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Craniofacial anomalies are one of the most frequent birth defects worldwide and are often caused by genetic and environmental factors such as pharmaceuticals and chemical agents. Although identifying adverse outcome pathways (AOPs) is a central issue for evaluating the teratogenicity, the AOP causing craniofacial anomalies has not been identified. Recently, zebrafish has gained interest as an emerging model for predicting teratogenicity because of high throughput, cost-effectiveness and availability of various tools for examining teratogenic mechanisms. Here, we established zebrafish sox10-EGFP reporter lines to visualize cranial neural crest cells (CNCCs) and have identified the AOPs for craniofacial anomalies. When we exposed the transgenic embryos to teratogens that were reported to cause craniofacial anomalies in mammals, CNCC migration and subsequent morphogenesis of the first pharyngeal arch were impaired at 24 hours post-fertilization. We also found that cell proliferation and apoptosis of the migratory CNCCs were disturbed, which would be key events of the AOP. From these results, we propose that our sox10-EGFP reporter lines serve as a valuable model for detecting craniofacial skeletal abnormalities, from early to late developmental stages. Given that the developmental process of CNCCs around this stage is highly conserved between zebrafish and mammals, our findings can be extrapolated to mammalian craniofacial development and thus help in predicting craniofacial anomalies in human., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society of Toxicology.)

Background: Tissue fusion is a mechanism involved in the development of the heart, iris, genital tubercle, neural tube, and palate during embryogenesis. Failed fusion of the palatal shelves could result in cleft palate (CP), a common birth defect. Organotypic models constructed of human cells offer an opportunity to investigate developmental processes in the human. Previously, our laboratory developed an organoid model of the human palate that contains human mesenchyme and epithelial progenitor cells to study the effects of chemicals on fusion., Methods: Here, we developed an organoid model more representative of the embryonic palate that includes three cell types: mesenchyme, endothelial, and epithelial cells. We measured fusion by a decrease in epithelial cells at the contact point between the organoids and compared the effects of CP teratogens on fusion and toxicity in the previous and current organoid models. We further tested additional suspect teratogens in our new model., Results: We found that the three-cell-type model is more sensitive to fusion inhibition by valproic acid and inhibitors of FGF, BMP, and TGFβRI/II. In this new model, we tested other suspect CP teratogens and found that nocodazole, topiramate, and Y27632 inhibit fusion at concentrations that do not induce toxicity., Conclusion: This sensitive human three-cell-type organotypic model accurately evaluates chemicals for cleft palate teratogenicity., (© 2023 Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Today, it is recognized that medicines will eventually be needed during pregnancy to help prevent to, ameliorate or treat an illness, either due to gestation-related medical conditions or pre-existing diseases. Adding to that, the rate of drug prescription to pregnant women has increased over the past few years, in accordance with the increasing trend to postpone childbirth to a later age. However, in spite of these trends, information regarding teratogenic risk in humans is often missing for most of the purchased drugs. So far, animal models have been the gold standard to obtain teratogenic data, but inter-species differences have limited the suitability of those models to predict human-specific outcomes, contributing to misidentified human teratogenicity. Therefore, the development of physiologically relevant in vitro humanized models can be the key to surpassing this limitation. In this context, this review describes the pathway towards the introduction of human pluripotent stem cell-derived models in developmental toxicity studies. Moreover, as an illustration of their relevance, a particular emphasis will be placed on those models that recapitulate two very important early developmental stages, namely gastrulation and cardiac specification.

Cannabis use has risen dangerously during pregnancy in the face of incipient therapeutic use and a growing perception of safety. The main psychoactive compound of the Cannabis sativa plant is the phytocannabinoid delta-9-tetrahydrocannabinol (A-9 THC), and its status as a teratogen is controversial. THC and its endogenous analogues, anandamide (AEA) and 2-AG, exert their actions through specific receptors (eCBr) that activate intracellular signaling pathways. CB1r and CB2r, also called classic cannabinoid receptors, together with their endogenous ligands and the enzymes that synthesize and degrade them, constitute the endocannabinoid system. This system is distributed ubiquitously in various central and peripheral tissues. Although the endocannabinoid system's most studied role is controlling the release of neurotransmitters in the central nervous system, the study of long-term exposure to cannabinoids on fetal development is not well known and is vital for understanding environmental or pathological embryo-fetal or postnatal conditions. Prenatal exposure to cannabinoids in animal models has induced changes in placental and embryo-fetal organs. Particularly, cannabinoids could influence both neural and nonneural tissues and induce embryo-fetal pathological conditions in critical processes such as neural respiratory control. This review aims at the acute and chronic effects of prenatal exposure to cannabinoids on placental function and the embryo-fetal neurodevelopment of the respiratory pattern. The information provided here will serve as a theoretical framework to critically evaluate the teratogen effects of the consumption of cannabis during pregnancy., (© 2023. Springer Nature Switzerland AG.)

Background: Valproic acid (VPA), a prescribed drug commonly used for various neurological perturbations, has been implicated in teratogenic inflictions on developing fetuses during pregnancy. The purpose of this research was to delineate the gross morphological and histological effects of VPA in the developing eye tunics and lens., Methods: A time-dependent administration of 500 mg/kg VPA to BALB/c groups of female mice was coordinated during organogenesis (gestational days 7, 8, and 9) and compared to controls that received normal saline. Seized fetuses were checked for macroscopic eye anomalies, histological malformations with Azan trichrome staining, and levels of apoptotic activity with the terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay., Results: Histochemical analysis showed that VPA-treated groups exhibited collagen deficiency (2.5-50% decrease in aniline blue intensity) and a marked increase in TUNEL-positive cells (p < .05) in corneal stroma and sclera/choroid layers while less was detected in retina and lens, when compared to controls., Conclusions: Since the evaluation of the inner structures did not manifest major differences, we conclude that VPA teratogenic influence display eclectic toxicity, as seen by increased apoptosis to eye layers with high degree fibrous context, particularly the outer tunics., (© 2022 Wiley Periodicals LLC.)

