scholarly journals Histopathology of Zebrafish (Danio rerio) in Nonclinical Toxicological Studies of New Drugs

2020 ◽  
Author(s):  
Raphaelle Sousa Borges ◽  
Arlindo César Matias Pereira ◽  
Gisele Custodio de Souza ◽  
José Carlos Tavares Carvalho
Keyword(s):  
Danio Rerio ◽  
New Drugs ◽  
Toxicological Studies

scholarly journals Cytochrome P450-dependent biotransformation capacities in embryonic, juvenile and adult stages of zebrafish (Danio rerio)—a state-of-the-art review

2021 ◽  
Author(s):  
Ann-Kathrin Loerracher ◽  
Thomas Braunbeck
Keyword(s):  
Cytochrome P450 ◽  
Phase I ◽  
Mrna Expression ◽  
Danio Rerio ◽  
Developmental Stages ◽  
State Of The Art ◽  
Adverse Outcome Pathway ◽  
Zebrafish Embryos ◽  
Toxicological Studies ◽  
Cyp Isoforms

AbstractGiven the strong trend to implement zebrafish (Danio rerio) embryos as translational model not only in ecotoxicological, but also toxicological testing strategies, there is an increasing need for a better understanding of their capacity for xenobiotic biotransformation. With respect to the extrapolation of toxicological data from zebrafish embryos to other life stages or even other organisms, qualitative and quantitative differences in biotransformation pathways, above all in cytochrome P450-dependent (CYP) phase I biotransformation, may lead to over- or underestimation of the hazard and risk certain xenobiotic compounds may pose to later developmental stages or other species. This review provides a comprehensive state-of-the-art overview of the scientific knowledge on the development of the CYP1-4 families and corresponding phase I biotransformation and bioactivation capacities in zebrafish. A total of 68 publications dealing with spatiotemporal CYP mRNA expression patterns, activities towards mammalian CYP-probe substrates, bioactivation and detoxification activities, as well as metabolite profiling were analyzed and included in this review. The main results allow for the following conclusions: (1) Extensive work has been done to document mRNA expression of CYP isoforms from earliest embryonic stages of zebrafish, but juvenile and adult zebrafish have been largely neglected so far. (2) There is insufficient understanding of how sex- and developmental stage-related differences in expression levels of certain CYP isoforms may impact biotransformation and bioactivation capacities in the respective sexes and in different developmental stages of zebrafish. (3) Albeit qualitatively often identical, many studies revealed quantitative differences in metabolic activities of zebrafish embryos and later developmental stages. However, the actual relevance of age-related differences on the outcome of toxicological studies still needs to be clarified. (4) With respect to current remaining gaps, there is still an urgent need for further studies systematically assessing metabolic profiles and capacities of CYP isoforms in zebrafish. Given the increasing importance of Adverse Outcome Pathway (AOP) concepts, an improved understanding of CYP capacities appears essential for the interpretation and outcome of (eco)toxicological studies.

The chick embryo chorioallantoic membrane model: a research approach for ex vivo and in vivo experiments

2021 ◽  
Vol 28 ◽  
Author(s):  
Ana Isabel Fraguas-Sánchez ◽  
Cristina Martín-Sabroso ◽  
Ana Isabel Torres-Suárez
Keyword(s):  
Animal Models ◽  
Chorioallantoic Membrane ◽  
New Drugs ◽  
Biological Research ◽  
Research Areas ◽  
Chick Chorioallantoic Membrane ◽  
Biodistribution Studies ◽  
Toxicological Studies ◽  
Cam Model

Background: The chick chorioallantoic membrane (CAM) model has attracted a great deal of interest in pharmaceutical and biological research as an alternative or complementary in vivo assay to animal models. Traditionally, CAM assay has been widely used to perform some toxicological studies, specifically to evaluate the skin, ocular and embryo toxicity of new drugs and formulations, and perform angiogenesis studies. Due to the possibility to generate the tumors onto the CAM, this model has also become an excellent strategy to evaluate the metastatic potential of different tumours and test the efficacy of novel anticancer therapies in vivo. Moreover, in the recent years, its use has considerably grown in other research areas, including the evaluation of new anti-infective agents, the development of biodistribution studies and tissue engineering research. Objectives: This manuscript provides a critical overview of the use of CAM model in pharmaceutical and biological research, especially to test the toxicity of new drugs and formulations and the biodistribution and the efficacy of novel anticancer and anti-infective therapies, analyzing its advantages and disadvantages compared to animal models. Conclusion: The chick chorioallantoic membrane model shows great utility in several research areas, such as cancer, toxicology, biodistribution studies and anti-infective therapies. In fact, it has become an intermediate stage between in vitro experiments and animal studies, and, in the case of toxicological studies (skin and ocular toxicity), has even replaced the animal models.

