Common teratogenic medication exposures-a population-based study of pregnancies in the United States.

BACKGROUND: Risk mitigation for most teratogenic medications relies on risk communication via drug label, and prenatal exposures remain common. Information on the types of and risk factors for prenatal exposures to medications with teratogenic risk can guide strategies to reduce exposure. OBJECTIVE: This study aimed to identify medications with known or potential teratogenic risk commonly used during pregnancy among privately insured persons. STUDY DESIGN: We used the Merative™ MarketScan® Commercial Database to identify pregnancies with live or nonlive (ectopic pregnancies, spontaneous and elective abortions, stillbirths) outcomes among persons aged 12 to 55 years from 2011 to 2018. Start/end dates of medication exposure and pregnancy outcomes were identified via an adapted algorithm based on validation studies. We required continuous health plan enrollment from 90 days before conception until 30 days after the pregnancy end date. Medications with known or potential teratogenic risk were selected from TERIS (Teratogen Information System) and drug monographs based on the level of risk and quality of evidence (138 with known and 60 with potential risk). We defined prenatal exposure on the basis of ≥1 outpatient pharmacy claim or medical encounter for medication administration during target pregnancy periods considering medication risk profiles (eg, risk only in the first trimester or at a certain dose threshold). Sex hormones and hormone analogs, and abortion and postpartum/abortion hemorrhage treatments were not considered as teratogenic medications because of challenges in separating pregnancy-related indications, nor were opioids (because of complex risk-benefit considerations) or antiobesity medications if their only teratogenic mechanism was weight loss. RESULTS: Among all pregnancies, the 10 medications with known teratogenic risk and the highest prenatal exposures were sulfamethoxazole/trimethoprim (1988 per 100,000 pregnancy-years), high-dose fluconazole (1248), topiramate (351), lisinopril (144), warfarin (57), losartan (56), carbamazepine (50), valproate (49), vedolizumab (28 since 2015), and valsartan (25). Prevalence of exposure to sulfamethoxazole/trimethoprim decreased from 2346 to 1453 per 100,000 pregnancy-years from 2011 to 2018, but prevalence of exposure to vedolizumab increased 6-fold since its approval in 2015. Prenatal exposures in the first trimester were higher among nonlive pregnancies than among live-birth pregnancies, with the largest difference observed for warfarin (nonlive 370 vs live birth 78), followed by valproate (258 vs 86) and topiramate (1728 vs 674). Prenatal exposures to medications with potential teratogenic risk were most prevalent for low-dose fluconazole (6495), metoprolol (1325), and atenolol (448). The largest first-trimester exposure differences between nonlive and live-birth pregnancies were observed for lithium (242 vs 89), gabapentin (1639 vs 653), and duloxetine (1914 vs 860). Steady increases in hydralazine and gabapentin exposures were observed during the study years, whereas atenolol exposure decreased (561 to 280). CONCLUSION: Several medications with teratogenic risk for which there are potentially safer alternatives continue to be used during pregnancy. The fluctuating rates of prenatal exposure observed for select teratogenic medications suggest that regular reevaluation of risk mitigation strategies is needed. Future research focusing on understanding the clinical context of medication use is necessary to develop effective strategies for reducing exposures to medications with teratogenic risk during pregnancy.

Mortality and malformation effects of acute vanadium (V) exposure on the African clawed frog (Xenopus laevis) embryos.