Background: Testing for developmental toxicity according to the current regulatory guidelines requires large numbers of animals, making these tests very resource intensive, time-consuming, and ethically debatable. Over the past decades, several alternative in vitro assays have been developed, but these often suffered from low predictability and the inability to provide a mechanistic understanding of developmental toxicity., Methods: To identify embryotoxic compounds, we developed a human induced pluripotent stem cells (hiPSCs)-based biomarker assay. The assay is based on the differentiation of hiPSCs into functional cardiomyocytes and hepatocytes. Proper stem cell differentiation is investigated by morphological profiling and assessment of time-dependent expression patterns of cell-specific biomarkers. In this system, a decrease in the expression of the biomarker genes and morphology disruption of the differentiated cells following compound treatment indicated teratogenicity., Results: The hiPSCs-based biomarker assay was validated with 21 well-established in vivo animal teratogenic and non-teratogenic compounds during cardiomyocyte and hepatocyte differentiation. The in vivo teratogenic compounds (e.g., thalidomide and valproic acid) markedly disrupted morphology, functionality, and the expression pattern of the biomarker genes in either one or both cell types. Non-teratogenic chemicals generally had no effect on the morphology of differentiated cells, nor on the expression of the biomarker genes. Compared to the in vivo classification, the assay achieved high accuracy (91%), sensitivity (91%), and specificity (90%)., Conclusion: The assay, which we named ReproTracker®, is a state-of-the-art in vitro method that can identify the teratogenicity potential of new pharmaceuticals and chemicals and signify the outcome of in vivo test systems., (© 2022 Wiley Periodicals LLC.)

Background: Induced pluripotent stem cells (iPSCs) generated from reprogrammed adult somatic cells are considered as a promising cell source in cell-based regenerative medicine. To avoid teratoma formation, which is a safety issue in iPSC-based cell therapy, it is important to selectively remove undifferentiated iPSCs that remain in the differentiated cell product before in vivo transplantation. Caffeic acid (CAA, 3,4-dihydroxy-cinnamic acid) is a phenolic compound synthesized from various vegetables, fruits, and herbs; it has shown various pharmacological activities against inflammation, cancer, infection, diabetes, and neurodegenerative diseases. However, the beneficial effects of CAA in iPSC-based cell therapy, such as the selective elimination of iPSCs and anti-teratoma effects, have not yet been explored., Results: Here, we found that CAA induced apoptotic cell death in iPSCs; this process did not occur in iPSC-derived mesenchymal progenitor cells (MPCs) or human dermal fibroblast (hDFs). Under co-culture conditions with MPCs and hDFs, CAA treatment selectively removed iPSCs. In addition, CAA treatment in mixed cell culture with iPSCs and MPCs prior to grafting markedly suppressed iPSC-derived teratoma formation. Finally, CAA did not induce DNA damage in MPCs or hDFs., Conclusion: Taken together, these results suggest that CAA is effective in preparing safe iPSC-based therapeutic cells without the risk of teratoma formation and DNA damage in normal cells and iPSC-derived differentiated cells., (Copyright © 2022 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Background: Teratogen-induced congenital diaphragmatic hernia (CDH) rat models are commonly used to study the pathophysiology. We have created a new and reliable surgically induced diaphragmatic hernia (DH) model to obtain a purely mechanical DH rat model, and avoid the confounding teratogen-induced effects on the lung development., Methods: Fetal DH was surgically created on fetuses at E18.5 and harvested at E21.5 in rats. Four groups were evaluated (n = 16): control (CONT), control exposed to Nitrofen (CONT NIT), DH surgically created (DH SURG), and CDH Nitrofen (CDH NIT). Body weight, total lung weights, and their ratio (BW, TLW, and TLBR) were compared. Air space (AS), parenchyma (PA), total protein, and DNA contents were measured to verify lung hypoplasia. Medial wall thickness (MWT) of pulmonary arterioles was also analyzed., Results: DH SURG showed significant hypoplasia (decreased in total protein and DNA) vs CONT (p < 0.05); DH SURG vs CDH NIT were similar in TLW and TLBR. DH SURG has less AS than CONT (p < 0.05) and similar PA compared to CONT NIT and CDH NIT, MWT were similarly increased in CONT NIT, DH SURG, and CDH NIT., Conclusions: This novel surgical model generates fetal lung hypoplasia contributing to the study of the mechanical compression effect on fetal lung development in DH., Impact: There is a critical need to develop a surgical model in rat to complement the findings of the well-known Nitrofen-induced CDH model. This experimental study is pioneer and can help to understand better the CDH pathophysiological changes caused by herniated abdominal viscera compression against the lung during the final stage of gestation in CDH fetuses, and also to develop more efficient treatments in near future., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

The exposure of organisms to the nanoparticulate is potentially hazardous, particularly when it occurs during embryogenesis. The effects of commercial SiO 2 NPs in early development were studied, using Xenopus laevis as a model to investigate their possible future employment by means of the Frog Embryo Teratogenesis Assay-Xenopus test (FETAX). The SiO 2 NPs did not change the survival but produced several abnormalities in developing embryos, in particular, the dorsal pigmentation, the cartilages of the head and branchial arches were modified; the encephalon, spinal cord and nerves are anomalous and the intestinal brush border show signs of suffering; these embryos are also bradycardic. In addition, the expression of genes involved in the early pathways of embryo development was modified. Treated embryos showed an increase of reactive oxygen species. This study suggests that SiO 2 NPs are toxic but non-lethal and showed potential teratogenic effects in Xenopus. The latter may be due to their cellular accumulation and/or to the effect caused by the interaction of SiO 2 NPs with cytoplasmic and/or nuclear components. ROS production could contribute to the observed effects. In conclusion, the data indicates that the use of SiO 2 NPs requires close attention and further studies to better clarify their activity in animals, including humans., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Valproic acid (VPA) is a well-established anticonvulsant drug discovered serendipitously and marketed for the treatment of epilepsy, migraine, bipolar disorder and neuropathic pain. Apart from this, VPA has potential therapeutic applications in other central nervous system (CNS) disorders and in various cancer types. Since the discovery of its anticonvulsant activity, substantial efforts have been made to develop structural analogues and derivatives in an attempt to increase potency and decrease adverse side effects, the most significant being teratogenicity and hepatotoxicity. Most of these compounds have shown reduced toxicity with improved potency. The simple structure of VPA offers a great advantage to its modification. This review briefly discusses the pharmacology and molecular targets of VPA. The article then elaborates on the structural modifications in VPA including amide-derivatives, acid and cyclic analogues, urea derivatives and pro-drugs, and compares their pharmacological profile with that of the parent molecule. The current challenges for the clinical use of these derivatives are also discussed. The review is expected to provide necessary knowledgebase for the further development of VPA-derived compounds.

