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Concept: Teratology

168

Thalidomide and its analog, Lenalidomide, are in current use clinically for treatment of multiple myeloma, complications of leprosy and cancers. An additional analog, Pomalidomide, has recently been licensed for treatment of multiple myeloma, and is purported to be clinically more potent than either Thalidomide or Lenalidomide. Using a combination of zebrafish and chicken embryos together with in vitro assays we have determined the relative anti-inflammatory activity of each compound. We demonstrate that in vivo embryonic assays Pomalidomide is a significantly more potent anti-inflammatory agent than either Thalidomide or Lenalidomide. We tested the effect of Pomalidomide and Lenalidomide on angiogenesis, teratogenesis, and neurite outgrowth, known detrimental effects of Thalidomide. We found that Pomalidomide, displays a high degree of cell specificity, and has no detectable teratogenic, antiangiogenic or neurotoxic effects at potent anti-inflammatory concentrations. This is in marked contrast to Thalidomide and Lenalidomide, which had detrimental effects on blood vessels, nerves, and embryonic development at anti-inflammatory concentrations. This work has implications for Pomalidomide as a treatment for conditions Thalidomide and Lenalidomide treat currently.

Concepts: Multiple myeloma, Thalidomide, Lenalidomide, In vitro, Bortezomib, Dexamethasone, Teratology, Teratogens

24

Phthalates, compounds used to add flexibility to plastics, are ubiquitous in the environment. In particular, the diethyl (DEP), di-n-propyl (DnPP), and di-n-butyl (DBP) phthalates were found to exert detrimental effects in both mammalian and non-mammalian studies, with toxic effects varying according to alkyl chain length. Embryos of Xenopus laevis, the African clawed frog, have been used to assess toxicity and teratogenicity of several compounds and serves as a model for assessing adverse and teratogenic effects of ortho-phthalate esters. The purpose of this study was to develop a model for comparison of developmentally toxic effects of ortho-phthalate esters using Xenopus embryos. In this study developing Xenopus laevis embryos were exposed to increasing concentrations of DEP, DnPP, and DBP using the 96-h Frog Embryo Teratogenesis Assay-Xenopus (FETAX), with 96-h lethal concentrations, effective concentrations to induce malformations, teratogenic indices, and concentrations to inhibit growth determined. DEP, DnPP, and DBP showed enhanced toxicity with increasing ester length. Developing Xenopus laevis exposed to DEP, DnPP, and DBP showed similar malformations that also occurred at lower concentrations with increasing alkyl chain length. Teratogenic risk did not change markedly with alkyl chain length, with data showing only DBP to be teratogenic.

Concepts: Embryo, Developmental biology, Phthalates, Phthalate, Model organisms, Pipidae, Teratology, African clawed frog

13

A European League Against Rheumatism (EULAR) task force was established to define points to consider on use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Based on a systematic literature review and pregnancy exposure data from several registries, statements on the compatibility of antirheumatic drugs during pregnancy and lactation were developed. The level of agreement among experts in regard to statements and propositions of use in clinical practice was established by Delphi voting. The task force defined 4 overarching principles and 11 points to consider for use of antirheumatic drugs during pregnancy and lactation. Compatibility with pregnancy and lactation was found for antimalarials, sulfasalazine, azathioprine, ciclosporin, tacrolimus, colchicine, intravenous immunoglobulin and glucocorticoids. Methotrexate, mycophenolate mofetil and cyclophosphamide require discontinuation before conception due to proven teratogenicity. Insufficient documentation in regard to fetal safety implies the discontinuation of leflunomide, tofacitinib as well as abatacept, rituximab, belimumab, tocilizumab, ustekinumab and anakinra before a planned pregnancy. Among biologics tumour necrosis factor inhibitors are best studied and appear reasonably safe with first and second trimester use. Restrictions in use apply for the few proven teratogenic drugs and the large proportion of medications for which insufficient safety data for the fetus/child are available. Effective drug treatment of active inflammatory rheumatic disease is possible with reasonable safety for the fetus/child during pregnancy and lactation. The dissemination of the data to health professionals and patients as well as their implementation into clinical practice may help to improve the management of pregnant and lactating patients with rheumatic disease.

