Recent research efforts in endocrine disruption have focused on evaluating non-EATS (estrogen, androgen, thyroid, and steroidogenesis) pathways. Retinoid signaling disruption is noteworthy because of its teratogenic effects and environmental relevance. However, current environmental risk assessments are limited in their ability to evaluate impacts on individuals and populations. This study characterizes an Adverse Outcome Pathway (AOP) network linking retinoid signaling disruption to teratogenicity and survival in zebrafish. We identified Retinoic Acid Receptor (RAR) overactivation as the molecular initiating event leading to key events including craniofacial (CFM) and tail (TM) malformations, posterior swim bladder (SB) non-inflation, impaired swimming performance, and reduced feeding, ultimately resulting in decreased survival. Our study (1) determines critical sensitivity windows for CFM, posterior SB non-inflation, and TM, (2) provides quantitative measurements for CFM and TM, and (3) defines impacts on higher biological levels including food ingestion, swimming, and survival. Results show that all-trans retinoic acid (ATRA) induces strong teratogenic effects with sensitivity windows between 4 and 48 h post fertilization (hpf) for CFM, TM, and posterior SB non-inflation. TM is the most sensitive indicator, with EC50 of 0.2 - 0.26 µg/L across exposure windows 4-48, 4-72, 4-96, and 4-120 hpf. Besides inducing known malformations, ATRA impaired posterior SB inflation with EC50 of 1 - 1.21 µg/L across the same exposure windows. ATRA exposure (1 µg/L) resulted in 50 % food ingestion inhibition at 7 days post fertilization (dpf) and 10 % survival at 14 dpf. This study provides a regulatory-relevant framework linking developmental effects to population outcomes, highlighting ecological risks and needs for improved risk assessments.

• Klíčová slova
• Adverse outcome pathway, Behavior toxicity, Developmental toxicity, Endocrine disruption, Retinoic acid, Retinoids, Survival/mortality, Teratogenicity,
• MeSH
• chemické látky znečišťující vodu * toxicita   MeSH
• dánio pruhované * MeSH
• dráhy škodlivých účinků * MeSH
• embryo nesavčí * účinky léků   MeSH
• receptory kyseliny retinové metabolismus   genetika   MeSH
• retinoidy metabolismus   MeSH
• signální transdukce * účinky léků   MeSH
• teratogeny * toxicita   MeSH
• tretinoin * metabolismus   toxicita   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• chemické látky znečišťující vodu * MeSH
• receptory kyseliny retinové MeSH
• retinoidy MeSH
• teratogeny * MeSH
• tretinoin * MeSH

Although information about the occurrence and distribution of retinoids in the environment is scarce, cyanobacterial water blooms have been identified as a significant source of these small molecules. Despite the confirmed presence of retinoids in the freshwater blooms dominated by cyanobacteria and their described teratogenic effects, reliable identification of retinoid producers and the mechanism of their biosynthesis is missing. In this study, the cultures of several taxonomically diverse species of axenic cyanobacteria were confirmed as significant producers of retinoid-like compounds. The consequent bioinformatic analysis suggested that the enzymatic background required for the biosynthesis of all-trans retinoic acid from retinal is not present across phylum Cyanobacteria. However, we demonstrated that retinal conversion into other retinoids can be mediated non-enzymatically by free radical oxidation, which leads to the production of retinoids widely detected in cyanobacteria and environmental water blooms, such as all-trans retinoic acid or all-trans 5,6epoxy retinoic acid. Importantly, the production of these metabolites by cyanobacteria in association with the mass development of water blooms can lead to adverse impacts in aquatic ecosystems regarding the described teratogenicity of retinoids. Moreover, our finding that retinal can be non-enzymatically converted into more bioactive retinoids, also in water, and out of the cells, increases the environmental significance of this process.