Many developmental disorders are thought to arise from an interaction between genetic and environmental risk factors. The Hedgehog (HH) signaling pathway regulates myriad developmental processes, and pathway inhibition is associated with birth defects, including holoprosencephaly (HPE). Cannabinoids are HH pathway inhibitors, but little is known of their effects on HH-dependent processes in mammalian embryos, and their mechanism of action is unclear. We report that the psychoactive cannabinoid Δ9-tetrahydrocannabinol (THC) induces two hallmark HH loss-of-function phenotypes (HPE and ventral neural tube patterning defects) in Cdon mutant mice, which have a subthreshold deficit in HH signaling. THC therefore acts as a 'conditional teratogen', dependent on a complementary but insufficient genetic insult. In vitro findings indicate that THC is a direct inhibitor of the essential HH signal transducer smoothened. The canonical THC receptor, cannabinoid receptor-type 1, is not required for THC to inhibit HH signaling. Cannabis consumption during pregnancy may contribute to a combination of risk factors underlying specific developmental disorders. These findings therefore have significant public health relevance., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

Competing Interests: None

To prevent congenital defects arising from maternal exposure, safety regulations require pre-market developmental toxicity screens for industrial chemicals and pharmaceuticals. Traditional embryotoxicity approaches depend heavily on the use of low-throughput animal models which may not adequately predict human risk. The validated embryonic stem cell test (EST) developed in murine embryonic stem cells addressed the former problem over 15 years ago. Here, we present a proof-of-concept study to address the latter challenge by updating all three endpoints of the classic mouse EST with endpoints derived from human induced pluripotent stem cells (hiPSCs) and human fibroblasts. Exposure of hiPSCs to selected test chemicals inhibited differentiation at lower concentrations than observed in the mouse EST. The hiPSC-EST also discerned adverse developmental outcomes driven by novel environmental toxicants. Evaluation of the early cardiac gene TBX5 yielded similar toxicity patterns as the full-length hiPSC-EST. Together, these findings support the further development of hiPSCs and early molecular endpoints as a biologically relevant embryotoxicity screening approach for individual chemicals and mixtures.

Objective: To evaluate pediatric subspecialists' practices and attitudes regarding sexual and reproductive healthcare for adolescent and young adult women for whom they prescribe teratogens., Study Design: We surveyed pediatric subspecialists at 1 tertiary care pediatric hospital. Items assessed attitudes and practices related to sexual and reproductive healthcare for adolescent and young adult women prescribed teratogens, and barriers and facilitators to sexual and reproductive healthcare provision. We used descriptive statistics, χ 2 tests, and logistic regression to analyze results., Results: There were 200 subspecialists from 17 subspecialties who completed the survey; 77% reported prescribing teratogens to adolescent and young adult women and 18% reported caring for a patient who became pregnant while taking a teratogen. Overall, 99% indicated that it is important to address sexual and reproductive healthcare. Respondents endorsed confidence in sexual and reproductive healthcare skills, including contraceptive counseling (71%), although 29% never or rarely discuss sexual and reproductive healthcare, and one-third never speak privately to this population. Of providers who discuss sexual and reproductive healthcare, 26% never assess reproductive intentions and 36% do so less often than annually. Nearly one-half never or rarely ask about sexual activity, and 68% never or rarely assess contraceptive knowledge. Barriers to sexual and reproductive healthcare provision included available time (80%) and the presence of family or partners at clinic visits (61%). Facilitators included a quick referral process to sexual and reproductive healthcare providers (92%) and access to lists of local sexual and reproductive healthcare providers (90%)., Conclusions: Pediatric subspecialists from a single institution report suboptimal sexual and reproductive healthcare provision for adolescent and young adult women prescribed teratogens. Identified barriers and facilitators may guide intervention development to improve sexual and reproductive healthcare for this population., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Adolescent social isolation (SI) might change the trajectory of brain development. In the present study, we investigated the effect of short-term adolescent SI on fear memory, anxiety and protein levels in the adult medial prefrontal cortex of rats prenatally treated with methylazoxymethanol, MAM-E17 model of schizophrenia. The animals were maintained in standard housing (SH) or social isolation (P30-P40, SI) conditions. Behavioural tests (trace or delay fear conditioning, light/dark box) were performed in late adolescence and early adulthood. The results showed that MAM treatment did not alter fear memory, which was investigated with the use of either trace or delay fear conditioning, at any age, and SI decreased the fear response in adult control animals only under trace conditioning. Neither MAM nor SI influenced anxiety-related behaviour measured in the light/dark box. A proteomics study showed that both MAM and SI changed the protein levels related to synapse maturation and cytoskeletal organization, energy transfer and metabolic processes. Prenatal or adolescent environmental factors are able to change the expression of proteins that are correlated with behavioural impairments. Moreover, SI reversed some alterations in proteins induced by MAM. Thus, normally developing brains showed different responses to adolescent SI than those with altering courses of MAM administration., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: Alcohol consumption causes several harmful effects on the organs, which is hugely understated. Many deformities occur in the fetus when pregnant mothers indulge in alcoholism. Alcohol is a known teratogen, hence organ formation, particularly development of parts brain critical for cognitive function may be affected. The oxidative brain damage also could contribute to reduced cognitive efficiency of brain exposed to alcohol. In this study, effect of Centella asiatica in relieving the oxidative brain damage in offspring of alcohol fed mother rats was evaluated., Methods: In this study we fed alcohol (5 g/kg body weight, 30% w/v) to a group of pregnant Wistar rats during gestation period, and another group served as control. Four groups of rats (n = 6 each) were selected from the offspring of these mother rats. The groups were, control, positive (treated) control, untreated and treated from alcohol-fed mother. Their cognitive parameters were tested in water maze, shuttle box and compared. Further their oxidative status was evaluated by estimating malondialdehyde (MDA), protein carbonyl, total antioxidants and glutathione reductase (GSH) in hippocampus., Results: The results suggested that there was significantly high cognitive performance in maze test and shuttle box memory retention in rats treated with C. asiatica water extract and the antioxidant levels were high in their hippocampus., Conclusions: The outcome of the study suggested that C. asiatica produced beneficial effects in reversing the alcohol induced brain damage in pregnancy., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Topiramate is an anti-epileptic drug that is commonly prescribed not just to prevent seizures but also migraine headaches, with over 8 million prescriptions dispensed annually. Topiramate use during pregnancy has been linked to significantly increased risk of babies born with orofacial clefts (OFCs). However, the exact molecular mechanism of topiramate teratogenicity is unknown. In this study, we first used an unbiased antibody array analysis to test the effect of topiramate on human embryonic palatal mesenchyme (HEPM) cells. This analysis identified 40 differentially expressed proteins, showing strong connectivity to known genes associated with orofacial clefts. However, among known OFC genes, only TGFβ1 was significantly upregulated in the antibody array analysis. Next, we validated that topiramate could increase expression of TGFβ1 and of downstream target phospho-SMAD2 in primary mouse embryonic palatal mesenchyme (MEPM) cells. Furthermore, we showed that topiramate treatment of primary MEPM cells increased expression of SOX9. SOX9 overexpression in chondrocytes is known to cause cleft palate in mouse. We propose that topiramate mediates upregulation of TGFβ1 signaling through activation of γ-aminobutyric acid (GABA) receptors in the palate. TGFβ1 and SOX9 play critical roles in orofacial morphogenesis, and their abnormal overexpression provides a plausible etiologic molecular mechanism for the teratogenic effects of topiramate., Competing Interests: The authors do not have any competing financial interests pertaining to the studies presented here.