Vanadium (V) is a transition metal that is found in low concentrations in aquatic ecosystems. These levels increase due to anthropogenic activities. The mortality and teratogenicity effects of V remain unexplored in amphibian species. To address this gap in the knowledge base, a standard Frog Embryo Teratogenic Index - Xenopus (FETAX) assessment was conducted. Vanadium pentoxide (V2O5) was chosen for its known toxicity in other aquatic biota and its solubility in water. A range-finding test was conducted in two different mediums, V2O5 in distilled water (VDH2O) and V2O5 in FETAX medium (VMED), to determine concentration ranges where effects occurred. Thereafter, definitive tests were conducted using two separate breeding pairs, with two replicate dishes per concentration containing 15 embryos each. Multiple endpoints were assessed including mortality, malformations, minimum concentration to inhibit growth (MCIG), and the teratogenic index (TI). Mortality and malformation effects occurred at different ranges, and therefore, the exposures were conducted in low dose and high dose ranges. The high dose range for mortality effects was conducted at 0, 10, 20, 40, 80, and 160 mg/L of V. The low dose exposures to assess malformation effects were conducted at 0.0001, 0.00025, 0.0005, 0.00075, and 0.001 mg/L. Binary logistic regression was used to determine the LC50 and EC50 for the two sets of definitive tests. The LC50s were determined to be 46.10 mg/L and 26.91 mg/L for VDH2O and 34.50 and 25.25 for VMED for the two breeding pairs respectively. The EC50 was calculated as 0.00053 mg/L and 0.00037 mg/L for VDH2O and 0.00036 mg/L and 0.00017 mg/L for VMED for the two definitive tests respectively. The TI was calculated as 86,981 and 72,729 for VDH2O and 95,833 and 148,526 for VMED. Ultimately, there were severe malformation effects in embryos exposed to low doses of V and V was determined to be a very strong teratogen.

Mutagenic and teratogenic toxicity evaluation of Forsythia suspensa leaves aqueous extract.

Forsythia suspensa leaves (FSL), rich in phillyrin, forsythiaside A, phillygenin, rutin, and other compounds, is a known traditional Chinese medicine (TCM). It has been effective in heat retreat and detoxification. In this study, we performed the mutagenic and teratogenic toxicity evaluation of FSL aqueous extract (FSLAE) using the bacterial reverse mutation assay (Ames test), mouse bone marrow micronucleus assay, spermatocyte chromosomal aberration assay in mice. Kunming mice and SD rats were used were for the mutagenic and the teratogenic studies, respectively. We found that FSLAE was not mutagenic and did not induce unfavorable chromosomal events. Additionally, the Ames test revealed FSLAE was not genotoxic and showed no mutagenic activity in histidine dependent strains of Salmonella typhimurium at concentrations up to 5000 µg/plate. Likewise, in vivo test revealed no induced micronucleus of mouse bone marrow or chromosome aberration in spermatocytes up to the dose of 10.00 g/kg BW. For the teratogenic evaluations, pregnant rats were treated with 1.04, 2.08, and 4.17 g/kg FSL, and fetuses were examined on the 6-15 day of pregnancy. We observed no maternal toxicity and embryotoxicity related to the treatment. Based on these in vitro and in vivo studies, we concluded the genotoxic and teratogenic safety of FSL.

Knockout mouse models are predictive of malformations or embryo-fetal death in drug safety evaluations.

Traditionally, understanding potential developmental toxicity from pharmaceutical exposures has been based on the results of ICH guideline studies in two species. However, support is growing for the use of weight of evidence approaches when communicating the risk of developmental toxicity, where the intended pharmacologic mode of action affects fundamental pathways in developmental biology or phenotypic data from genetically modified animals may increasingly be included in the overall assessment. Since some concern surrounds the use of data from knockout (KO) mice to accurately predict the risk for pharmaceutical modulation of a target, a deeper understanding of the relevance and predictivity of adverse developmental effects in KO mice for pharmacological target modulation is needed. To this end, we compared the results of embryo-fetal development (EFD) studies for 86 drugs approved by the FDA from 2017 to 2019 that also had KO mouse data available in the public domain. These comparisons demonstrate that data from KO mouse models are overall highly predictive of malformations or embryo-fetal lethality (MEFL) from EFD studies, but less so of a negative outcome in EFD studies. This information supports the use of embryo-fetal toxicity data in KO models as part of weight of evidence approaches in the communication of developmental toxicity risk of pharmaceutical compounds.

Review of embryo-fetal developmental toxicity studies performed for pharmaceuticals approved by FDA in 2018 and 2019.

