ASSESSING RISKS CAUSED BY NICKEL-CONTAINING NANOMATERIALS: HAZARD CHARACTERIZATION IN VIVO

Health Risk Analysis ◽

10.21668/health.risk/2021.3.18 ◽

2021 ◽

pp. 177-191

Author(s):

I.V. Gmoshinski ◽

◽

S.A. Khotimchenko ◽

Keyword(s):

Human Health Risk ◽

Reproductive Toxicity ◽

Construction Materials ◽

Toxic Effects ◽

Laboratory Animals ◽

Hazard Characterization ◽

Carcinogenic Potential ◽

Transforma Tion

Nanoparticles (NP) of nickel (Ni) and its compounds are promising materials for being used as catalysts in chemical, pharmaceutical and food industry; as construction materials in electronics and optoelectronics, in manufacturing current sources, medications, diagnostic preparations, and pesticides. Annual production volumes for these materials in their nano- form are equal to dozen tons and are expected to growth further. According to data obtained via multiple research nano- forms of Ni and its compounds are toxic to many types of cells; stimulate apoptosis; and can induce malignant transforma- tion in vitro. It indicates that this group of nanomaterials can possibly be hazardous for human health. Risk assessment in- cludes such a necessary stage as quantitative hazard characterization, that is, establishing toxic and maximum no-observed- adverse-effect levels (NOAEL) for a nanomaterial that penetrates into a body via inhalation, through undamaged skin, or the gastrointestinal tract. Experiments in vivo performed on laboratory animals with Ni-containing materials revealed overall toxic effects; toxicity to specific organs (including hepatoxoticity and cardiotoxicity); atherogenic, allergenic, and immune- toxic effects, as well as reproductive toxicity. There are multiple available data indicating that all Ni-containing nanomate- rials are genotoxic and mutagenic, though data on their carcinogenic potential are rather scarce. Factors that determine toxicity of Ni and its compounds in nanoform are their ability to penetrate through biological barriers and to release free Ni++ ions in biological media. The review focuses on analyzing and generalizing data on toxicity signs in vivo and effective toxic doses under various introductions of Ni and its compounds in nanoform into a body over a period starting predominantly from 2011.

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ASSESSING RISKS CAUSED BY NICKEL-CONTAINING NANOMATERIALS: HAZARD CHARACTERIZATION IN VIVO

Health Risk Analysis ◽

10.21668/health.risk/2021.3.18.eng ◽

2021 ◽

pp. 177-191

Author(s):

I.V. Gmoshinski ◽

◽

S.A. Khotimchenko ◽

◽

Keyword(s):

Human Health Risk ◽

Reproductive Toxicity ◽

Construction Materials ◽

Toxic Effects ◽

Laboratory Animals ◽

Hazard Characterization ◽

Carcinogenic Potential ◽

Transforma Tion

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Evaluation of Resmethrin Toxicity to Neonatal Testes in Organ Culture

Toxicological Sciences ◽

10.1093/toxsci/kfz212 ◽

2019 ◽

Vol 173 (1) ◽

pp. 53-64 ◽

Cited By ~ 5

Author(s):

Hyun-Jung Park ◽

Won-Young Lee ◽

Mingtian Zhang ◽

Kwon-Ho Hong ◽

Chankyu Park ◽

...

Keyword(s):

Organ Culture ◽

Germ Cells ◽

Methodological Approach ◽

Reproductive Toxicity ◽

Laboratory Animals ◽

Marker Genes ◽

Low Toxicity ◽

Apoptotic Effects

Abstract Resmethrin is a widely used pyrethroid insecticide, which causes low toxicity in mammals. However, its toxicity in testes has not been fully investigated. Therefore, we evaluated the toxicity of resmethrin in mouse testes using an in vitro organ culture. Mouse testicular fragments (MTFs) derived from neonates were cultured in medium containing resmethrin for 30 days. Effects on spermatogenesis in the cultured testes were investigated as functions of both time and dose. Resmethrin significantly downregulated the transcription levels of marker genes for spermatogonia and the number of spermatogenic germ cells relative to those of the controls, according to quantitative PCR and immunostaining. In addition, spermatocyte was observed in the control, but not in 50 μM resmethrin-exposed cultures. Levels of the SYCP3 meiotic marker and phosphorylated H2AX decreased by resmethrin treatment, as observed by Western blotting. Toxic or apoptotic effects of resmethrin in Sertoli and Leydig cells from MTFs were not observed by immunostaining and Tunnel assay. No changes in the expression of steroidogenic enzymes were noted. Apoptosis was only detected in the germ cells of resmethrin-treated MTFs. Thus, the highest dose of resmethrin tested (50 μM) completely inhibited spermatogenesis, because of apoptosis of germ cells and spermatocytes. Although the in vivo toxicity of resmethrin has not yet been studied in detail, significant evidence for cytotoxicity was observed in our organ cultures. This methodological approach is useful for the study of reproductive toxicity before proceeding to animal models, as it greatly reduces the use of laboratory animals.