• Klíčová slova
• aldehyde dehydrogenases, biosynthesis, cyanobacteria, reactive oxygen species, retinoids,
• MeSH
• ekosystém MeSH
• retinoidy analýza   metabolismus   toxicita   MeSH
• sinice * metabolismus   MeSH
• teratogeny * toxicita   MeSH
• tretinoin toxicita   MeSH
• voda metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• retinoidy MeSH
• teratogeny * MeSH
• tretinoin MeSH
• voda MeSH

Retinoids are newly detected compounds in aquatic ecosystems associated with cyanobacterial water blooms. Their potential health risks are only scarcely described despite numerous detections of all-trans retinoic acid (ATRA) and its derivatives in the environment. Besides the known teratogen ATRA there is only little or no information about their potency and namely their effects in vivo. We characterize ATRA and 8 other retinoids reported to occur in the environment for their bioactivity and teratogenicity using four in vitro reporter gene assays and zebrafish (Danio rerio) embryotoxicity assay. Our results document the ability of these compounds to interfere with retinoid signalling and cause teratogenicity at environmentally relevant levels with EC50 values at nM (hundreds of ng/L) levels and teratogenic indexes ranging from 2.8 (9cis retinoic acid) to 15.8 (retinal). The relative potency of individual compounds for teratogenicity ranged from 0.059 (retinal) to 0.96 (5,6-epoxy ATRA) when compared to ATRA. An environmentally relevant mixture of retinoids was tested showing good predictability of teratogenicity from the in vitro activities and additive toxicity of the mixture. The high teratogenicity of the newly described compounds associated with cyanobacteria presents a concern for developmental stages due to high conservation of the retinoid signalling across vertebrates.

• Klíčová slova
• In vitro, RAR, Retinoids, Teratogenicity, Zebrafish,
• MeSH
• chemické látky znečišťující vodu * toxicita   MeSH
• dánio pruhované genetika   MeSH
• ekosystém MeSH
• Microcystis * MeSH
• retinoidy toxicita   MeSH
• sinice * MeSH
• teratogeny toxicita   MeSH
• tretinoin toxicita   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• chemické látky znečišťující vodu * MeSH
• retinoidy MeSH
• teratogeny MeSH
• tretinoin MeSH

Phenytoin is a long-standing, anti-seizure drug widely used in clinical practice. It has also been evaluated in the context of many other illnesses in addition to its original epilepsy indication. The narrow therapeutic index of phenytoin and its ubiquitous daily use pose a high risk of poisoning. This review article focuses on the chemistry, pharmacokinetics, and toxicology of phenytoin, with a special focus on its mutagenicity, carcinogenicity, and teratogenicity. The side effects on human health associated with phenytoin use are thoroughly described. In particular, DRESS syndrome and cerebellar atrophy are addressed. This review will help in further understanding the benefits phenytoin use in the treatment of epilepsy.

• Klíčová slova
• Cerebellar atrophy, DRESS syndrome, Pharmacokinetics, Phenytoin, Side effect, Toxicity,
• MeSH
• antikonvulziva chemie   farmakologie   toxicita   MeSH
• fenytoin chemie   farmakologie   toxicita   MeSH
• lidé MeSH
• teratogeny toxicita   MeSH
• testy genotoxicity MeSH
• testy karcinogenity MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antikonvulziva MeSH
• fenytoin MeSH
• teratogeny MeSH

Cyanobacteria routinely release potentially harmful bioactive compounds into the aquatic environment. Several recent studies suggested a potential link between the teratogenicity of effects caused by cyanobacteria and production of retinoids. To investigate this relationship, we analysed the teratogenicity of field-collected cyanobacterial bloom samples by means of an in vivo zebrafish embryo test, an in vitro reporter gene bioassay and by the chemical analysis of retinoids. Extracts of biomass from cyanobacterial blooms with the dominance of Microcystis aeruginosa and Aphanizomenon klebahnii were collected from water bodies in the Czech Republic and showed significant retinoid-like activity in vitro, as well as high degrees of teratogenicity in vivo. Chemical analysis was then used to identify a set of retinoids in ng per gram of dry weight concentration range. Subsequent fractionation and bioassay-based characterization identified two fractions with significant in vitro retinoid-like activity. Moreover, in most of the retinoids eluted from these fractions, teratogenicity with malformations typical for retinoid signalling disruption was observed in zebrafish embryos after exposure to the total extracts and these in vitro effective fractions. The zebrafish embryo test proved to be a sensitive toxicity indicator of the biomass extracts, as the teratogenic effects occurred at even lower concentrations than those expected from the activity detected in vitro. In fact, teratogenicity with retinoid-like activity was detected at concentrations that are commonly found in biomasses and even in bulk water surrounding cyanobacterial blooms. Overall, these results provide evidence of a link between retinoid-like activity, teratogenicity and the retinoids produced by cyanobacterial water blooms in the surrounding environment.