Details of embryo-fetal development (EFD) studies were compiled for all FDA drug approvals in 2018-19. EFD studies were performed for 82 % of approvals (84 % of small molecules and 70 % of biopharmaceuticals). Rats and rabbits were used for 84 % of small molecule (SM) drugs for which EFD studies were submitted. There was at least a 2-fold difference in sensitivity between the rat and the rabbit relative to the human exposure for the majority of drugs (62 %, small molecules and biopharmaceuticals combined) tested in both species. On average, however, the rat and rabbit were equally sensitive to developmental toxicity. Over the last 2 years, the use of non-human primates (NHP) for the developmental toxicity testing of biopharmaceuticals has fallen (26 % of biologics license applications), with many more biopharmaceuticals now tested in rodents (44 % of BLAs). EFD studies were not required for oncology drugs when the mode of action was associated with known developmental risk. One-third of SM non-oncology drugs and two-thirds of SM oncology drugs induced dysmorphogenesis in at least one species. The newly revised ICH S5(R3) guideline will bring about changes to the design of future EFD studies, particularly with respect to high dose selection. The revised guideline will also influence the interpretation of the findings in EFD studies (e.g. fetal morphological variations) and risk assessment.

Green synthesized selenium doped zinc oxide nano-antibiotic: synthesis, characterization and evaluation of antimicrobial, nanotoxicity and teratogenicity potential.

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.

Incorporation of in vitro techniques for botanicals dietary supplement safety assessment - Towards evaluation of developmental and reproductive toxicity (DART).

As complex mixtures, botanicals present unique challenges when assessing safe use, particularly when endpoint gaps exist that cannot be fully resolved by existing toxicological literature. Here we explore in vitro gene expression as well receptor binding and enzyme activity as alternative assays to inform on developmental and reproductive toxicity (DART) relevant modes of action, since DART data gaps are common for botanicals. Specifically, botanicals suspected to have DART effects, in addition to those with a significant history of use, were tested in these assays. Gene expression changes in a number of different cell types were analysed using the connectivity mapping approach (CMap) to identify modes of action through a functional read across approach. Taken together with ligand affinity data obtained using a set of molecular targets customised towards known DART relevant modes of action, it was possible to inform DART risk using functional analogues, potency comparisons and a margin of internal exposure approach.

Anti-Inflammatory Activity of Exopolysaccharides from Phormidium sp. ETS05, the Most Abundant Cyanobacterium of the Therapeutic Euganean Thermal Muds, Using the Zebrafish Model.

The Euganean Thermal District (Italy) represents the oldest and largest thermal center in Europe, and its therapeutic mud is considered a unique product whose beneficial effects have been documented since Ancient Roman times. Mud properties depend on the heat and electrolytes of the thermal water, as well as on the bioactive molecules produced by its biotic component, mainly represented by cyanobacteria. The investigation of the healing effects of compounds produced by the Euganean cyanobacteria represents an important goal for scientific validation of Euganean mud therapies and for the discovering of new health beneficial biomolecules. In this work, we evaluated the therapeutic potential of exopolysaccharides (EPS) produced by Phormidium sp. ETS05, the most abundant cyanobacterium of the Euganean mud. Specifically, Phormidium EPS resulted in exerting anti-inflammatory and pro-resolution activities in chemical and injury-induced zebrafish inflammation models as demonstrated using specific transgenic zebrafish lines and morphometric and expression analyses. Moreover, in vivo and in vitro tests showed no toxicity at all for the EPS concentrations tested. The results suggest that these EPS, with their combined anti-inflammatory and pro-resolution activities, could be one of the most important therapeutic molecules present in the Euganean mud and confirm the potential of these treatments for chronic inflammatory disease recovery.

Optimizing Isotretinoin Treatment of Acne: Update on Current Recommendations for Monitoring, Dosing, Safety, Adverse Effects, Compliance, and Outcomes.

Acne vulgaris is the most common skin disease treated by dermatologists. It can be severe and result in permanent scars. Isotretinoin is the most effective treatment for acne and has the potential for long-term clearance. Prescribing and monitoring protocols can vary widely among prescribers. Recent studies, reports, and consensus statements help shed light on optimizing the use of isotretinoin for acne. A recent literature review is summarized in this article to help the practitioner optimize isotretinoin use for acne. The article outlines the advantages and disadvantages of standard, high-dose, and low-dose isotretinoin regimens; discusses the current status of controversies surrounding isotretinoin (including depression/suicide, pregnancy, and inflammatory bowel disease); reviews monitoring recommendations and treatment for hypertriglyceridemia and elevated transaminase levels; and discusses common adverse effects seen with isotretinoin, along with their treatment and prevention.