Background: In our previous studies, we had demonstrated the efficiency and specificity of constructed bladder tissue-specific adenovirus Ad-PSCAE-UPII-E1A-AR (APU-EIA-AR) on bladder cancer. The virus biodistribution and body toxicity in nude mice have also been investigated. However, the safety of the bladder cancer-specific oncolytic adenovirus on fetal mice and F1 mice should be under intense investigation., Objective: In order to evaluate the teratogenic toxicity of bladder cancer-specific oncolytic adenovirus APU-EIA-AR on mice, in this study, we investigated the fetal mice weight, fetal body length and tail length, fetal skeleton development, as well as the F1 mice weight, growth curve, and major organ pathology. These teratogenic toxicity data of bladder tissue-specific adenovirus Ad-PSCAE- UPII-E1A-AR (AD) would provide safe information prior to embarking on clinical trials., Methods: On the sixth day of being fertilized, the pregnant mice began to be intramuscularly administrated with AD (1×10 7 VP, 1×10 8 VP, 1×10 9 VP) every other day for ten days. The pregnant mice were then divided into two groups. One group was euthanized on the seventeenth day; the fetal mice were taken out, and the bone structure of the infants was observed. The other group was observed until natural childbirth. The Filial Generation (F1) is fed for 30 days; the variations in the growth progress and development were assessed. The mice were then euthanized; The tissues from major organs were harvested and observed under the microscope., Results: In the process of teratogenic toxicity test, the Placenta weight, fetal mice weight, body length, and a tail length of mice fetal in adenovirus treated group did not reveal any alteration. Meanwhile, comparing with the PBS group, there is no obvious change in the skeleton of fetal mice treated with adenovirus. During the development process of F1 mice treated with adenovirus, the changes in mice weight show statistical significance. However, in the progress of the growth curve, this difference is not very obvious. Furthermore, the pathological section showed no obvious alteration in major organs., Conclusion: Our study demonstrated that bladder cancer-specific adenovirus Ad-PSCAE-UPII- E1A-AR appears safe in pregnant mice without any discernable effects on fetal mice and F1 development. Hence, it is relatively safe for tumor gene therapy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Prenatal alcohol exposure (PAE) is perhaps the most common environmental cause of human birth defects. These exposures cause a range of structural and neurological defects, including facial dysmorphologies, collectively known as fetal alcohol spectrum disorders (FASD). While PAE causes FASD, phenotypic outcomes vary widely. It is thought that multifactorial genetic and environmental interactions modify the effects of PAE. However, little is known of the nature of these modifiers. Disruption of the Hedgehog (Hh) signaling pathway has been suggested as a modifier of ethanol teratogenicity. In addition to regulating the morphogenesis of craniofacial tissues commonly disrupted in FASD, a core member of the Hh pathway, Smoothened, is susceptible to modulation by structurally diverse chemicals. These include environmentally prevalent teratogens like piperonyl butoxide (PBO), a synergist found in thousands of pesticide formulations., Methods: Here, we characterize multifactorial genetic and environmental interactions using a zebrafish model of craniofacial development., Results: We show that loss of a single allele of shha sensitized embryos to both alcohol- and PBO-induced facial defects. Co-exposure of PBO and alcohol synergized to cause more frequent and severe defects. The effects of this co-exposure were even more profound in the genetically susceptible shha heterozygotes., Conclusions: Together, these findings shed light on the multifactorial basis of alcohol-induced craniofacial defects. In addition to further implicating genetic disruption of the Hh pathway in alcohol teratogenicity, our findings suggest that co-exposure to environmental chemicals that perturb Hh signaling may be important variables in FASD and related craniofacial disorders., (© 2020 The Authors. Alcoholism: Clinical & Experimental Research published by Wiley Periodicals LLC on behalf of Research Society on Alcoholism.)

A facile, green synthesis of selenium doped zinc oxide nano-antibiotic (Se-ZnO-NAB) using the Curcuma longa extract is reported to combat the increased emergence of methicillin-resistant Staphylococcus aureus (MRSA). The developed Se-ZnO-NAB were characterized for their physicochemical parameters and extensively evaluated for their toxicological potential in an animal model. The prepared Se-ZnO-NABs were characterized via Fourier transformed infrared spectroscopy to get functional insight into their surface chemistry, scanning electron microscopy revealing the polyhedral morphology with a size range of 36 ± 16 nm, having -28.9 ± 6.42 mV zeta potential, and inductively coupled plasma optical emission spectrometry confirming the amount of Se and Zn to be 14.43 and 71.70 mg L-1 respectively. Moreover, the antibacterial activity against MRSA showed significantly low minimum inhibitory concentration at 6.2 μg mL-1 when compared against antibiotics. Also, total protein content and reactive oxygen species production in MRSA, under the stressed environment of Se-ZnO-NAB, significantly (p < 0.05) decreased compared to the negative control. Moreover, the results of acute oral toxicity in rats showed moderate variations in blood biochemistry and histopathology of vital organs. The teratogenicity and fetal evaluations also revealed some signs of toxicity along with changes in biochemical parameters. The overall outcomes suggest that Se-ZnO-NAB can be of significant importance for combating multi-drug resistance but must be used with extreme caution, particularly in pregnancy, as moderate toxicity was observed at a toxic dose of 2000 mg kg-1.