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Neurotoxicity of Pesticides: The Roadmap for the Cubic Mode of Action

Current Medicinal Chemistry ◽

10.2174/0929867326666190704142354 ◽

2020 ◽

Vol 27 (1) ◽

pp. 54-77 ◽

Cited By ~ 2

Author(s):

Bogdan Bumbăcilă ◽

Mihai V. Putz

Keyword(s):

Biological Activity ◽

Wiener Index ◽

Laboratory Animals ◽

Covalent Bonds ◽

Organophosphate Compounds ◽

Sar Studies ◽

Structure Activity ◽

Cubic Structure

Pesticides are used today on a planetary-wide scale. The rising need for substances with this biological activity due to an increasing consumption of agricultural and animal products and to the development of urban areas makes the chemical industry to constantly investigate new molecules or to improve the physicochemical characteristics, increase the biological activities and improve the toxicity profiles of the already known ones. Molecular databases are increasingly accessible for in vitro and in vivo bioavailability studies. In this context, structure-activity studies, by their in silico - in cerebro methods, are used to precede in vitro and in vivo studies in plants and experimental animals because they can indicate trends by statistical methods or biological activity models expressed as mathematical equations or graphical correlations, so a direction of study can be developed or another can be abandoned, saving financial resources, time and laboratory animals. Following this line of research the present paper reviews the Structure-Activity Relationship (SAR) studies and proposes a correlation between a topological connectivity index and the biological activity or toxicity made as a result of a study performed on 11 molecules of organophosphate compounds, randomly chosen, with a basic structure including a Phosphorus atom double bounded to an Oxygen atom or to a Sulfur one and having three other simple covalent bonds with two alkoxy (-methoxy or -ethoxy) groups and to another functional group different from the alkoxy groups. The molecules were packed on a cubic structure consisting of three adjacent cubes, respecting a principle of topological efficiency, that of occupying a minimal space in that cubic structure, a method that was called the Clef Method. The central topological index selected for correlation was the Wiener index, since it was possible this way to discuss different adjacencies between the nodes in the graphs corresponding to the organophosphate compounds molecules packed on the cubic structure; accordingly, "three dimensional" variants of these connectivity indices could be considered and further used for studying the qualitative-quantitative relationships for the specific molecule-enzyme interaction complexes, including correlation between the Wiener weights (nodal specific contributions to the total Wiener index of the molecular graph) and the biochemical reactivity of some of the atoms. Finally, when passing from SAR to Q(uantitative)-SAR studies, especially by the present advanced method of the cubic molecule (Clef Method) and its good assessment of the (neuro)toxicity of the studied molecules and of their inhibitory effect on the target enzyme - acetylcholinesterase, it can be seen that a predictability of the toxicity and activity of different analogue compounds can be ensured, facilitating the in vivo experiments or improving the usage of pesticides.

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Bioavailability Evaluation of Perchlorate in Different Foods In Vivo: Comparison with In Vitro Assays and Implications for Human Health Risk Assessment

Journal of Agricultural and Food Chemistry ◽

10.1021/acs.jafc.1c00539 ◽

2021 ◽

Author(s):

Xin Liu ◽

Hu Zhang ◽

Yimei Tian ◽

Min Fang ◽

Lin Xu ◽

...

Keyword(s):

Risk Assessment ◽

Health Risk ◽

Human Health ◽

Health Risk Assessment ◽

Human Health Risk ◽

Human Health Risk Assessment ◽

In Vitro Assays

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In Vitro Toxicology Methods in Risk Assessment

Alternatives to Laboratory Animals ◽

10.1177/026119299602400305 ◽

1996 ◽

Vol 24 (3) ◽

pp. 325-331

Author(s):

Iain F. H. Purchase

Keyword(s):