Arsenite-Induced Mitochondrial Superoxide Formation: Time and Concentration Requirements for the Effects of the Metalloid on the Endoplasmic Reticulum and Mitochondria.

The present study used human myeloid leukemia U937 cells, a versatile promonocytic cellular system that, based on its endoplasmic reticulum (ER)/mitochondria functional relationships, responds to low micromolar concentrations of arsenite with a single, defined mechanism of superoxide (O2 -.) formation. Under these conditions, we observe an initial Ca2+ mobilization from the ER associated with the mitochondrial accumulation of the cation, which is followed by Ca2+-dependent mitochondrial O2 -. (mitoO2 -.) formation. These events, which were barely detectable after 3 hours, were better appreciated at 6 hours. We found that markedly shorter exposure to arsenite and lower concentrations of arsenite are required to induce extensive O2 - formation in cells supplemented with inositol-1,4,5-trisphosphate receptor (IP3R) or ryanodine receptor (RyR) agonists. Indeed, nanomolar arsenite induced maximal O2 -. formation after only 10 minutes of exposure, and this response was uniquely dependent on the enforced mitochondrial Ca2+ accumulation. The dramatic anticipation of and sensitization to the effects of arsenite caused by the IP3R or RyR agonists were accompanied by a parallel significant genotoxic response in the absence of detectable mitochondrial dysfunction and cytotoxicity. We conclude that the prolonged, low-micromolar arsenite exposure paradigm resulting in mitoO2 -. formation is necessary to affect Ca2+ homeostasis and accumulate the cation in mitochondria. The arsenite requirements to promote mitoO2 -. formation in the presence of sufficient mitochondrial Ca2+ were instead remarkably lower in terms of both concentration and time of exposure. These conditions were associated with the induction of extensive DNA strand scission in the absence of detectable signs of toxicity. SIGNIFICANCE STATEMENT: In respiration-proficient cells, arsenite causes mitochondrial Ca2+ accumulation and Ca2+-dependent mitochondrial superoxide formation. We now report that the second event requires remarkably lower concentrations of and time of exposure to the metalloid than the former. Indeed, a brief exposure to nanomolar levels of arsenite produced maximal effects under conditions in which the mitochondrial Ca2+ concentration ([Ca2+]m) was increased by inositol-1,4,5-trisphosphate receptor or ryanodine receptor agonists. Hence, specific substances or conditions enhancing the [Ca2+]m may potentiate the deleterious effects of arsenite by selectively increasing mitochondrial superoxide formation.

Iron nanoparticle bio-interactions evaluated in Xenopus laevis embryos, a model for studying the safety of ingested nanoparticles.

Iron nanoparticles (NPs) have been proposed as a tool in very different fields such as environmental remediation and biomedical applications, including food fortification against iron deficiency, even if there is still concern about their safety. Here, we propose Xenopus laevis embryos as a suitable model to investigate the toxicity and the bio-interactions at the intestinal barrier of Fe3O4 and zerovalent iron (ZVI) NPs compared to Fe(II) and (III) salts in the 5 to 100 mg Fe/L concentration range using the Frog Embryo Teratogenesis Assay in Xenopus (FETAX). Our results demonstrated that, at concentrations at which iron salts induce adverse effects, both iron NPs do not cause acute toxicity or teratogenicity even if they accumulate massively in the embryo gut. Prussian blue staining, confocal and electron microscopy allowed mapping of iron NPs in enterocytes, along the paracellular spaces and at the level of the basement membrane of a well-preserved intestinal epithelium. Furthermore, the high bioaccumulation factor and the increase in embryo length after exposure to iron NPs suggest greater iron intake, an essential element for organisms. Together, these results improve the knowledge on the safety of orally ingested iron NPs and their interaction with the intestinal barrier, useful for defining the potential risks associated with their use in food/feed fortification.

Endopleura uchi (Huber) Cuatrec.: A medicinal plant for gynecological treatments - A reproductive toxicity assessment in zebrafish (Danio rerio).