Background: My career goal in 1971 was to learn about the causes of malformations. Attending the annual meetings of the Teratology Society and reading the articles in Teratology exposed me to the scientists and clinicians involved in this research and the methods being used., Methods: Over a period of 49 years (1972-2020), I heard many presentations about several exposures in pregnancy that can cause birth defects. Symposia and platform presentations provided unique and stimulating information on the fetal effects of the teratogen thalidomide., Results: I developed research studies and presented the results from our studies on teratogenic exposures, such as anticonvulsant drugs, the prenatal diagnosis procedure chorionic villus sampling, and the abortifacient misoprostol. The annual Pregnancy Registry Workshop was developed as a forum for discussing issues related to this new method of evaluating potential teratogenic exposures in pregnancy., Conclusion: Attending the annual meetings and reading the articles in the journal Teratology (now Birth Defects Research) have been an instructive and enjoyable way to learn about the causes of malformations., (© 2020 Wiley Periodicals, Inc.)

Phthalates used as plasticizers have become a part of human life because of their important role in various industries. Human exposure to these compounds is unavoidable, and therefore their mechanisms of toxicity should be investigated. Due to their structure and function, human erythrocytes are increasingly used as a cell model for testing the in vitro toxicity of various xenobiotics. Therefore, the purpose of our study was to assess the effect of selected phthalates on methemoglobin (metHb), reactive oxygen species (ROS) including hydroxyl radical levels, as well as the activity of antioxidative enzymes, such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), in human erythrocytes. Erythrocytes were incubated with di-n-butyl phthalate (DBP), butylbenzyl phthalate (BBP), and their metabolites, i.e., mono-n-butyl phthalate (MBP) and monobenzyl phthalate (MBzP), at concentrations ranging from 0.5 to 100 µg/mL for 6 or 24 h. This study shows that the analyzed phthalates disturbed the redox balance in human erythrocytes. DBP and BBP, at much lower concentrations than their metabolites, caused a statistically significant increase of metHb and ROS, including hydroxyl radical levels, and changed the activity of antioxidant enzymes. The studied phthalates disturbed the redox balance in human erythrocytes, which may contribute to the accelerated removal of these cells from the circulation.

The objective of this work was to evaluate whether tetracycline (TC) in environmentally relevant concentrations was able to induce alterations to embryonic development and teratogenic effects in oocytes and embryos of Cyprinus carpio. For this purpose, an embryolethality study was conducted and the lethal concentration 50 (LC 50 ) and effective concentration 50 of malformations (EC 50 ) were calculated, and with these data the teratogenic index (TI) was determined. The main alterations to embryonic development and the teratogenic effects produced by TC on embryos of C. carpio were determined using the Kimmel and Hersem scale adapted for Cyprinus carpio. LC 50 and EC 50 were respectively 500.08 and 145.3 μg L -1 .TC was shown to be teratogenic with teratogenic index of 3.44, and the main malformations identified in concentrations of 90-900 μg L -1 were malformation in tail, modified chorda structure, pericardical edema, scoliosis and malformations of the heart. A significant decrease in concentration-dependent in Kimmel and Hersem score was observed. The results allow us to conclude that TC at environmentally relevant concentrations is capable of inducing embryotoxic and teratogenic effects, generating risk in the integrity of the common carp C. Carpio., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Early (EOP) and late onset (LOP) preeclampsia are two subtypes of preeclampsia. This study examines the effect of maternal omega-3 fatty acids and vitamin E supplementation in a rat model of preeclampsia. Method: Pregnant Wistar rats were assigned to control; EOP; LOP; EOP+omega-3 fatty acid supplementation+vitamin E and LOP+omega-3 fatty acid supplementation+vitamin E. L-Nitroarginine methylester was used to induce preeclampsia. Blood Pressure (BP) was recorded during pregnancy and dams were dissected at d14 and d20 of gestation. Results: Animals from EOP and LOP groups demonstrated higher systolic and diastolic BP, lower weight gain, lower conceptuses size, lower conceptuses weight and fetal weight as compared to control. EOP and LOP groups showed higher percentage of fetal resorptions and embryotoxicity (deformities and hematomas). Conclusion: Supplementation reduced the diastolic BP, percentage of resorptions and embryotoxicity only in the LOP group, suggesting a need for differential supplementation regime for the two subtypes of preeclampsia.

In response to pathogens, plant cells exhibit a rapid increase in the intracellular calcium concentration and a burst of reactive oxygen species (ROS). The cytosolic increase in Ca 2+ and the accumulation of ROS are critical for inducing programmed cell death (PCD), but the molecular mechanism is not fully understood. We screened an Arabidopsis mutant, sad2-5, which harbours a T-DNA insertion in the 18 th exon of the importin beta-like gene, SAD2. The H 2 O 2 -induced increase in the [Ca 2+ ] cyt of the sad2-5 mutant was greater than that of the wild type, and the sad2-5 mutant showed clear cell death phenotypes and abnormal H 2 O 2 accumulation under fumonisin-B1 (FB1) treatment. CaCl 2 could enhance the FB1-induced cell death of the sad2-5 mutant, whereas lanthanum chloride (LaCl 3 ), a broad-spectrum calcium channel blocker, could restore the FB1-induced PCD phenotype of sad2-5. The sad2-5 fbr11-1 double mutant exhibited the same FB1-insensitive phenotype as fbr11-1, which plays a critical role in novo sphingolipid synthesis, indicating that SAD2 works downstream of FBR11. These results suggest the important role of nuclear transporters in calcium- and ROS-mediated PCD response as well as provide an important theoretical basis for further analysis of the molecular mechanism of SAD2 function in PCD and for improvement of the resistance of crops to adverse environments., (© 2019 The Authors The Plant Journal © 2019 John Wiley & Sons Ltd.)

Background: Retinoic acid (RA) is a synthetic vitamin derivative. It exerts toxic and teratogenic effects on the development of embryonic organs in dose- and time-dependent manners in mice. Curcumin is a compound obtained from rhizomes of turmeric (Curcuma longa) and has protective effects on teratogenic agents. The current study examined the effects of curcumin on embryos treated with RA., Methods: A total of 24 female NMRI mice (8-week-old pregnant mice) were investigated in the current study. All of them were treated for 10 days during days 15 to 50 of pregnancy. In the first group, the animals were fed with normal diets (control); in the second group, with 60 mg/kg all- trans RA; in the third group, with 10 mg/kg curcumin; and in the fourth group, with RA and curcumin in their diets. The animals were killed by cervical dislocation at the 18th day of pregnancy and embryos were separated from the uteruses. The embryo weight and crown rump (CR) length were measured, and the SPSS software was used to analyze data., Results: There was a significant increase in the lengths of CR and weights of embryos after using curcumin, but RA had no effect on the length of CR and weight of embryos at a dose of 60 mg/kg. Morphometric assay of liver tissue was performed, and data analysis indicated that there were significant differences between groups in terms of morphometric parameters of liver tissue. Therefore, RA increased the cell number and sinusoid diameter and decreased the cell areas in the embryonic liver tissue. However, curcumin decreased these side effects of RA on the embryonic liver tissue., Conclusion: The results indicated that curcumin could decrease the toxic and teratogenic effects of RA in mouse embryos., (© 2019 Wiley Periodicals, Inc.)