• Klíčová slova
• All-trans retinoic acid, Cyanobacteria, Retinoid-like activity, Retinoids, Teratogenicity, Zebrafish,
• MeSH
• Aphanizomenon patogenita   MeSH
• dánio pruhované embryologie   genetika   MeSH
• embryo nesavčí účinky léků   MeSH
• Microcystis patogenita   MeSH
• reportérové geny MeSH
• retinoidy biosyntéza   toxicita   MeSH
• sinice chemie   patogenita   MeSH
• teratogeny toxicita   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• retinoidy MeSH
• teratogeny MeSH

Glycodendrimers (Glyco-DDMs) represent a rapidly growing class of nanoparticles with promising properties for biomedical applications but concerns regarding the impact on human health and environment are still justified. Here we report, for the first time, the comparative study of in vivo developmental toxicity of carbosilane Glyco-DDMs and their cytotoxicity in vitro. Carbosilane Glyco-DDMs (generation 1-3) containing 4, 8, and 16 β-d-glucopyranosyl units at the periphery (DDM1Glu, DDM2Glu, and DDM3Glu) were synthesized and characterized by 1H, 13C and 29Si NMR, mass spectrometry, dynamic light scattering, atomic force microscopy (AFM), and computer modeling. In vitro cytotoxicity assay (MTT) of DDM1-3Glu was performed on three different rodent cell lines (Cricetulus griseus) - B14 (ATCC, CCL-14.1), BRL 3A (ATCC, CRL-1442), and NRK 52E (ATCC, CRL-1571). Overall, very low cytotoxicity was observed with calculated IC50 in mM range with slight difference between each cell line and DDM generation investigated. Modified fish embryo test (FET) was further used for DDM3Glu developmental toxicity testing on zebrafish (Danio rerio) embryos. While seemingly harmless to intact embryos, adverse effects of DDMs on the embryonic development become evident after chorion removal (LD50=2.78 µM at 96 hpe). We summarized that the modified FET test showed a two to three orders of magnitude difference between the in vitro cytotoxicity and in vivo developmental toxicity of DDM3Glu. While, in general, the Glyco-DDMs show great promises as efficient vectors in targeted drug delivery or as therapeutic molecules itself, we suggest that their developmental toxicity should be thoroughly investigated to exclude safety risks associated with their potential biomedical use.

• Klíčová slova
• Carbosilane dendrimers, glycodendrimers, molecular modeling, teratogenicity, toxicity, zebrafish,
• MeSH
• buněčné linie MeSH
• Cricetulus MeSH
• dánio pruhované * embryologie   MeSH
• dendrimery chemie   toxicita   MeSH
• embryo nesavčí účinky léků   MeSH
• embryonální vývoj účinky léků   MeSH
• glukosa chemie   MeSH
• LD50 MeSH
• lidé MeSH
• molekulární modely MeSH
• povrchové vlastnosti MeSH
• silany chemie   toxicita   MeSH
• teratogeny chemie   toxicita   MeSH
• testy toxicity MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• carbosilane MeSH Prohlížeč
• dendrimery MeSH
• glukosa MeSH
• silany MeSH
• teratogeny MeSH

