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1.
Arch Toxicol ; 98(6): 1937-1951, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38563870

RESUMO

The high incidence of colorectal cancer (CRC) is closely associated with environmental pollutant exposure. To identify potential intestinal carcinogens, we developed a cell transformation assay (CTA) using mouse adult stem cell-derived intestinal organoids (mASC-IOs) and assessed the transformation potential on 14 representative chemicals, including Cd, iPb, Cr-VI, iAs-III, Zn, Cu, PFOS, BPA, MEHP, AOM, DMH, MNNG, aspirin, and metformin. We optimized the experimental protocol based on cytotoxicity, amplification, and colony formation of chemical-treated mASC-IOs. In addition, we assessed the accuracy of in vitro study and the human tumor relevance through characterizing interdependence between cell-cell and cell-matrix adhesions, tumorigenicity, pathological feature of subcutaneous tumors, and CRC-related molecular signatures. Remarkably, the results of cell transformation in 14 chemicals showed a strong concordance with epidemiological findings (8/10) and in vivo mouse studies (12/14). In addition, we found that the increase in anchorage-independent growth was positively correlated with the tumorigenicity of tested chemicals. Through analyzing the dose-response relationship of anchorage-independent growth by benchmark dose (BMD) modeling, the potent intestinal carcinogens were identified, with their carcinogenic potency ranked from high to low as AOM, Cd, MEHP, Cr-VI, iAs-III, and DMH. Importantly, the activity of chemical-transformed mASC-IOs was associated with the degree of cellular differentiation of subcutaneous tumors, altered transcription of oncogenic genes, and activated pathways related to CRC development, including Apc, Trp53, Kras, Pik3ca, Smad4 genes, as well as WNT and BMP signaling pathways. Taken together, we successfully developed a mASC-IO-based CTA, which might serve as a potential alternative for intestinal carcinogenicity screening of chemicals.


Assuntos
Testes de Carcinogenicidade , Transformação Celular Neoplásica , Neoplasias Colorretais , Poluentes Ambientais , Organoides , Animais , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/efeitos dos fármacos , Testes de Carcinogenicidade/métodos , Organoides/efeitos dos fármacos , Organoides/patologia , Camundongos , Poluentes Ambientais/toxicidade , Neoplasias Colorretais/patologia , Neoplasias Colorretais/induzido quimicamente , Humanos , Carcinógenos/toxicidade , Intestinos/efeitos dos fármacos , Intestinos/patologia , Neoplasias Intestinais/induzido quimicamente , Neoplasias Intestinais/patologia , Relação Dose-Resposta a Droga
2.
Crit Rev Toxicol ; 54(3): 153-173, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38470145

RESUMO

The Ramazzini Institute (RI) has been conducting animal carcinogenicity studies for decades, many of which have been considered by authoritative bodies to determine potential carcinogenicity in humans. Unlike other laboratories, such as the U.S. National Toxicology Program (NTP), the RI does not provide a report or record of historical control data. Transparently documenting historical control data is critical in the interpretation of individual study results within the same laboratory. Historical control data allow an assessment of significant trends, either increasing or decreasing, resulting from changes in laboratory methods or genetic drift. In this investigation: (1) we compiled a dataset of the tumors reported in control groups of Sprague-Dawley rats and Swiss mice based on data included in published RI studies on specific substances, and (2) conducted case studies to compare data from this RI control dataset to the findings from multiple RI studies on sweeteners and corresponding breakdown products. We found considerable variability in the tumor incidence across multiple tumor types when comparing across control groups from RI studies. When compared to the tumor incidence in treated groups from multiple studies, the incidence of some tumors considered to be treatment-related fell within the variability of background incidence from the RI control dataset.


Assuntos
Neoplasias , Ratos , Camundongos , Humanos , Animais , Ratos Sprague-Dawley , Incidência , Testes de Carcinogenicidade , Neoplasias/induzido quimicamente , Neoplasias/epidemiologia
3.
Food Chem Toxicol ; 188: 114524, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38428799

RESUMO

Sucralose, a sugar substitute first approved for use in 1991, is a non-caloric sweetener regulated globally as a food additive. Based on numerous experimental animal studies (dating to the 1980s) and human epidemiology studies, international health agencies have determined that sucralose is safe when consumed as intended. A single lifetime rodent carcinogenicity bioassay conducted by the Ramazzini Institute (RI) reported that mice fed diets containing sucralose develop hematopoietic neoplasia, but controversy continues regarding the validity and relevance of these data for predicting health effects in humans. The present paper addresses the controversy by providing the perspective of experienced pathologists on sucralose-related animal toxicity and carcinogenicity data generally, and the RI carcinogenicity bioassay findings specifically, using results from publicly available papers and international regulatory authority decisions. In the authors' view, flaws in the design, methodology, data evaluation, and reporting of the RI carcinogenicity bioassay for sucralose diminish the value of the data as evidence that this agent represents a carcinogenic hazard to humans. This limitation will remain until the RI bioassay is repeated under Good Laboratory Practices and the design, data, and accuracy of the pathology diagnoses and interpretations are reviewed by qualified pathologists with experience in evaluating potential chemically-induced carcinogenic hazards.