Thoracolumbar supernumerary ribs (TSRs) are classified as less severe skeletal anomalies in rat developmental toxicity studies, although their incidence is relatively high in rodent studies. To investigate the characteristics of the critical window for chemically-induced TSR, in this study, rats were administered 5-fluorocytocine (5-FC) or sodium salicylate (SAL) at one of three time periods on gestational day (GD) 9, early morning (7:00 am), midday (12:00 pm to 1:00 pm), or late afternoon (4:00 pm or 7:00 pm). The incidence of TSR and other anomalies were assessed in GD20 fetuses. A single treatment with both chemicals on GD9-induced TSR, with the incidence highest when administered at 7:00 Am, decreasing gradually when administered later. This trajectory was clearer in rats treated with 5-FC than with SAL. The critical period of TSR induction is shorter in rats administered 5-FC than SAL. The characteristics of the critical window may cause variability in the incidence of TSR observed in developmental toxicity studies., (© 2018 Japanese Teratology Society.)

The aim of this review was to scrutinize the current literature available on teratogenic safety of third-generation antiepileptic drugs (TGAEDs) considering their clinical implications and to highlight for further research need in the interest of the diseased population in general and women with epilepsy in particular. For evaluation of the teratogenic potential of TGAEDs, this review summarized the existing information on controlled clinical trials conducted by the pharmaceutical companies, case reports, scholarly articles (prospective and retrospective studies), and experimental tests carried out so far. Firstly, clinical reports have reviewed on each drug followed by non-clinical studies reported hitherto. The Pub-Med and Google search engine was used to explore the relevant articles with pertinent keywords like pregnancy, epilepsy, seizures, women with epilepsy, antiepileptic or anticonvulsant drugs, first-second/new and third/ newest generation antiepileptic drugs, teratogenicity, teratological potential, birth defects, congenital anomalies, epilepsy and pregnancy registries, malformation surveillance program. The search was also carried out by the individual name of 20 third-generation AEDs. This review declared that although much research has been carried out on clinical and non-clinical implications for the assessment of the teratogenic potential of FGAEDs and SGAEDs, reports on the teratogenic safety of TGAEDs are still limited. It is concluded that there is an urgent need to exaggerate a large number of clinical intervention trials/reports and experimental studies to draw a definite conclusion for the teratogenic safety of TGAEDs. This is a pioneer attempt by our laboratory to review the teratogenic potential of third-generation antiepileptic drugs., (Copyright © 2019 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.)

Valproic acid is an established structural and neurodevelopmental teratogen. Recently, we demonstrated that valproate alters the barrier function of perfused term human placentas. Here, we conducted a pilot study to evaluate the effects of subchronic valproate exposure on carrier expression in cultured placental villous explants from early human pregnancies. Placental tissue of gestational age 6-13 weeks was collected from elective pregnancy terminations in women without known epilepsy. The effects of valproate (42, 83, or 166 μg/mL) on the mRNA expression of 37 major placental carriers and related genes were evaluated by a customized gene expression array (n = 5, 5 days). Five-day exposure to valproate was associated with high variability in gene expression. However, two main gene clusters were identified, including a cluster of three major folate carriers. Exposure to low therapeutic levels of valproate (42 μg/mL) was associated with a tendency toward reduced mRNA expression of genes encoding folate and amino acid and fatty acid carriers (P = 0.065, paired analysis). Our initial findings suggest that valproate can affect the function of the human placenta during early pregnancy., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)

Prescribing for pregnant or lactating patients and male patients wishing to father children can be a difficult area for dermatologists. There is a lack of review articles of commonly used systemic medications in dermatology with respect to their effects on developing embryogenesis and their potential transfer across the placenta, in breast milk and in seminal fluid. This paper aims to provide an up to date summary of evidence to better equip dermatologists to inform patients about the effects of systemic medications commonly used in dermatology to treat conditions such as atopic dermatitis, psoriasis and acne, on current and future embryogenesis and fertility.

Thalidomide embryopathy results from the ingestion of thalidomide in the first trimester during pregnancy, causing multiple forms of congenital abnormalities of variable severity that involve all systems. The skeletal findings most frequently affect the limbs, particularly the upper limbs and hands. Increasingly, several genetic disorders with similar birth defects have been identified. New cases of malformations owing to possible exposure to thalidomide continue to present through both historical and current usage. However, inadequate proof of ingestion, marked phenotypic variation and the possibility of an alternative genetic condition, hinder the diagnosis of thalidomide embryopathy. We introduce a 'diagnostic algorithm for thalidomide embryopathy' (DATE) diagnostic software that can potentially provide a numerical score for the likelihood of birth defects in an individual as being caused by exposure to thalidomide and to provide a differential diagnosis based on the pattern of malformation.

Thalidomide remains notorious as a result of the damage it caused to children born to mothers who used it to treat morning sickness between 1957 and 1961. The re-emergence of the drug to treat a range of conditions including erythema nodosum leprosum (a complication of leprosy) has led to a new generation of thalidomide damaged children being born in Brazil. Although thalidomide affects most of the developing tissues and organs of the body, the damage to the limbs is striking. Indeed phocomelia, the severe reduction or loss of the proximal long bones with retention of the distal hand/foot plate remains the stereotypical image of thalidomide. This review focuses on the type and range of damage thalidomide caused to the limbs, reviews current understanding of the mechanisms underlying thalidomide-induced limb malformations and outlines some of the challenges remaining in elucidating its teratogenicity.