Concepts: Pregnancy, Rheumatoid arthritis, Rheumatology, Rheumatism, Immunosuppressants, Mycophenolic acid, Disease-modifying antirheumatic drug, Teratology

6

Immunomodulatory drugs (IMiDs), such as thalidomide and its derivatives lenalidomide and pomalidomide, are key treatment modalities for hematologic malignancies, particularly multiple myeloma (MM) and del(5q) myelodysplastic syndrome (MDS). Cereblon (CRBN), a substrate receptor of the CRL4 ubiquitin ligase complex, is the primary target by which IMiDs mediate anticancer and teratogenic effects. Here we identify a ubiquitin-independent physiological chaperone-like function of CRBN that promotes maturation of the basigin (BSG; also known as CD147) and solute carrier family 16 member 1 (SLC16A1; also known as MCT1) proteins. This process allows for the formation and activation of the CD147-MCT1 transmembrane complex, which promotes various biological functions, including angiogenesis, proliferation, invasion and lactate export. We found that IMiDs outcompete CRBN for binding to CD147 and MCT1, leading to destabilization of the CD147-MCT1 complex. Accordingly, IMiD-sensitive MM cells lose CD147 and MCT1 expression after being exposed to IMiDs, whereas IMiD-resistant cells retain their expression. Furthermore, del(5q) MDS cells have elevated CD147 expression, which is attenuated after IMiD treatment. Finally, we show that BSG (CD147) knockdown phenocopies the teratogenic effects of thalidomide exposure in zebrafish. These findings provide a common mechanistic framework to explain both the teratogenic and pleiotropic antitumor effects of IMiDs.

Concepts: Protein, Multiple myeloma, Thalidomide, Lenalidomide, Hematology, Proteasome, Virtual Karyotype, Teratology

6

Unintended exposure to teratogenic compounds can lead to various birth defects; however current animal-based testing is limited by time, cost and high inter-species variability. Here, we developed a human-relevant in vitro model, which recapitulated two cellular events characteristic of embryogenesis, to identify potentially teratogenic compounds. We spatially directed mesoendoderm differentiation, epithelial-mesenchymal transition and the ensuing cell migration in micropatterned human pluripotent stem cell (hPSC) colonies to collectively form an annular mesoendoderm pattern. Teratogens could disrupt the two cellular processes to alter the morphology of the mesoendoderm pattern. Image processing and statistical algorithms were developed to quantify and classify the compounds' teratogenic potential. We not only could measure dose-dependent effects but also correctly classify species-specific drug (Thalidomide) and false negative drug (D-penicillamine) in the conventional mouse embryonic stem cell test. This model offers a scalable screening platform to mitigate the risks of teratogen exposures in human.

Concepts: Developmental biology, Stem cell, Thalidomide, Cellular differentiation, Embryonic stem cell, Induced pluripotent stem cell, Teratology, Teratogens

2

Interferon Beta (IFNβ) was the first proven drug for the treatment of Multiple Sclerosis (MS). The diagnosis of MS frequently occurs in women at childbearing age (especially in twenties and thirties). Therefore, the pregnancy process is major concern for many women with MS. Data on women exposed to IFNβ during pregnancy are limited. The aim of our study was to investigate the teratogenic potential of IFNβ on embryonic development via embryo culture technique. Recently, this technique has been often used for determined teratogenic effect of pharmacologic drugs and potential teratogens on embryonic development.

Concepts: Multiple sclerosis, Teratology

2

Rates of adult women receiving contraceptive provision when simultaneously prescribed a known teratogen are alarmingly low. The prevalence of this behavior among pediatric providers and their adolescent patients is unknown. The objective of this study was to describe pediatric provider behaviors for prescribing teratogens concurrently with counseling, referral, and/or prescribing of contraception (collectively called contraceptive provision) in the adolescent population.