ETHNOPHARMACOLOGICAL RELEVANCE: Endopleura uchi (Huber) Cuatrec is a plant species from the Brazilian Amazon. The barks of this tree are used in folk medicine - mainly as a decoction - for dyslipidemia, uterine infection, fibroids, polycystic ovary, menstrual disorders, as a contraceptive and abortive agent, among others. However, the data available about its developmental toxicity are still insufficient. AIM OF THE STUDY: This study aimed to evaluate the reproductive toxicity and teratogenic effects in embryos from zebrafish treated with the hydroethanolic extract from the barks of Endopleura uchi (EEu). MATERIALS AND METHODS: Both sexes of zebrafish (Danio rerio) were treated with EEu either through immersion (1.2, 2.5, and 5 mg/L) or orally (75, 200, and 500 mg/kg) over 21 consecutive days. Next, we assessed their fertility and gonads' histopathology; in their embryos were assessed teratogenesis, lethalities, and heart rate during daily observations (24, 48, 72, and 96 hpf). RESULTS: The phytochemical analysis of EEu through HPLC/MS shows bergenin as the major compounds. After 21 days of treatment were detected minor histopathological changes in parental fishes, such as atretic oocytes, interstitial fibrosis, and decreased the percentage of early vitellogenic oocytes, but without impairing the reproduction of treated animals. However, in the embryos was observed significantly increased frequency of malformation in all the groups treated through immersion, and in the group treated orally with the highest concentration (500 mg/kg). CONCLUSION: Based on the results, EEu caused no adverse effects in the progenitors on both treatments (immersion and oral). However, it was observed that the concentrations 1.2, 2.5, and 5 mg/L (immersion), and the dose 500 mg/kg (oral) caused malformations in the offspring (F1 generation). These results emphasize the need for attention when using preparations from E. uchi, mainly for pregnant women. Further studies are needed to compare its effects with the extract's primary compound (bergenin).

[Teratogenic effects of Xanthoceras sorbifolia Bunge seed on SD rats].

OBJECTIVE: To study the teratogenic effect caused by Xanthoceras sorbifolia Bunge seed on SD rats. METHODS: The experiments were performed in the groups of 2. 0, 4. 0 and 8. 0 g/kg, purified water negative control group and cyclophosphamide positive control group. On the 6 th to 15 th day of pregnancy, the SPF SD rats were exposed to Xanthoceras sorbifolia Bunge seed. All the rats were sacrificed on the day before delivery. Examination were performed on the bones stained by alizarin red and internal organs fixed with Bouins fluid. RESULTS: Maternal body weight, weight gain, uterine fetal weight, net weigh, bed number, corpus luteum number, absorbing births number, live births number, still birth number and percentage and the abnormal rate of appearance, bone, internal organs of each dose group of Xanthoceras sorbifolia, there was no statistical significant difference between Bunge seed groups and negative control group. CONCLUSION: Under the conditions of this experiment, the Xanthoceras sorbifolia Bunge seed had no maternal toxicity to pregnant SD rats, no teratogenic and developmental toxicity to fetal rats. No Observed Adverse Effect Level of maternal toxicity and the minimum teratogenic dose of fetal rats is >8. 0 g/kg.

Accuracy, discriminative properties and reliability of a human ESC-based in vitro toxicity assay to distinguish teratogens responsible for neural tube defects.

The poor correlation of developmental toxicity studies in animals with human outcome data has emphasized the need for complementary assays based on human cells and tissues. As neural tube defects represent an important proportion of congenital malformations, we evaluated here the accuracy of a human embryonic stem cell (hESC)-based assay to predict chemically induced disruption of neural tube formation. As teratogenic compounds, we used cyclopamine (CPA), valproic acid (VPA), ochratoxin A (OTA) and mycophenolic acid (MMF), all suspected or known inducers of human neural tube defects, as well as theophylline and saccharin as negative control compounds. We analyzed their effects on the ability of hES cells to give rise to neural precursors (expressing specific marker Nestin), to form neural tube-like structures (rosettes), and to express specific markers (Sox1, Otx2, Lix1, EvI1, Rspo3) during rosette formation. The results showed that various effects of the selected compounds on early neural development could be specifically revealed in vitro through related alterations of neurogenic differentiation of hESC. Furthermore, it was possible to discriminate toxicants acting at different time points during embryonic development and, therefore, responsible for distinct adverse effects on neural tube formation. By comparing four different hESC lines, we observed a significant (up to fivefold) variability of the line-dependent response to toxicants. We highlight at least two sources of variability: one related to the heterogeneity of hESC lines in culture (stemness/commitment profiles); the second to possible genetically determined differences in individual sensitivity to teratogens.