Embryologic development involves cell differentiation and organization events that are unique to each tissue and organ and are susceptible to developmental toxicants. Animal models are the gold standard for identifying putative teratogens, but the limited throughput of developmental toxicological studies in animals coupled with the limited concordance between animal and human teratogenicity motivates a different approach. In vitro organoid models can mimic the three-dimensional (3D) morphogenesis of developing tissues and can thus be useful tools for studying developmental toxicology. Common themes during development like the involvement of epithelial-mesenchymal transition and tissue fusion present an opportunity to develop in vitro organoid models that capture key morphogenesis events that occur in the embryo. We previously described organoids composed of human stem and progenitor cells that recapitulated the cellular features of palate fusion, and here we further characterized the model by examining pharmacological inhibitors targeting known palatogenesis and epithelial morphogenesis pathways as well as 12 cleft palate teratogens identified from rodent models. Organoid survival was dependent on signaling through EGF, IGF, HGF, and FGF pathways, and organoid fusion was disrupted by inhibition of BMP signaling. We observed concordance between the effects of EGF, FGF, and BMP inhibitors on organoid fusion and epithelial cell migration in vitro, suggesting that organoid fusion is dependent on epithelial morphogenesis. Three of the 12 putative cleft palate teratogens studied here (theophylline, triamcinolone, and valproic acid) significantly disrupted in vitro organoid fusion, while tributyltin chloride and all-trans retinoic acid were cytotoxic to fusing organoids. The study herein demonstrates the utility of the in vitro fusion assay for identifying chemicals that disrupt human organoid morphogenesis in a scalable format amenable to toxicology screening.

Acetylcholinesterase inhibitors are widely used for a variety of medical, agricultural and public health purposes. Consequently, exposure is highly possible during lifetime. However, their systematic use raises concerns for the potential impact on the fetus and newborn since these substances may affect angiogenesis, the neonatal and maternal intensive care, neuroimmune function and response, mammary growth/lactation via cholinergic/non-cholinergic central and peripheral neuroendocrine pathways. New methodologies, neuroscientific technologies and research studies are needed to harness existing knowledge along with the proper management, availability for new acetylcholinesterase inhibitors, with stable pharmacodynamics and clinical outcomes., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Fetal alcohol spectrum disorder is one of the leading causes of mental health issues worldwide. Analysis of zebrafish exposed to alcohol during embryonic development confirmed that even low concentrations of alcohol for a short period of time may have lasting behavioral consequences at the adult or old age. The mechanism of this alteration has not been studied. Here, we immersed zebrafish embryos into 1% alcohol solution (vol/vol%) at 24 hr post-fertilization (hpf) for 2 hr and analyzed potential changes using immunohistochemistry. We measured the number of BDNF (brain-derived neurotrophic factor) and NCAM (neuronal cell adhesion molecule)-positive neurons and the intensity of synaptophysin staining in eight brain regions: lateral zone of the dorsal telencephalic area, medial zone of the dorsal telencephalic area, dorsal nucleus of the ventral telencephalic area, ventral nucleus of the ventral telencephalic area, parvocellular preoptic nucleus, ventral habenular nucleus, corpus cerebella and inferior reticular formation. We found embryonic alcohol exposure to significantly reduce the number of BDNF- and NCAM-positive cells in all brain areas studied as compared to control. We also found alcohol to significantly reduce the intensity of synaptophysin staining in all brain areas except the cerebellum and preoptic area. These neuroanatomical changes correlated with previously demonstrated reduction of social behavior in embryonic alcohol-exposed zebrafish, raising the possibility of a causal link. Given the evolutionary conservation across fish and mammals, we emphasize the implication of our current study for human health: even small amount of alcohol consumption may be unsafe during pregnancy., (© 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Herein, we propose using a nanosecond pulsed electric field (nsPEF) technique to assess teratogenicity and embryonic developmental toxicity of estradiol-17β (E 2 ) and predict the molecular mechanisms of teratogenicity and embryonic developmental defects caused by E 2 on medaka (Oryzias latipes). The 5 hour post-fertilization embryos were exposed to co-treatment with 10 μm E 2 and nsPEF for 2 hours and then continuously cultured under non-E 2 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, 6 day post-fertilization embryos that had been continuously cultured under the non-E 2 and nsPEF condition after 2 hour co-treatments were used. DNA microarray analysis identified 542 upregulated genes and one downregulated gene in the 6 day post-fertilization embryos. Furthermore, bioinformatic analyses using differentially expressed genes revealed that E 2 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 E 2 and predict their molecular mechanisms in medaka embryos., (Copyright © 2017 John Wiley & Sons, Ltd.)

Thalidomide was once administered to pregnant women as a mild sedative; however, it was subsequently shown to be strongly teratogenic. Recently, there has been renewed interest in thalidomide because of its curative effects against intractable diseases. However, the teratogenicity of thalidomide is manifested in various ways and is still not fully understood. In the present study, we evaluated the effects of thalidomide on early mesodermal differentiation by examining the differentiation of human induced pluripotent stem cells (hiPSCs). The most common symptom of thalidomide teratogenicity is limb abnormality, which led us to hypothesize that thalidomide prevents early mesodermal differentiation. Therefore, mesodermal differentiation of hiPSCs was induced over a 6-d period. To induce early mesoderm differentiation, 1 d after seeding, the cells were incubated with the small molecule compound CHIR99021 for 3 d. Thalidomide exposure was initiated at the same time as CHIR99021 treatment. After 5 d of thalidomide exposure, the hiPSCs began expressing a mesodermal marker; however, the number of viable cells decreased significantly as compared to that of control cells. We observed that the proportion of apoptotic and dead cells increased on day 2; however, the proportion of dead cells on day 5 had decreased, suggesting that the cells were damaged by thalidomide during early mesodermal differentiation (days 0-2). Our findings may help elucidate the mechanism underlying thalidomide teratogenicity and bring us closer to the safe use of this drug.

Thalidomide possesses two optical isomers which have been reported to exhibit different pharmacological and toxicological activities. However, the precise mechanism by which the two isomers exert their different activities remains poorly understood. Here, we present structural and biochemical studies of (S)- and (R)-enantiomers bound to the primary target of thalidomide, cereblon (CRBN). Our biochemical studies employed deuterium-substituted thalidomides to suppress optical isomer conversion, and established that the (S)-enantiomer exhibited ~10-fold stronger binding to CRBN and inhibition of self-ubiquitylation compared to the (R)-enantiomer. The crystal structures of the thalidomide-binding domain of CRBN bound to each enantiomer show that both enantiomers bind the tri-Trp pocket, although the bound form of the (S)-enantiomer exhibited a more relaxed glutarimide ring conformation. The (S)-enantiomer induced greater teratogenic effects on fins of zebrafish compared to the (R)-enantiomer. This study has established a mechanism by which thalidomide exerts its effects in a stereospecific manner at the atomic level.

