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Birth Defects Research. Part C, Embryo... Jun 2015Nearly 60 years ago thalidomide was prescribed to treat morning sickness in pregnant women. What followed was the biggest man-made medical disaster ever, where over... (Review)
Review
Nearly 60 years ago thalidomide was prescribed to treat morning sickness in pregnant women. What followed was the biggest man-made medical disaster ever, where over 10,000 children were born with a range of severe and debilitating malformations. Despite this, the drug is now used successfully to treat a range of adult conditions, including multiple myeloma and complications of leprosy. Tragically, a new generation of thalidomide damaged children has been identified in Brazil. Yet, how thalidomide caused its devastating effects in the forming embryo remains unclear. However, studies in the past few years have greatly enhanced our understanding of the molecular mechanisms the drug. This review will look at the history of the drug, and the range and type of damage the drug caused, and outline the mechanisms of action the drug uses including recent molecular advances and new findings. Some of the remaining challenges facing thalidomide biologists are also discussed.
Topics: Abnormalities, Drug-Induced; Adult; Animals; Female; History, 20th Century; History, 21st Century; Humans; Male; Pregnancy; Teratogenesis; Teratogens; Thalidomide
PubMed: 26043938
DOI: 10.1002/bdrc.21096 -
Science (New York, N.Y.) Jan 2014Thalidomide-like drugs such as lenalidomide are clinically important treatments for multiple myeloma and show promise for other B cell malignancies. The biochemical...
Thalidomide-like drugs such as lenalidomide are clinically important treatments for multiple myeloma and show promise for other B cell malignancies. The biochemical mechanisms underlying their antitumor activity are unknown. Thalidomide was recently shown to bind to, and inhibit, the cereblon ubiquitin ligase. Cereblon loss in zebrafish causes fin defects reminiscent of the limb defects seen in children exposed to thalidomide in utero. Here we show that lenalidomide-bound cereblon acquires the ability to target for proteasomal degradation two specific B cell transcription factors, Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3). Analysis of myeloma cell lines revealed that loss of IKZF1 and IKZF3 is both necessary and sufficient for lenalidomide's therapeutic effect, suggesting that the antitumor and teratogenic activities of thalidomide-like drugs are dissociable.
Topics: Adaptor Proteins, Signal Transducing; Antineoplastic Agents; Cell Line, Tumor; HEK293 Cells; Humans; Ikaros Transcription Factor; Lenalidomide; Multiple Myeloma; Peptide Hydrolases; Proteolysis; Teratogens; Thalidomide; Ubiquitin-Protein Ligases
PubMed: 24292623
DOI: 10.1126/science.1244917 -
International Journal of Molecular... Aug 2021Prenatal alcohol exposure (PAE) can have immediate and long-lasting toxic and teratogenic effects on an individual's development and health. As a toxicant, alcohol can... (Review)
Review
Prenatal alcohol exposure (PAE) can have immediate and long-lasting toxic and teratogenic effects on an individual's development and health. As a toxicant, alcohol can lead to a variety of physical and neurological anomalies in the fetus that can lead to behavioral and other impairments which may last a lifetime. Recent studies have focused on identifying mechanisms that mediate the immediate teratogenic effects of alcohol on fetal development and mechanisms that facilitate the persistent toxic effects of alcohol on health and predisposition to disease later in life. This review focuses on the contribution of epigenetic modifications and intercellular transporters like extracellular vesicles to the toxicity of PAE and to immediate and long-term consequences on an individual's health and risk of disease.
Topics: Adolescent; Adolescent Development; Adult; Epigenesis, Genetic; Ethanol; Extracellular Vesicles; Female; Fetal Development; Gene Expression Regulation; Humans; Pregnancy; Prenatal Exposure Delayed Effects; Teratogenesis
PubMed: 34445488
DOI: 10.3390/ijms22168785 -
Epileptic Disorders : International... Aug 2020Special considerations are required for women with epilepsy. These include issues such as catamenial exacerbation, concerns for contraception, teratogenesis (including...
Special considerations are required for women with epilepsy. These include issues such as catamenial exacerbation, concerns for contraception, teratogenesis (including both anatomical and neurodevelopmental effects), and other concerns for pregnancy complications such as increased seizures or adverse obstetric outcomes. In this manuscript, several cases are presented and discussed addressing some of the important issues in the management of women with epilepsy.
Topics: Adult; Anticonvulsants; Epilepsy; Female; Humans; Pregnancy; Pregnancy Complications; Teratogens; Women; Young Adult
PubMed: 32723702
DOI: 10.1684/epd.2020.1173 -
Birth Defects Research. Part C, Embryo... Dec 2011Congenital heart disease (CHD) is a highly prevalent problem with mostly unknown origins. Many cases of CHD likely involve an environmental exposure coupled with genetic... (Review)
Review
Congenital heart disease (CHD) is a highly prevalent problem with mostly unknown origins. Many cases of CHD likely involve an environmental exposure coupled with genetic susceptibility, but practical and ethical considerations make nongenetic causes of CHD difficult to assess in humans. The development of the heart is highly conserved across all vertebrate species, making animal models an excellent option for screening potential cardiac teratogens. This review will discuss exposures known to cause cardiac defects, stages of heart development that are most sensitive to teratogen exposure, benefits and limitations of animal models of cardiac development, and future considerations for cardiac developmental toxicity research.