scholarly journals Use of zebrafish (Danio rerio) as a model for research in toxicological studies

2021 ◽  
Vol 13 (3) ◽  
pp. 846-852
Author(s):  
Kalpana Singh ◽  
Satyendra Kumar Kashyap ◽  
Vandana Garg
Keyword(s):  
Danio Rerio ◽  
Health And Safety ◽  
Test System ◽  
Model Organisms ◽  
Molecular Signaling ◽  
Environmental Health And Safety ◽  
Good Test ◽  
Toxicological Studies ◽  
The Three Rs ◽  
Molecular Signaling Pathway

Danio rerio, commonly known as zebrafish, is a freshwater aquarium fish and is native to parts of South Asia. It is considered an important organism for analyzing the noxious effects of toxicants and pollutants of the environment. In terms of the molecular signaling pathway, molecular properties, organ functions and structures, and neurogenesis, zebrafish are similar to certain other higher-order vertebrates. The 3Rs, refinement,reduction, and replacement in researchhavegradually evolved with time. The accumulation of toxicants in the environment and the human health conditions from exposure to toxicants present in the environment is a serious concern, and zebrafish serves as an excellent model to research such effects. The three Rs are met by zebrafish, larvae can also be used to discover harmful medication compounds, permitting safer compounds to be explored in model organisms and it could also be used to substitute certain toxicological testing.Also, because embryos are fertilized outside and are visible during the initial days of life, the early larval model of zebrafish enables flexibility to animal research study, subsequently reducing the number of animals employed in experiments.For various experimentation studies, the larva of the zebrafish is proved to be a useful model for the system.Thus, being a good test system, zebrafish are used in environmental health and safety studies.This review focuses on the toxicological studiesin zebrafish and outlines the toxicological studies done on zebrafish with arsenic and 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) as well as microplastic toxicity.

scholarly journals Mixture toxic impacts and the related mechanism of aflatoxin B1 and deoxynivalenol on embryonic zebrafish (Danio rerio)

2021 ◽  
Vol 33 (1) ◽  
Author(s):  
Yanhua Wang ◽  
Qiang Wang ◽  
Chun Ji ◽  
Xiaoxuan Guo ◽  
Guiling Yang ◽  
...  
Keyword(s):  
Danio Rerio ◽  
Aflatoxin B1 ◽  
Caspase 3 ◽  
Endocrine System ◽  
Combined Toxicity ◽  
Single Exposure ◽  
Comprehensive Investigation ◽  
Toxicological Studies ◽  
Food And Feed ◽  
Cellular Apoptosis

Abstract Background Although humans and animals are often simultaneously exposed to a variety of mycotoxins via feed and food consumption, in which aflatoxin B1 (AFB1) and deoxynivalenol (DON) is one of the most prevalent combination of mycotoxins. Many toxicological studies have merely focused on the impacts of single mycotoxins. In the present study, the combined toxicity and the related mechanism of AFB1 and DON to zebrafish (Danio rerio) were investigated. Results Results exhibited that DON had lower toxicity to embryonic zebrafish with a 7-day LC50 of 218.3 mg a.i. L−1 in comparison to AFB1 (0.031 mg a.i. L−1). The mixture of AFB1 and DON elicited an additive combined effect on zebrafish embryos. The levels of CAT, caspase-3, and T4 markedly varied in most single and mixture groups. The expressions of four genes (cas3, apaf-1, cc-chem, and cyp19a) associated with oxidative stress, cellular apoptosis, immune system, and endocrine system were markedly varied upon the mixture exposure in comparison to the corresponding single exposure of AFB1 or DON. Conclusions Our results revealed that the impacts of a mixture could not be estimated solely based on toxicities of the single mycotoxins. Taken together, our comprehensive investigation on the mycotoxin mixtures and their potential mechanisms could better reflect the reality of mycotoxin contamination in food and feed.

scholarly journals Feasibility of intravitreal injections and ophthalmic safety assessment in marmoset (Callithrix jacchus) monkeys

2017 ◽  
Vol 4 (1) ◽  
pp. 93-100
Author(s):  
Birgit Korbmacher ◽  
Jenny Atorf ◽  
Stephanie Fridrichs-Gromoll ◽  
Marilyn Hill ◽  
Sven Korte ◽  
...  
Keyword(s):  
Cynomolgus Monkey ◽  
Toxicity Testing ◽  
Common Marmoset ◽  
Callithrix Jacchus ◽  
Study Data ◽  
New Drugs ◽  
Intravitreal Injections ◽  
Ocular Toxicity ◽  
Toxicological Studies ◽  
The Common