Western blotting permits immunodetection, characterization, and quantification of proteins in cell (or tissue) homogenates. It also enables detection of protein modification (e.g., phosphorylation) or degradation (e.g., hydrolysis), even at low abundance. Sodium dodecyl sulfate (SDS)-polyacrylamide gel is used to separate proteins from homogenate which are then transferred electrophoretically to polyvinylidene difluoride (PVDF) membranes. After membrane "blocking," to reduce nonspecific binding, proteins of interest are detected using specific antibodies (antigen detection), which are then bound to a secondary antibody linked to a label (e.g., fluorescent, chemiluminescent, or chromophore). After signal detection and acquisition, quantification of the resulting bands is achieved using densitometry software. Results are normalized against controls and housekeeping proteins (e.g., GAPDH, beta-actin and tubulin), which are constitutively expressed proteins that maintain cell viability. This chapter outlines the use of the Western blot technique optimized for the in vitro analysis of changes in the protein expression induced by teratogenic exposure.

Apart from morphological, biochemical, and genetic alterations induced by teratogen compounds, there is an increase interest in characterizing behavioral alterations. Behavior is a sensitive parameter that can provide information regarding developmental disruptions noninvasively, as it is the result of brain processes. Behavioral disturbances interfere with animals' capacity to cope with the environment, having an impact on the organism's life. Hereby, it is proposed behavioral assays consisting on recording larvae in multiwell plates and video analysis with a proper software, allowing for teratogen screening of behavior. How to evaluate locomotor, anxiety-like and avoidance-like behaviors, and the integrity of sensory-motor functions and learning are discussed in this chapter.

The genotoxicity methods applied to rats are tests that can detect any damage, including changes in the number of chromosomes or in the structure of chromosomes, and nucleotide changes with structural abnormality in the DNA of animal cells. However, the method of teratogenicity is used to detect the effects of chemicals which cause congenital defects in living organisms. This study contains information about the effectiveness, reliability, ways of application, and methodology of genotoxic and teratogenic methods applied in vivo in rats.

Histological analysis of mouse embryos, fetuses, or newborns remains one the most common methods and in some cases the "gold standard" used in teratology studies to detect abnormal morphogenesis during development. Histochemistry methods are based on the selectivity of certain chemical compounds for certain cellular or tissue components, several of them related to specific maturation processes. In this chapter, specific histochemistry techniques that allow for the monitoring of critical stages of tissue and organ formation, such as skeleton and muscle differentiation, neuronal maturation, neuronal connectivity, and neurodevelopment after teratogenic exposure are described in detail.

Investigations of teratogenic effects of drugs generally involve testing the drug on animals and zebrafish embryo is a commonly used animal model for that purpose. In these studies, cardiovascular function of the animals needs to be evaluated to reveal the influence of exposure on the development of the cardiovascular system as well as on the growth of the whole animal. Here, relevant microscopy imaging and analysis protocols are described to calculate a variety of hemodynamic parameters for zebrafish embryos exposed to clinical drugs.

Valproic acid (VPA) is an antiepileptic drug (AED) that has the broadest spectrum across all types of seizures and epileptic syndromes. Unfortunately, approximately 30% of epileptic patients are refractory to the classical AED. Metal ions have been frequently incorporated into pharmaceuticals for therapeutic or diagnostic purposes and research. In this preliminary study, we assess the embryo toxicity and the anticonvulsant activity of 4 novel metallodrugs, with Zn +2 and Cu +2 , a derivative of valproic acid and the N-donor ligand in an adult zebrafish epileptic seizure model induced by pentylenetetrazole. The most toxic complex was [Cu(Valp) 2 Bipy], in which the LC 50 was 0.22 μM at 48 h post fertilization (HPF) and 0.12 μM at 96 HPF, followed by [Zn(Valp) 2 Bipy] (LC 50  = 10 μM). These same metallodrugs ([Cu(Valp) 2 Bipy] 10 mM/kg and [Zn(Valp) 2 Bipy] 30 mM and 100 mM/kg) displayed superior activity, thus reducing the seizure intensity by approximately 20 times compared to sodium valproate (175 mM/kg). Overall, [Cu(Valp) 2 Bipy] showed the best anticonvulsant effects. However, because of the toxicity of copper, [Zn(Valp) 2 Bipy] is considered the most promising anticonvulsant for future studies., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Traditional toxicological screens based on the zebrafish model use observable phenotypic endpoints during their development to determine the toxicity of teratogens. Yet toxicity does not always translate to obvious phenotypic changes and the criteria used to score the toxicity of a teratogen are frequently subjected to human perception. The advancement in omics-based technologies has allowed us to quantitatively and objectively determine the toxicity of a teratogen based on biomolecular changes. The field of proteomics has been gaining popularity as a valuable tool in toxicology. Hence, in this chapter, we described a protocol for both label-free and label-based proteomic methods to analyse proteomic changes in both embryos and adult livers of zebrafish exposed to the teratogen TCDD (tetrachlorodibenzo-p-dioxin) as an example.

Background: Cervical ribs in rat fetuses have been widely reported to occur in controls as well as in response to various maternal chemical exposures. However, few evaluations of cervical ribs have been reported in rats postnatally. The available literature has indicated that the postnatal incidences of cervical ribs in control rats are no higher than in perinatal fetuses., Methods: In a developmental toxicity study in rats conducted by the inhalation route, a control group of 44 time-mated female rats was exposed to filtered air only from gestation day (GD) 6 to 20, and divided into two cohorts. For one cohort, fetuses were removed from dams by laparohysterectomy for skeletal evaluation on GD 21. The other cohort of dams was permitted to deliver, and adult offspring were euthanized on postnatal day 65 for a subsequent postnatal skeletal evaluation of cervical ribs., Results: The incidence of cervical ribs (mean percentage of affected fetuses or adults per litter) was observed to increase during postnatal development, from 1.0% on GD 21 to 12.7% on postnatal day 65. Further evaluation is ongoing to determine whether these observations were attributable to the inhalation exposure conditions used in this study., Conclusion: These results, while limited to the evaluation of one skeletal alteration in control rats, support the need for additional research into the area of postnatal development of skeletal abnormalities observed in developmental toxicity studies and the relevance of these skeletal observations to human risk assessment. Birth Defects Research 109:1301-1304, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)