Deoxynivalenol (DON) is a toxic fungal secondary metabolite produced by molds of the Fusarium genus, and it is known to cause a spectrum of diseases both in humans and animals, such as emesis, diarrhea, anorexia, immunotoxicity, hematological disorders, impairment of maternal reproduction, and fetal development. The recently revealed teratogenic potential of DON has received much attention. In various animal models, it has been shown that DON led to skeletal deformities of the fetus. However, the underlying mechanisms are not yet fully understood, and toxicological data are also scarce. Several animal research studies highlight the potential link between morphological abnormalities and changes of autophagy in the reproductive system. Because autophagy is involved in fetal development, maintenance of placental function, and bone remodeling, this mechanism has become a high priority for future research. The general aim of the present review is to deliver a comprehensive overview of the current state of knowledge of DON-induced reproductive toxicity in different animal models and to provide some prospective ideas for further research. The focus of the current review is to summarize toxic and negative effects of DON exposure on the reproductive system and the potential underlying molecular mechanisms in various animal models.

• Klíčová slova
• Autophagy, Deoxynivalenol, Fetal development, Oxidative stress, Reproductive toxicity,
• MeSH
• autofagie účinky léků   MeSH
• lidé MeSH
• plod abnormality   účinky léků   MeSH
• pohlavní orgány účinky léků   MeSH
• teratogeny toxicita   MeSH
• trichotheceny toxicita   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• deoxynivalenol MeSH Prohlížeč
• teratogeny MeSH
• trichotheceny MeSH

Teratogenic effects, which were remarkably similar to those induced by retinoic acids, have been seen in wild frogs indicating possible source of retinoids in the environment. Recent studies indicate that some cyanobacterial species can contain teratogenic retinoic acids (RAs) and their analogues. Retinoids are known to regulate important processes such as differentiation, development, and embryogenesis. The study investigated the effects of exudates (extracellular compounds) of two cyanobacteria species with retinoic-like activity and one algae species on embryonic development of amphibians. The retinoid-like activity determined by in vitro reporter gene assay reached 528ng retinoid equivalents (REQ)/L and 1000ng REQ/L in exudates of Cylindrospermopsis raciborskii and Microcystis aeruginosa, respectively, while algal exudates showed no detectable activity. Total mean of retinoid-like copounds into exudate was 35.6ng ATRA/mil.cells for M.aeruginosa and 6.71ng ATRA/mil.cells for C.raciborskii, respectively. Toxicity tests with amphibian embryos up to 96h of development were carried out according to the standard guide for the Frog Embryo Teratogenesis Assay Xenopus. Lowest observed effect concentrations (LOEC) of malformations (2.5-2.6µg/L REQ) were two times lower than LOEC for ATRA (5µg/L). The exudates of both cyanobacteria were indeed provoking diverse teratogenic effects (e.g. tail, gut and eyes deformation) and interference with growth in frogs embryos, while such effects were not observed for the algae. Xenopus embryos were also exposed to all-trans retinoic acid (ATRA) in concentration range (1-40µg/L) equivalent to the REQs detected in cyanobacterial exudates. ATRA (10µg/L) caused similar teratogenic phenotypes at corresponding REQs as cyanobacterial exudates. The study confirms the ability of some species of cyanobacteria to produce retinoids naturally and excrete them directly into the environment at concentrations which might have adverse influence on the development of amphibians.

• Klíčová slova
• All-trans retinoic acid, Cyanobacterial exudates, Embryonic development, Retinoid-like activity, Retinoids, Xenopus laevis,
• MeSH
• biotest MeSH
• chemické látky znečišťující vodu toxicita   MeSH
• embryonální vývoj účinky léků   MeSH
• fytoplankton metabolismus   MeSH
• Microcystis účinky léků   MeSH
• reportérové geny účinky léků   MeSH
• sinice metabolismus   MeSH
• teratogeny toxicita   MeSH
• tretinoin metabolismus   toxicita   MeSH
• Xenopus laevis embryologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• chemické látky znečišťující vodu MeSH
• teratogeny MeSH
• tretinoin MeSH