Concepts: Teratology, Teratogens

1

A combination of ethinylestradiol and 10mg norethisterone under the brand names of Duogynon (Germany) or Primodos (UK) was used as a pregnancy test until the 1970s. Until very recently there was continuing public concern about the safety of these drugs and legal proceedings were instituted against the medicinal authorization holder. Given the lack of epidemiological studies focusing on Duogynon/Primodos, the present study evaluates 296 consumer reports of the German Duogynon database and compares the reported birth defects with data from a population based birth registry. The most striking result is an increase of bladder exstrophy (OR=37.27; 95%-CI 14.56-95.28). Neural tube defects (OR=2.99; 95%-CI 1.85-4.84) and renal agenesis (OR=2.53; 95%-CI 1.17-5.45) were also significantly increased. Bladder exstrophy may be a yet undetected teratogenic effect of Duogynon, but may also represent a reporting bias. The present study highlights the difficulties of evaluating consumer reports which may be influenced by public media.

Concepts: Kidney, Developmental biology, Urology, Obstetrics, Report, Pregnancy test, Congenital, Teratology

0

The aim of this research is to investigate the teratogenic effects of chitosan oligosaccharide in Wistar female rats (Rattus norvegicus). Chitosan LD50 value was calculated by probit analysis. High dose, 1/10 LD50 which equal to 150 mg/kg body weight, and low dose, 1/30 LD50 which equal to 50 mg/kg body weight, were administrated orally to Wistar female rats to examine the teratogenic effect during organogenesis period from 6th day to 15th day of gestation. Treated and control rats were sacrificed and their foetuses were examined for external, skeletal and visceral anomalies, number and length of foetuses and their weights. Obtained results showed toxicity and teratogenic effects of chitosan on treated rats and their progenies, i.e. high fetal mortality, offspring’s weight and length reduction, and high incidence of fetal external, skeletal and visceral abnormalities. This suggested that chitosan is a teratogenic compound, restricted to current results from orally treated Wistar rats.

Concepts: Embryo, Developmental biology, Rat, Cat, Laboratory rat, Brown rat, Perinatal mortality, Teratology

0

Glyphosate is the active ingredient in broad-spectrum herbicide formulations used in agriculture, domestic area and aquatic weed control worldwide. Its market is growing steadily concurrently with the cultivation of glyphosate-tolerant transgenic crops and emergence of weeds less sensitive to glyphosate. Ephemeral and lentic waters near to agricultural lands, representing favorite habitats for amphibian reproduction and early life-stage development, may thus be contaminated by glyphosate based herbicides (GBHs) residues. Previous studies on larval anuran species highlighted increased mortality and growth effects after exposure to different GBHs in comparison to glyphosate itself, mainly because of the surfactants such as polyethoxylated tallow amine present in the formulations. Nevertheless, these conclusions are not completely fulfilled when the early development, characterized by primary organogenesis events, is considered. In this study, we compare the embryotoxicity of Roundup® Power 2.0, a new GBH formulation currently authorized in Italy, with that of technical grade glyphosate using the Frog Embryo Teratogenesis Assay-Xenopus (FETAX). Our results evidenced that glyphosate was not embryolethal and only at the highest concentration (50 mg a.e./L) caused edemas. Conversely, Roundup® Power 2.0 exhibited a 96 h LC50 of 24.78 mg a.e./L and a 96 h EC50 of 7.8 mg a.e./L. A Teratogenic Index of 3.4 was derived, pointing out the high teratogenic potential of the Roundup® Power 2.0. Specific concentration-dependent abnormal phenotypes, such as craniofacial alterations, microphthalmia, narrow eyes and forebrain regionalization defects were evidenced by gross malformation screening and histopathological analysis. These phenotypes are coherent with those evidenced in Xenopus laevis embryos injected with glyphosate, allowing us to hypothesize that the teratogenicity observed for Roundup® Power 2.0 may be related to the improved efficacy in delivering glyphosate to cells, guaranteed by the specific surfactant formulation. In conclusion, the differences in GBH formulations should be carefully considered by the authorities, since sub-lethal and/or long-term effects (e.g. teratogenicity) can be significantly modulated by the active ingredient salt type and concentration of the adjuvants. Finally, the mechanistic toxicity of glyphosate and GBHs are worthy of further research.

Concepts: Agriculture, Developmental biology, Surfactant, Frog, Herbicide, Roundup, Teratology, Polyethoxylated tallow amine