitive inhibition of retinoic acid synthesis. Generalized oxidative stress in response to ethanol may also play a role in its teratogenicity. Among the developmental defects that ethanol has been implicated in is holoprosencephaly, a failure to define the midline of the forebrain and midface that is associated with a deficiency in Sonic hedgehog pathway function. Etiologically, holoprosencephaly is thought to arise from a complex combination of genetic and environmental factors. We have developed a gene-environment interaction model of holoprosencephaly in mice, in which mutation of the Sonic hedgehog coreceptor, Cdon, synergizes with transient in utero exposure to ethanol. This system was used to address whether oxidative metabolism is required for ethanol’s teratogenic activity in holoprosencephaly. We report here that t-butyl alcohol, which is neither a substrate nor an inhibitor of alcohol dehydrogenases or Cyp2E1, is a potent inducer of holoprosencephaly in Cdon mutant mice. Additionally, antioxidant treatment did not prevent ethanol- or t-butyl alcohol-induced HPE in these mice. These findings are consistent with the conclusion that ethanol itself, rather than a consequence of its metabolism, is a holoprosencephaly-inducing teratogen.

Teratogenic hazard of BPEI-coated silver nanoparticles to Xenopus laevis

Silver nanoparticles (AgNPs) are among the most exploited antimicrobial agents and are used in many consumer products. Size and surface reactivity are critical physico-chemical properties responsible for NPs toxicity, and surface coatings, often used to functionalize or stabilize AgNPs, can influence their toxic profile and biocompatibility. In the current study the developmental toxicity of (1) negatively charged citrate-coated AgNPs (Cit-AgNPs), (2) positively charged branched polyethylenimine-coated AgNPs (BPEI-AgNPs), and (3) Ag+ (from 0.0625 to 0.75 mg Ag/L) was investigated by the standard Frog Embryo Teratogenesis Assay – Xenopus (FETAX). In order to identify the most sensitive developmental phase, embryos were also exposed during different embryonic stages. Morphological and bio-physical studies were performed to characterize tissue lesions and NP uptake. The results suggest that Ag+ was strongly embryo-lethal. Contrary to Cit-AgNPs, the positively charged BPEI-AgNPs exert a concentration-dependent effect on lethality and malformations of embryos. The BPEI-AgNPs showed the highest teratogenic index (TI = 1.6), pointing out the role of functional coating in determining the developmental hazard. The highest susceptibility to BPEI-AgNPs was during early embryogenesis, when embryos are still enclosed in the fertilization envelope, and the post-stomodeum opening stages, when NPs ingestion occurs. In BPEI-AgNPs treated larvae, the histological examination revealed irregular intestinal diverticula coupled with edematous connective tissue. Small NPs aggregates are mapped throughout the intestinal mucosa and secondary target organs by two-photon excitation microscopy. We conclude that a teratogenic risk may be associated with BPEI-AgNPs exposure, but the modality of NP-tissue interactions and the teratogenic mechanism need further investigations to be better defined.

Hydrocephalus and arthrogryposis in an immunocompetent mouse model of ZIKA teratogeny: A developmental study.

The teratogenic mechanisms triggered by ZIKV are still obscure due to the lack of a suitable animal model. Here we present a mouse model of developmental disruption induced by ZIKV hematogenic infection. The model utilizes immunocompetent animals from wild-type FVB/NJ and C57BL/6J strains, providing a better analogy to the human condition than approaches involving immunodeficient, genetically modified animals, or direct ZIKV injection into the brain. When injected via the jugular vein into the blood of pregnant females harboring conceptuses from early gastrulation to organogenesis stages, akin to the human second and fifth week of pregnancy, ZIKV infects maternal tissues, placentas and embryos/fetuses. Early exposure to ZIKV at developmental day 5 (second week in humans) produced complex manifestations of anterior and posterior dysraphia and hydrocephalus, as well as severe malformations and delayed development in 10.5 days post-coitum (dpc) embryos. Exposure to the virus at 7.5–9.5 dpc induces intra-amniotic hemorrhage, widespread edema, and vascular rarefaction, often prominent in the cephalic region. At these stages, most affected embryos/fetuses displayed gross malformations and/or intrauterine growth restriction (IUGR), rather than isolated microcephaly. Disrupted conceptuses failed to achieve normal developmental landmarks and died in utero. Importantly, this is the only model so far to display dysraphia and hydrocephalus, the harbinger of microcephaly in humans, as well as arthrogryposis, a set of abnormal joint postures observed in the human setting. Late exposure to ZIKV at 12.5 dpc failed to produce noticeable malformations. We have thus characterized a developmental window of opportunity for ZIKV-induced teratogenesis encompassing early gastrulation, neurulation and early organogenesis stages. This should not, however, be interpreted as evidence for any safe developmental windows for ZIKV exposure. Late developmental abnormalities correlated with damage to the placenta, particularly to the labyrinthine layer, suggesting that circulatory changes are integral to the altered phenotypes.