Risk Assessment ◽

Hazard Assessment ◽

Human Health Risk ◽

In Vitro Test ◽

In Vitro Methods ◽

New Concepts ◽

Vitro Test

The title of this paper is challenging, because the question of how in vitro methods and results contribute to human health risk assessment is rarely considered. The process of risk assessment usually begins with hazard assessment, which provides a description of the inherent toxicological properties of the chemical. The next step is to assess the relevance of this to humans, i.e. the human hazard assessment. Finally, information on exposure is examined, and risk can then be assessed. In vitro methods have a limited, but important, role to play in risk assessment. The results can be used for classification and labelling; these are methods of controlling exposure, analogous to risk assessment, but without considering exposure. The Ames Salmonella test is the only in vitro method which is incorporated into regulations and used widely. Data from this test can, at best, lead to classification of a chemical with regard to genotoxicity, but cannot be used for classification and labelling on their own. Several in vitro test systems which assess the topical irritancy and corrosivity of chemicals have been reasonably well validated, and the results from these tests can be used for classification. The future development of in vitro methods is likely to be slow, as it depends on the development of new concepts and ideas. The in vivo methods which currently have reasonably developed in vitro alternatives will be the easiest to replace. The remaining in vivo methods, which provide toxicological information from repeated chronic dosing, with varied endpoints and by mechanisms which are not understood, will be more difficult to replace.

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Pharmacokinetic and toxicology assessment of INTERCEPT (S-59 and UVA treated) platelets

Human & Experimental Toxicology ◽

10.1191/096032701718120319 ◽

2001 ◽

Vol 20 (10) ◽

pp. 533-550 ◽

Cited By ~ 55

Author(s):

V Ciaravino ◽

T McCullough ◽

A D Dayan

Keyword(s):

Ex Vivo ◽

Reproductive Toxicity ◽

In Vivo Studies ◽

Pathogen Inactivation ◽

Platelet Concentrates ◽

Baxter Healthcare ◽

Safety Margins ◽

Toxicology Assessment

The pathogen inactivation process developed by Cerus and Baxter Healthcare Corporations uses the psoralen, S-59 (amotosalen) in an ex vivo photochemical treatment (PCT) process to inactivate viruses, bacteria, protozoans, and leukocytes in platelet concentrates and plasma. Studies were performed by intravenous infusion of S-59 PCT formulations-compound adsorption device (CAD) treatment and with non-UVA illuminated S-59, using doses that were multiples of potential clinical exposures. The studies comprised full pharmacokinetic, single and repeated-dose (up to 13 weeks duration) toxicity, safety pharmacology (CNS, renal, and cardiovascular), reproductive toxicity, genotoxicity, carcinogenicity testing in the p53- mouse, vein irritation, and phototoxicity. No specific target organ toxicity (clinical or histopathological), reproductive toxicity, or carcinogenicity was observed. S-59 and/or PCT formulations demonstrated CNS, ECG, and phototoxicity only at supraclinical doses. Based on the extremely large safety margins (>30,000 fold expected clinical exposures), the CNS and ECG observations are not considered to have any toxicological relevance. Additionally, after a complete assessment, mutagenicity and phototoxicity results are not considered relevant for the proposed use of INTERCEPT platelets. Thus, the results of an extensive series of in vitro and in vivo studies have not demonstrated any toxicologically relevant effects of platelet concentrates prepared by the INTERCEPT system.

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The potential reproductive effects of exposure of domestic ruminants to endocrine disrupting compounds

Animal Science ◽

10.1017/s1357729800052164 ◽

2002 ◽

Vol 74 (1) ◽

pp. 3-12 ◽

Cited By ~ 16

Author(s):

M.L. Boerjan ◽

S. Freijnagel ◽

S.M. Rhind ◽

G.A.L. Meijer

Keyword(s):

Drinking Water ◽

Reproductive Function ◽

Endocrine Disrupting Compounds ◽

Laboratory Animals ◽

Domestic Ruminants ◽

Reproductive Effects ◽

Endocrine Disrupting ◽

Contaminated Food

AbstractChemical compounds that mimic or block some of the actions of the steroid hormone oestradiol, have created public concern primarily because of potential adverse reproductive effects in wildlife and humans. Many studies, in vivo and in vitro, have revealed abnormal reproductive function following exposure to these compounds. The number of chemicals known to have the potential to modulate endocrine functions is increasing. In contrast to humans and wildlife, the potential reproductive effects of exposure of domestic animals to endocrine disrupting compounds (EDC) have been studied little. The aim of this overview is to evaluate the possible contribution of EDC to reproductive failure in domestic ruminants.Sources and classes of EDC are discussed as well as their structure and the modes of hormone disruption. Endocrine disrupting agents may interfere with the reproductive processes of both males and females at several points of the reproductive cycle and through a range of physiological mechanisms. Extrapolating from the results obtained with laboratory animals, the mechanisms whereby infertility in domestic ruminants might be expressed by exposure to EDC through contaminated food and drinking water are addressed.A preliminary risk assessment is included and it is concluded that under certain circumstances there may be a significantly enhanced intake of oestrogenic hormones and EDC through sewage-contaminated water or soil-contaminated herbage. The physiological consequences for domestic ruminants of EDC ingestion, at the rates estimated, are largely unknown. However, the levels of exposure to oestrogenic hormones and phthalates in grazing ruminants are such that when studying fertility problems in high-yielding dairy cattle the impacts of exposure to endocrine disruptors via the food and drinking water cannot be neglected.