Comparative Analysis of the Developmental Toxicity in Xenopus laevis and Danio rerio Induced by Al2 O3 Nanoparticle Exposure.

Engineered aluminum oxide nanoparticles (Al2 O3 NPs) having high-grade thermal stability and water-dispersion properties are extensively used in different industries and personal care products. Toxicological response evaluation of these NPs is indispensable in assessing the health risks and exposure limits because of their industrial disposal into the aquatic environment. We assessed and compared the developmental toxicity of Al2 O3 NPs in Xenopus laevis and Danio rerio over a period of 96 h using the frog embryo teratogenic assay Xenopus and a fish embryo toxicity assay. Engineered Al2 O3 NP exposure produced dose-dependent embryonic mortality and decreased the embryo length, indicating a negative effect on growth. Moreover, Al2 O3 NPs induced various malformations, such as small head size, a bent/deformed axis, edema, and gut malformation, dose-dependently and altered the expression of heart- and liver-specific genes in both X. laevis and D. rerio, as revealed by whole-mount in-situ hybridization and reverse transcriptase polymerase chain reaction. In conclusion, the toxicological data suggest that Al2 O3 NPs are developmentally toxic and teratogenic and negatively affect the embryonic development of X. laevis and D. rerio. Our study can serve as a model for the toxicological evaluation of nanomaterial exposure on vertebrate development that is critical to ensure human and environmental safety. Environ Toxicol Chem 2019;38:2672-2681. © 2019 SETAC.

Plasmonic MXene-based nanocomposites exhibiting photothermal therapeutic effects with lower acute toxicity than pure MXene.

Purpose: Here, we fabricated two plasmonic 2D Ti3C2Tx-based nanocomposites (Au/MXene and Au/Fe3O4/MXene) with similarly high anti-cancer photothermal therapy (PTT) capabilities, but with less in vivo toxicity than a pure MXene. Methods: Au/MXene was synthesized by in situ reduction of tetrachloroauric acid using NaBH4 on Ti3C2Tx flakes. For targeted PTT, magnetic Au/Fe3O4/MXene was synthesized via a reaction between freshly prepared magnetite Fe3O4 NPs and MXene solution, followed by in situ integration of gold nanoparticles (AuNPs). Results: Morphological characterization by XRD, SEM, and TEM revealed the successful synthesis of Au/MXene and Au/Fe3O4/MXene. Both new composites exhibited a significant in vitro dose-dependent PTT effect against human breast cancer cells MCF7. Interestingly, in vivo acute toxicity assays using zebrafish embryos indicated that Au/MXene and Au/Fe3O4/MXene had less embryonic mortality (LC50 ≫ 1000 µg/mL) than pure MXene (LC50=257.46 µg/mL). Conclusion: Our new Au/MXene and Au/Fe3O4/MXene nanocomposites could be safer and more suitable than the pure MXene for biomedical applications, especially when targeted PTT is warranted.

Evaluation of in vitro embryotoxicity tests for Chinese herbal medicines.

Chinese herbal medicines (CHMs) have been widely used during pregnancy, but feto-embryo safety tests are lacking. Here we evaluated in vitro embryotoxicity tests (IVTs) as alternative methods in assessing developmental toxicity of CHMs. Ten CHMs were selected and classified as strongly, weakly and non-embryotoxic. Three well validated IVTs and prediction models (PMs), including embryonic stem cell test (EST), micromass (MM) and whole embryo culture (WEC), were compared. All strongly embryotoxic CHMs were predicted by MM and WEC PM2. While all weakly embryotoxic CHMs were predicted by MM and WEC PM1. All non-embryotoxic CHMs were classified by EST, MM, but over-classified as weakly embryotoxic by WEC PM1. Overall predictivity, precision and accuracy of WEC determined by PM2 were better than EST and MM tests. Compared with validated chemicals, performance of IVTs for CHMs was comparable. So IVTs are adequate to identify and exclude embryotoxic potential of CHMs in this training set.