Abstract. To safeguard patients, regulatory authorities require that new drugs that are to be given by the intravitreal (IVT) route are assessed for their safety in a laboratory species using the same route of administration. Due to the high similarity of ocular morphology and physiology between humans and nonhuman primates (NHPs) and due to the species specificity of many biotherapeutics, the monkey is often the only appropriate model. To this end, intravitreal administration and assessment of ocular toxicity are well established in cynomolgus monkeys (Macaca fascicularis). In contrast, the common marmoset monkey (Callithrix jacchus) is not a standard model for ocular toxicity studies due to its general sensitivity to laboratory investigations and small eye size. It was the purpose of the present work to study whether the marmoset is a useful alternative to the cynomolgus monkey for use in intravitreal toxicological studies. Six marmoset monkeys received repeated (every 2 weeks for a total of four doses) intravitreal injections of 10 or 20 µL of a placebo. The animals were assessed for measurements of intraocular pressure (IOP), standard ophthalmological investigations and electroretinography (ERG). At the end of the dosing period, the animals were sacrificed and the eyes were evaluated histologically. ERG revealed similar results when comparing predose to end-of-study data, and there was no difference between the two dose volumes. A transient increase in the IOP was seen immediately after dosing, which was more pronounced after dosing of 20 µL compared to 10 µL. Ophthalmologic and microscopic observations did not show any significant changes. Therefore, it can be concluded that 10 µL as well as 20 µL intravitreal injections of a placebo are well tolerated in the marmoset. These results demonstrate that the common marmoset is an alternative to the cynomolgus monkey for intravitreal toxicity testing.

Investigation of Genotoxicity and Cytotoxicity of Nanocomposite Highly Dispersed Silica with Silver Nanoparticles

10.12737/2725 ◽  
2013 ◽  
Vol 20 (4) ◽  
pp. 44-47
Author(s):  
Савченко ◽  
D. Savchenko
Keyword(s):  
Silver Nanoparticles ◽  
Antimicrobial Agents ◽  
High Efficiency ◽  
Practical Interest ◽  
Eukaryotic Cell ◽  
New Drugs ◽  
Carcinoma Larynx ◽  
Highly Dispersed Silica ◽  
Toxicological Studies ◽  
Highly Dispersed

Provision of high efficiency and quality of drugs developed on the basis of nanotechnology is possible only under the requirements for the development, research, production and introduction of new pharmacological agents. Determination of genotoxicity and cytotoxicity is the first stage of toxicological studies of newly synthetized substances, the aim of which is to determine the ability to induce primary DNA and cell cultures damages. Such studies provide information about primary toxic effects of substances and constitute a basis for confirming the safety of new drugs. Considering a constant need for the introduction of new antimicrobial agents for treatment of intestinal infections, it is expedient to develop combinative drugs which will have better efficacy and safety. Significant scientific and practical interest has study of drugs based on nanosilver, which is active against antibiotic-resistant microorganisms. By the Department of Pharmacology and Clinical Pharmacology of Bogomoletz National Medical University and Chuiko Institute of Surface Chemistry NAS of Ukraine was specifically designed and synthesized nanocomposite highly dispersed silica with silver nanoparticles, which is considered as a promising drug with a complex of antibacterial and sorption-detoxication properties. The purpose of this work is to study the cytotoxicity and genotoxicity of nanocomposite highly dispersed silica with silver nanoparticles. The degree of DNA damage by nanocomposite was studied by alkaline gel electrophoresis of isolated cell test culture CHO-Kl. Investigation of cytotoxicity was carried out on passaged eukaryotic cell culture of human epidermoid carcinoma larynx (Hep-2). It is shown that nanocomposite highly dispersed silica with silver nanoparticles does not have genotoxic properties, and its cytotoxicity disappears at concentrations below 0,007%.

scholarly journals Effects of alkaloids on peripheral neuropathic pain: a review

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Chunhao Zhu ◽  
Ning Liu ◽  
Miaomiao Tian ◽  
Lin Ma ◽  
Jiamei Yang ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Molecular Mechanisms ◽  
Herbal Medicines ◽  
New Drugs ◽  
Intractable Pain ◽  
Chinese Herbal Medicines ◽  
Peripheral Neuropathic Pain ◽  
Chinese Herbal ◽  
Toxicological Studies ◽  
Novel Drugs