In recent years, the environmental presence of pharmaceuticals - including anticancer drugs - is an emerging issue. Because of the lack of appropriate critical studies about anticancer drug effects in frogs, the aim of the present study was to investigate lethal and teratogenic effects of five anticancer drugs widely used in large quantities, i.e. 5-flourouracil, capecitabine, cisplatin, etoposide, and imatinib, in the embryos of the South African clawed frog, Xenopus laevis, using FETAX - Frog Embryo Teratogenesis Assay in Xenopus. None of the studied anticancer drugs induced statistically significant mortality within the concentrations tested (0.01-50mg/L, depending on the studied compound), and no growth inhibition of embryos after a 96-h exposure was observed. Except for cisplatin, the other pharmaceuticals induced an increase of developmental malformations such as abdominal edema, axial flexure, head, eyes, gut and heart malformations with statistically significant effects observed at the highest concentrations tested (50mg/L for 5-flourouracil; 30mg/L for etoposide and 20mg/L for capecitabine and imatinib). The results indicate that anticancer drugs can affect embryogenesis mechanisms.

• Klíčová slova
• Anticancer drugs, FETAX, Teratogenicity, Xenopus laevis,
• MeSH
• abnormality vyvolané léky etiologie   MeSH
• antitumorózní látky toxicita   MeSH
• biotest MeSH
• capecitabinum toxicita   MeSH
• cisplatina toxicita   MeSH
• embryo nesavčí účinky léků   MeSH
• embryonální vývoj účinky léků   MeSH
• etoposid toxicita   MeSH
• fluorouracil toxicita   MeSH
• imatinib mesylát toxicita   MeSH
• teratogeny toxicita   MeSH
• testy toxicity MeSH
• Xenopus laevis embryologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antitumorózní látky MeSH
• capecitabinum MeSH
• cisplatina MeSH
• etoposid MeSH
• fluorouracil MeSH
• imatinib mesylát MeSH
• teratogeny MeSH

Cyanobacteria contain various types of bioactive compounds, which could cause adverse effects on organisms. They are released into surface waters during cyanobacterial blooms, but there is little information on their potential relevance for effects in vivo. In this study presence of bioactive compounds was characterized in cyanobacteria Microcystis aeruginosa (Chroococcales), Planktothrix agardhii (Oscillatoriales) and Aphanizomenon gracile (Nostocales) with selected in vitro assays. The in vivo relevance of detected bioactivities was analysed using transgenic zebrafish embryos tg(cyp19a1b-GFP). Teratogenic potency was assessed by analysis of developmental disorders and effects on functions of the neuromuscular system by video tracking of locomotion. Estrogenicity in vitro corresponded to 0.95-54.6 ng estradiol equivalent(g dry weight (dw))(-1). In zebrafish embryos, estrogenic effects could not be detected potentially because they were masked by high toxicity. There was no detectable (anti)androgenic/glucocorticoid activity in any sample. Retinoid-like activity was determined at 1-1.3 μg all-trans-retinoic acid equivalent(g dw)(-1). Corresponding to the retinoid-like activity A. gracile extract also caused teratogenic effects in zebrafish embryos. Furthermore, exposure to biomass extracts at 0.3 gd wL(-1) caused increase of body length in embryos. There were minor effects on locomotion caused by 0.3 gd wL(-1)M. aeruginosa and P. agardhii extracts. The traditionally measured cyanotoxins microcystins did not seem to play significant role in observed effects. This indicates importance of other cyanobacterial compounds at least towards some species or their developmental phases. More attention should be paid to activity of retinoids, estrogens and other bioactive substances in phytoplankton using in vitro and in vivo bioassays.

• Klíčová slova
• Blue-green algae, Estrogenicity, Fish, Retinoid-like activity, Teratogenicity,
• MeSH
• Aphanizomenon chemie   MeSH
• biotest MeSH
• dánio pruhované embryologie   genetika   metabolismus   MeSH
• embryo nesavčí účinky léků   MeSH
• endokrinní disruptory toxicita   MeSH
• geneticky modifikovaná zvířata embryologie   genetika   metabolismus   MeSH
• Microcystis chemie   MeSH
• neurotoxiny toxicita   MeSH
• sinice chemie   MeSH
• teratogeny toxicita   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• endokrinní disruptory MeSH
• neurotoxiny MeSH
• teratogeny MeSH