Angiogenesis-related genes and thalidomide teratogenesis in humans: an approach on genetic variation and review of past in vitro studies

Thalidomide embryopathy (TE) has affected more than 10,000 babies worldwide. The hypothesis of antiangiogenesis as the teratogenic mechanism of thalidomide has been investigated in several experimental models; but, in humans, it has only been accessed by in vitro studies. Here, we hypothesized the effect of thalidomide upon angiogenesis-related molecules or proteins, previously identified in human embryonic cells, through the in silico STRING-tool. We also investigated ten polymorphisms in angiogenesis-related genes in 38 Brazilian TE individuals and 136 non-affected Brazilians. NOS2, PTGS2, and VEGFA polymorphisms were chosen for genotyping. The STRING-tool suggested nitric oxide and β-catenin as the central angiogenesis-related molecules affected by thalidomide’s antiangiogenic property. We did not identify a significant difference of allelic, genotypic or haplotypic frequencies between the groups. We could not predict a risk allele or a protective one for TE in NOS2, PTGS2, or VEGFA, although other genes should be analyzed in larger samples. The role of nitric oxide and β-catenin must be further evaluated, regarding thalidomide teratogenesis complex etiology.

Intrauterine valproate exposure is associated with alterations in hippocampal cell numbers and folate metabolism in a rat model of valproate teratogenicity

PurposeValproate is one of the most commonly used anticonvulsive drugs. Despite its significant benefits, the teratogenicity of valproate is a relevant problem in the treatment of women of childbearing age. In addition to major congenital malformations, such as neural tube defects, reduced intelligence and attention after intrauterine valproate exposure are reported. Until now the mechanisms of teratogenicity of VPA are poorly understood and concepts how to reduce valproate teratogenicity are lacking. MethodsIn a rat model of valproate teratogenicity we examined hippocampal cell structure in 4 week old animals with a stereological approach. As potential mechanisms of VPA teratogenicity we examined histone acetylation by western blotting and metabolites of the folate metabolism as well as global DNA methylation by tandem mass spectrometry in the brain and liver tissue of newborn pups (p0). ResultsWe found an increase in the number of neurons in the hippocampal areas CA1/2 (p=0.018) and CA3 (p=0.022), as well as a decreased number of astrocytes in CA1/2 (p=0.004) and CA3 (p=0.003) after intrauterine VPA exposure, as a possible indication of altered cell differentiation during intrauterine VPA exposure. Valproate exposure was also associated with an increase in 5-methyl-tetrahydrofolate (THF) (p=0.002) and a decrease in 5-10-methenyl-THF in the brain of newborn pups, as well as a reduced homocysteine plasma level (p<0.001). The described changes in hippocampal cell numbers and folate metabolism were only significant after high-dose intrauterine VPA exposure indicating a dose-dependent effect.VPA exposure was not associated with changes in histone acetylation or global DNA methylation in brain tissue in newborn pups. ConclusionThis study shows that intrauterine VPA exposure is associated with changes in hippocampal cell numbers in the CA1/2 and CA3 region and in folate metabolism.

Adverse effect of valproic acid on an in vitro gastrulation model entails activation of retinoic acid signaling

Valproic acid (VPA), an antiepileptic drug, is a teratogen that causes neural tube and axial skeletal defects, although the mechanisms are not fully understood. We previously established a gastrulation model using mouse P19C5 stem cell embryoid bodies (EBs), which exhibits axial patterning and elongation morphogenesis in vitro. Here, we investigated the effects of VPA on the EB axial morphogenesis to gain insights into its teratogenic mechanisms. Axial elongation and patterning of EBs were inhibited by VPA at therapeutic concentrations. VPA elevated expression levels of various developmental regulators, including Cdx1 and Hoxa1, known transcriptional targets of retinoic acid (RA) signaling. Co-treatment of EBs with VPA and BMS493, an RA receptor antagonist, partially rescued axial elongation as well as gene expression profiles. These results suggest that VPA requires active RA signaling to interfere with EB morphogenesis.

Human teratogens and genetic phenocopies. Understanding pathogenesis through human genes mutation

Exposure to teratogenic drugs during pregnancy is associated with a wide range of embryo-fetal anomalies and sometimes results in recurrent and recognizable patterns of malformations; however, the comprehension of the mechanisms underlying the pathogenesis of drug-induced birth defects is difficult, since teratogenesis is a multifactorial process which is always the result of a complex interaction between several environmental factors and the genetic background of both the mother and the fetus. Animal models have been extensively used to assess the teratogenic potential of pharmacological agents and to study their teratogenic mechanisms; however, a still open issue concerns how the information gained through animal models can be translated to humans. Instead, significant information can be obtained by the identification and analysis of human genetic syndromes characterized by clinical features overlapping with those observed in drug-induced embryopathies. Until now, genetic phenocopies have been reported for the embryopathies/fetopathies associated with prenatal exposure to warfarin, leflunomide, mycophenolate mofetil, fluconazole, thalidomide and ACE inhibitors. In most cases, genetic phenocopies are caused by mutations in genes encoding for the main targets of teratogens or for proteins belonging to the same molecular pathways. The aim of this paper is to review the proposed teratogenic mechanisms of these drugs, by the analysis of human monogenic disorders and their molecular pathogenesis.