Abstract Neuropathic pain is a debilitating pathological pain condition with a great therapeutic challenge in clinical practice. Currently used analgesics produce deleterious side effects. Therefore, it is necessary to investigate alternative medicines for neuropathic pain. Chinese herbal medicines have been widely used in treating intractable pain. Compelling evidence revealed that the bioactive alkaloids of Chinese herbal medicines stand out in developing novel drugs for neuropathic pain due to multiple targets and satisfactory efficacy. In this review, we summarize the recent progress in the research of analgesic effects of 20 alkaloids components for peripheral neuropathic pain and highlight the potential underlying molecular mechanisms. We also point out the opportunities and challenges of the current studies and shed light on further in-depth pharmacological and toxicological studies of these bioactive alkaloids. In conclusion, the alkaloids hold broad prospects and have the potentials to be novel drugs for treating neuropathic pain. This review provides a theoretical basis for further applying some alkaloids in clinical trials and developing new drugs of neuropathic pain.

scholarly journals Investigation of Fertilizing Capacity of Zebrafish (Danio rerio) Sperm Exposed to Heavy Metals

Dose-Response ◽  
2020 ◽  
Vol 18 (2) ◽  
pp. 155932582091959
Author(s):  
Flóra Kerekes ◽  
Tímea Kollár ◽  
Gyöngyi Gazsi ◽  
Eszter Kása ◽  
Béla Urbányi ◽  
...  
Keyword(s):  
Heavy Metals ◽  
Embryonic Development ◽  
Danio Rerio ◽  
Aquatic Environment ◽  
Fertilization Rate ◽  
Effective Concentration ◽  
Toxicological Studies ◽  
Half Maximal Effective Concentration ◽  
The Given

The objective of our study was to investigate the effects of heavy metals on the fertilizing capacity of exposed zebrafish sperm, on embryonic survival, and on occurrence of embryonic deformities following fertilization with exposed sperm. It is important to test heavy metals because they are well-known pollutants. Sperm of externally fertilizing species can get in contact with pollutants found in aquatic environment. Zebrafish sperm, despite its advantages, has seldom been used in in vitro toxicological studies and no reports are available regarding the fertilizing capacity of exposed sperm. Zebrafish sperm was stripped and exposed to concentrations of the tested heavy metals (Zn2+, Cd2+, Cr3+, Cu2+, Ni2+, Hg2+, As3+) for 30 or 120 minutes. Calculated half-maximal effective concentration (EC50) values do not differ significantly from those calculated for motility for any of the tested heavy metals, which means fertilization rate can indicate the toxicity of the given substance following exposure of sperm. Thus, its application as in vitro toxicological end point is reasonable. The survival of embryos and embryonic development have not been affected by the exposure of spermatozoa, which means all alterations in spermatozoa caused by heavy metals have been expressed before 24 hours post fertilization.

scholarly journals Organ-on-a-Chip systems for new drugs development

ADMET & DMPK ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 111-141
Author(s):  
Ronny Vargas ◽  
Laura Medina ◽  
Andrea Egurbide
Keyword(s):  
Cell Lines ◽  
Cell Cultures ◽  
Three Dimensional ◽  
New Drugs ◽  
Human Beings ◽  
Functional Impairments ◽  
Chip Technology ◽  
Toxicological Studies ◽  
Organ Tissue ◽  
Organ On A Chip

Research on alternatives to the use of animal models and cell cultures has led to the creation of organ-on-a-chip systems, in which organs and their physiological reactions to the presence of external stimuli are simulated. These systems could even replace the use of human beings as subjects for the study of drugs in clinical phases and have an impact on personalized therapies. Organ-on-a-chip technology present higher potential than traditional cell cultures for an appropriate prediction of functional impairments, appearance of adverse effects, the pharmacokinetic and toxicological profile and the efficacy of a drug. This potential is given by the possibility of placing different cell lines in a three-dimensional-arranged polymer piece and simulating and controlling specific conditions. Thus, the normal functioning of an organ, tissue, barrier, or physiological phenomenon can be simulated, as well as the interrelation between different systems. Furthermore, this alternative allows the study of physiological and pathophysiological processes. Its design combines different disciplines such as materials engineering, cell cultures, microfluidics and physiology, among others. This work presents the main considerations of OoC systems, the materials, methods and cell lines used for their design, and the conditions required for their proper functioning. Examples of applications and main challenges for the development of more robust systems are shown. This non-systematic review is intended to be a reference framework that facilitates research focused on the development of new OoC systems, as well as their use as alternatives in pharmacological, pharmacokinetic and toxicological studies.

Zebrafish (Danio rerio) neuromast: Promising biological endpoint linking developmental and toxicological studies

2009 ◽  
Vol 95 (4) ◽  
pp. 307-319 ◽  
Author(s):  
Mirjam Froehlicher ◽  
Anja Liedtke ◽  
Ksenia J. Groh ◽  
Stephan C.F. Neuhauss ◽  
Helmut Segner ◽  
...  
Keyword(s):  
Danio Rerio ◽  
Toxicological Studies ◽  
Biological Endpoint
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