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In vitro immunization approach to generate specific murine monoclonal IgG antibodies

10.1101/2020.11.24.393728 ◽

2020 ◽

Author(s):

Sophia Michelchen ◽

Burkhard Micheel ◽

Katja Hanack

Keyword(s):

Monoclonal Antibodies ◽

Legionella Pneumophila ◽

B Lymphocyte ◽

Laboratory Animals ◽

Igg Antibody ◽

Simplified Approach ◽

Humoral Immune ◽

Viral Coat

AbstractGenerating monoclonal antibodies to date is a time intense process requiring immunization of laboratory animals. The transfer of the humoral immune response into in vitro settings shortens this process and circumvents the necessity of animal immunization. However, orchestrating the complex interplay of immune cells in vitro is very challenging. We aimed for a simplified approach focusing on the protagonist of antibody production: the B lymphocyte. We activated purified murine B lymphocytes in vitro with combinations of antigen and stimuli. Within ten days of culture we induced specific IgM and IgG antibody responses against a viral coat protein. Permanently antibody-producing hybridomas were generated. Furthermore we used this method to induce a specific antibody response against Legionella pneumophila. We thus established an effective protocol to generate monoclonal antibodies in vitro. By overcoming the necessity of in vivo immunization it may be the first step towards a universal strategy to generate antibodies from various species.

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Silica nanoparticles inducing the apoptosis of spermatocyte cell through microRNA-450b-3p targeting MTCH2-mediating mitochondrial signaling pathway

10.21203/rs.3.rs-24673/v1 ◽

2020 ◽

Author(s):

Guiqing Zhou ◽

Jianhui Liu ◽

Xiangyang Li ◽

Yujian Sang ◽

Yue Zhang ◽

...

Keyword(s):

Cytochrome C ◽

Silica Nanoparticles ◽

Caspase 3 ◽

Reproductive Toxicity ◽

Control Group ◽

Caspase 9 ◽

Protein Expressions ◽

Underlying Mechanisms

Abstract Background: Silica nanoparticles (SiNPs) are found in environmental particulate matter and are proven to have adverse effects on fertility. The relationship and underlying mechanisms between miRNAs and apoptosis induced by SiNPs during spermatogenesis is currently ambiguous. Experimental design: The present study was designed to investigate the role of miRNA-450b-3p in the reproductive toxicity caused by SiNPs. In vivo, 40 male mice were randomly divided into control and SiNPs groups, 20 per group. The mice in the SiNPs group were administrated 20 mg/kg SiNPs by tracheal perfusion once every 5 days, for 35 days, and the control group were given the equivalent of a normal luminal saline. In vitro, spermatocyte cells were divided into 0 and 5 μg/mL SiNPs groups, after passaged for 30 generations, the GC-2spd cells in 5 μg/mL SiNPs groups were transfected with miRNA-450b-3p and its mimic and inhibitor. Results: In vivo, the results showed that SiNPs damaged tissue structures of testis, decreased the quantity and quality of the sperm, reduced the expression of miR-450b-3p, and increased the protein expressions of the MTCH2, BID, BAX, Cytochrome C, Caspase-9, and Caspase-3 in the testis. In vitro, SiNPs obviously repressed the viability and increased the LDH level and apoptosis rate, decreased the levels of the miR-450b-3p, significantly enhanced the protein expressions of the MTCH2, BID, BAX, Cytochrome C, Caspase-9, Caspase-3; while the mimic of miR-450b-3p reversed the changes induced by SiNPs, but inhibitor further promoted the effects induced by SiNPs.Conclusion: The result suggested that SiNPs could induce the spermatocyte apoptosis by inhibiting the miR-450b-3p expression to target promoting the MTCH2 resulting in activating mitochondrial apoptotic signaling pathways in the spermatocyte cells.

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