Exposure assessments in reproductive and developmental toxicity testing: An IQ-DruSafe industry survey on current practices and experiences in support of exposure-based high dose selection.

The draft ICH S5(R3) guideline includes an exposure-based endpoint as an option for selecting the high dose in developmental and reproductive toxicity (DART) studies. In 2016, IQ DruSafe conducted an anonymous survey to identify industry practices and experiences related to pharmacokinetic assessments in DART studies in order to facilitate a pragmatic data-driven approach to development of an acceptable multiple of the clinical exposure to be proposed for dose selection in the guideline. Questions in the survey were designed to explore pharmacokinetic differences in pregnant versus non-pregnant animals, and to assess exposure levels attained in the absence of maternal toxicity as well as DART outcomes in animal studies associated with those exposures. Small molecule and therapeutic proteins were analyzed separately. The key findings for small molecules were: a) differences in exposures between pregnant and non-pregnant animals were generally ≤3-fold, b) Cmax or AUC exposures ≥25-fold the clinical exposure were achieved in the absence of maternal toxicity for 31% and 23% of rat and rabbit developmental toxicity studies, respectively, and c) only 3.3% (5/153) and 1.6% (2/128) of the developmental toxicity studies were positive for malformations or embryofetal lethality in rats and rabbits, respectively, that were not observed until exposure margins were ≥25-fold.

Hollow selenium nanoparticles from potato extract and investigation of its biological properties and developmental toxicity in zebrafish embryos.

A facile synthesis of hollow selenium nanoparticles (hSeNPs) was prepared using potato starch as a reducing and capping agent. The morphological and structural characters of the hSeNPs were characterised by ultraviolet-visible spectroscopy (UV), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM) coupled with energy dispersive X-ray spectroscopy (EDX) and zeta potential analyser. The optical characteristics of hSeNPs were confirmed by UV. The presence of various functional groups in the hSeNPs suspension was confirmed by FTIR. The SEM results suggested that the synthesised hSeNPs were uniformly distributed and circular in shape with a hollow. The average size of the hSeNPs was found to be around 115 nm. The EDX analysis also confirmed the presence of hSeNPs in the sample. The zebrafish embryos were treated with hSeNPs of various concentrations ranging from 10 to 50 µg/ml. Abnormalities such as improper heartbeat, embryo sac oedema, ocular oedema and head oedema were noted at higher concentrations (30-50 µg/ml). A concentration-dependent antioxidant activity of hSeNPs was observed. The hSeNPs showed good antibacterial activity against gram-positive Bacillus subtilis and gram-negative Escherichia coli. The results of this study indicate that potato extract reduces the toxicity of hSeNPs and lower concentrations of hSeNPs could be used for various biomedical applications in near future.

Lethality, neurotoxicity, morphological, histological and cellular alterations of Ni-Al nanoceramics on the embryo-larval development of Rhinella arenarum.

Alumina nanoparticles (NP-Al2O3) are widely used but their environmental effects are unknown, so they can become potentially dangerous. The aim of this study was to evaluate the toxicity of a nanoceramic catalyst Ni/γ-Al2O3 (NC) and NPs involved in their synthesis, γ-Al2O3 support (SPC) and NiO/γ-Al2O3 precursor (PC) on Rhinella arenarum embryo-larval development. The NPs toxicity significantly increased over time obtaining a similar sensitivity to PC and NC (336 h-LC50 = 4.03 and 5.11 mg/L respectively) and very low sensitivity to SPC (336 h-LC50 = 90.83 mg/L). Embryos exposed to SPC and PC exhibited general underdevelopment, axial flexures and behavioral alterations. Pharyngeal and intestinal epithelia alterations at the level of cell surface as dissociation, apoptosis and numerous lysosomes were observed at light and transmission electronic microscopy. Images of scanning electron microscope with backscattered electron detector revealed the presence of nickel in the intestinal epithelium. The increased toxicity of PC could be due to the presence of Ni as oxide which could interfere with vital functions such as breathing and feeding. Taking into account the exponential production and use of these NPs it is expected that their pollution levels will considerably increase and amphibians will be more exposed and at higher risk.