The impact of thalidomide use in birth defects in Brazil

Although the thalidomide tragedy occurred more than 50 years ago, the medication is still being used worldwide for different reasons, and several aspects regarding its teratogenicity remain unsolved. Despite the strict regulation implemented, new cases of thalidomide embryopathy (TE) are still being registered in Brazil. Furthermore, the molecular processes that lead to malformations when the embryo is exposed to thalidomide have not yet been fully identified. In this article, we perform a critical analysis of thalidomide's history in Brazil, highlighting aspects of the occurrence of TE over the decades. Finally, we present the main perspectives and challenges for ongoing surveillance and prevention of TE in Brazil. The effective control of dispensing thalidomide, especially in areas where leprosy is endemic, is one of the most important and challenging points. Furthermore, the emergence of thalidomide analogues is fast approaching, and their availability would pose additional concerns. The understanding of the molecular mechanisms and targets of thalidomide in both experimental and human models is essential for generating new insights into teratogenic mechanisms, so that safer thalidomide analogues can be developed.

An Update on Fetal Alcohol Syndrome-Pathogenesis, Risks, and Treatment.

Alcohol is a well-established teratogen that can cause variable physical and behavioral effects on the fetus. The most severe condition in this spectrum of diseases is known as fetal alcohol syndrome (FAS). The differences in maternal and fetal enzymes, in terms of abundance and efficiency, in addition to reduced elimination, allow for alcohol to have a prolonged effect on the fetus. This can act as a teratogen through numerous methods including reactive oxygen species (generated as by products of CYP2E1), decreased endogenous antioxidant levels, mitochondrial damage, lipid peroxidation, disrupted neuronal cell-cell adhesion, placental vasoconstriction, and inhibition of cofactors required for fetal growth and development. More recently, alcohol has also been shown to have epigenetic effects. Increased fetal exposure to alcohol and sustained alcohol intake during any trimester of pregnancy is associated with an increased risk of FAS. Other risk factors include genetic influences, maternal characteristics, for example, lower socioeconomic statuses and smoking, and paternal chronic alcohol use. The treatment options for FAS have recently started to be explored although none are currently approved clinically. These include prenatal antioxidant administration food supplements, folic acid, choline, neuroactive peptides, and neurotrophic growth factors. Tackling the wider impacts of FAS, such as comorbidities, and the family system have been shown to improve the quality of life of FAS patients. This review aimed to focus on the pathogenesis, especially mechanisms of alcohol teratogenicity, and risks of developing FAS. Recent developments in potential management strategies, including prenatal interventions, are discussed.

Shared mechanism of teratogenicity of anti-angiogenic drugs identified in the chicken embryo model.

Angiogenesis, the formation of new blood vessels, is essential for tumor growth, stabilization and progression. Angiogenesis inhibitors are now widely used in the clinic; however, there are relatively few published studies on the mechanism of their presumed teratogenic effects. To address this issue, we screened a variety of angiogenesis inhibitors in developing zebrafish and chicken embryo models to assess for developmental defects and potential teratogenic effects. We confirmed previous reports that sunitinib, sorafenib and TNP-470 are teratogenic and demonstrate that axitinib, pazopanib, vandetanib, and everolimus are also teratogens in these models. A dose response study identified the drugs inhibit HUVEC cell proliferation in vitro, and also target the developing blood vessels of embryos in vivo. This provides further evidence for the potential risk of fetal toxicity when using these drugs in a clinical setting, and emphasizes the importance of the development and maintenance of the vasculature in the embryo. We conclude that angiogenesis inhibitors, regardless of the molecular target, are teratogenic when exposed to chicken embryos.

Maternal Hypertensive Disorders, Antihypertensive Medication Use, and the Risk of Birth Defects: A Case-Control Study

(BJOG. 2015;122(7):1002–1009) Both hypertensive disorders and antihypertensive medication use in early pregnancy may affect fetal development directly either through vascular dysfunction or teratogenic mechanisms. Studies have evaluated the possible link between the prevalence of specific birth defects and hypertension or its treatment. This case-control study tested hypotheses from previous studies to investigate whether defects associated with pharmacological treatment of hypertension might actually be associated with the underlying hypertension itself. Specific kinds of hypertensive disorders during different time windows during pregnancy were investigated.