Topics: Animals; Disease Models, Animal; Heart; Heart Defects, Congenital; Humans; Mice; Teratogens
PubMed: 22271678
DOI: 10.1002/bdrc.20219 -
Therapeutic Delivery Jan 2019
Topics: Clinical Trials, Phase I as Topic; Humans; Myeloid-Derived Suppressor Cells; Neoplasms; Receptors, Peptide; Teratogens; Toxins, Biological; Treatment Outcome; alpha-Fetoproteins
PubMed: 30730821
DOI: 10.4155/tde-2018-0068 -
Continuum (Minneapolis, Minn.) Feb 2016Caring for a woman with epilepsy requires familiarity with the implications of antiepileptic drugs (AEDs) for pregnancy and contraception as well as an understanding of... (Review)
Review
PURPOSE OF REVIEW
Caring for a woman with epilepsy requires familiarity with the implications of antiepileptic drugs (AEDs) for pregnancy and contraception as well as an understanding of the effects of female hormones on epilepsy.
RECENT FINDINGS
AED pregnancy registries and prospective studies of cognitive development continue to confirm that valproate poses a significantly increased risk of structural and cognitive teratogenesis. In contrast, data thus far suggest that lamotrigine and levetiracetam are associated with a relatively low risk for both anatomic and developmental adverse effects, although further studies are needed for these and other AEDs. The intrauterine device is a good contraceptive option for many women with epilepsy as it is highly effective and not subject to the drug-drug interactions seen between hormonal contraception and many AEDs. Hormonal-sensitive seizures are common among women with epilepsy; however, highly effective treatments for refractory catamenial seizures are limited.
SUMMARY
Women with epilepsy should be counseled early and regularly about reproductive health as it relates to epilepsy. AED selection for women of childbearing age should take future pregnancies and contraceptive needs into consideration.
Topics: Adult; Anticonvulsants; Disease Management; Epilepsy; Female; Humans; Pregnancy; Pregnancy Complications; Teratogenesis; Vitamins
PubMed: 26844738
DOI: 10.1212/CON.0000000000000270 -
Canadian Medical Association Journal Sep 1962The probability that a teratogen, applied to a pregnant mammal, will produce malformations in the embryo depends on the agent, the dose, the species, the genetic...
The probability that a teratogen, applied to a pregnant mammal, will produce malformations in the embryo depends on the agent, the dose, the species, the genetic constitution of mother and embryo, and the developmental stage of the embryo. Several drugs (including salicylates and antibiotics) now being used in medical practice are teratogenic in experimental animals, some at doses comparable, on a body-weight basis, to those used therapeutically. Demonstration of teratogenicity in experimental animals can serve as a warning of possible teratogenic effects in man, and as a guide to the types of malformations the drug might produce, but failure to demonstrate teratogenic effects experimentally does not prove the drug's harmlessness to the human embryo. If thalidomide had produced only common malformations, such as cleft lip, its teratogenic nature might still be unrecognized. The final test must be careful follow-up of babies born to mothers who have taken the drug in question.
Topics: Animals; Animals, Laboratory; Cleft Lip; Congenital Abnormalities; Drug Therapy; Female; Humans; Infant; Male; Parturition; Pregnancy; Teratogenesis; Teratogens
PubMed: 13894748
DOI: No ID Found -
Integrative Biology : Quantitative... Sep 2018Birth defects are a common occurrence in the United States and worldwide. Currently, evaluation of potential developmental toxicants (i.e., teratogens) relies heavily on... (Review)
Review
Birth defects are a common occurrence in the United States and worldwide. Currently, evaluation of potential developmental toxicants (i.e., teratogens) relies heavily on animal-based models which do not always adequately mimic human development. In order to address this, researchers are developing in vitro human-based models which utilize human pluripotent stem cells (hPSCs) to assess the teratogenic potential of chemical substances. The field of human developmental toxicity assays includes a variety of platforms including monolayer, micropattern, embryoid body, and 3D organoid cultures. In this review, we will overview the field of human teratogenic assays, detail the most recent advances, and discuss current limitations and future perspectives.
Topics: Animals; Cell Differentiation; Cell Movement; Cell Proliferation; Embryo Culture Techniques; Embryoid Bodies; Embryonic Stem Cells; Gene Expression Regulation; Humans; Pluripotent Stem Cells; Teratogens; Toxicity Tests
PubMed: 30095839
DOI: 10.1039/c8ib00082d -
Reproductive Toxicology (Elmsford, N.Y.) Apr 2010
Topics: Abnormalities, Drug-Induced; Animals; Drug-Related Side Effects and Adverse Reactions; Embryo Culture Techniques; Embryo Loss; Embryo, Mammalian; Pharmaceutical Preparations; Reproduction; Teratogens; Terminology as Topic; Toxicity Tests
PubMed: 19958827
DOI: 10.1016/j.reprotox.2009.11.010