Assuntos
Testes de Carcinogenicidade , Sacarose , Animais , Sacarose/análogos & derivados , Sacarose/toxicidade , Camundongos , Humanos , Projetos de Pesquisa , Bioensaio/métodos , Edulcorantes/toxicidade , Ratos , Carcinógenos/toxicidade , Patologistas
4.
Toxicol Pathol ; 52(1): 13-20, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38445634

RESUMO

The Tumor Combination Guide was created at the request of the U. S. Food and Drug Administration (FDA) by a Working Group of biopharmaceutical experts from international societies of toxicologic pathology, the Food and Drug Administration (FDA), and members of the Standard for Exchange of Nonclinical Data (SEND) initiative, to assist pharmacology/toxicology reviewers and biostatisticians in statistical analysis of nonclinical tumor data. The guide will also be useful to study and peer review pathologists in interpreting the tumor data. This guide provides a higher-level hierarchy of tumor types or categories correlating the tumor names from the International Harmonization of Nomenclature and Diagnostic Criteria (INHAND) publications with those available in the NEOPLASM controlled terminology (CT) code list in SEND. The version of CT used in a study should be referenced in the nonclinical study data reviewer's guide (SDRG) (section 3.1) of electronic submissions to the FDA. The tumor combination guide instructions and examples are in a tabular format to make informed decisions for combining tumor data for statistical analysis. The strategy for combining tumor types for statistical analysis is based on scientific criteria gleaned from the current scientific literature; as SEND and INHAND terminology and information evolve, this guide will be updated.


Assuntos
Testes de Carcinogenicidade , Animais , Testes de Carcinogenicidade/métodos , Testes de Carcinogenicidade/normas , Neoplasias/induzido quimicamente , Neoplasias/patologia , Estados Unidos , Ratos , United States Food and Drug Administration , Roedores , Camundongos , Guias como Assunto , Interpretação Estatística de Dados
5.
Mutagenesis ; 39(2): 69-77, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38301659

RESUMO

Chemical safety testing plays a crucial role in product and pharmacological development, as well as chemoprevention; however, in vitro genotoxicity safety tests do not always accurately predict the chemicals that will be in vivo carcinogens. If chemicals test positive in vitro for genotoxicity but negative in vivo, this can contribute to unnecessary testing in animals used to confirm erroneous in vitro positive results. Current in vitro tests typically evaluate only genotoxicity endpoints, which limits their potential to detect non-genotoxic carcinogens. The frequency of misleading in vitro positive results can be high, leading to a requirement for more informative in vitro tests. It is now recognized that multiple-endpoint genotoxicity testing may aid more accurate detection of carcinogens and non-carcinogens. The objective of this review was to evaluate the utility of our novel, multiple-endpoint in vitro test, which uses multiple cancer-relevant endpoints to predict carcinogenic potential. The tool assessed micronucleus frequency, p53 expression, p21 expression, mitochondrial respiration, cell cycle abnormalities and, uniquely, cell morphology changes in human lymphoblastoid cell lines, TK6 and MCL-5. The endpoints were used to observe cellular responses to 18 chemicals within the following categories: genotoxic carcinogens, non-genotoxic carcinogens, toxic non-carcinogens, and misleading in vitro positive and negative agents. The number of endpoints significantly altered for each chemical was considered, alongside the holistic Integrated Signature of Carcinogenicity score, derived from the sum of fold changes for all endpoints. Following the calculation of an overall score from these measures, carcinogens exhibited greater potency than non-carcinogens. Genotoxic carcinogens were generally more potent than non-genotoxic carcinogens. This novel approach therefore demonstrated potential for correctly predicting whether chemicals with unknown mechanism may be considered carcinogens. Overall, while further validation is recommended, the test demonstrates potential for the identification of carcinogenic compounds. Adoption of the approach could enable reduced animal use in carcinogenicity testing.


Assuntos
Carcinogênese , Carcinógenos , Animais , Humanos , Carcinógenos/toxicidade , Testes de Carcinogenicidade/métodos , Testes de Mutagenicidade/métodos , Dano ao DNA , Técnicas In Vitro
6.
Arch Toxicol ; 98(1): 335-345, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37874342

RESUMO

Triclosan is a widely used antimicrobial agent in personal care products, household items, medical devices, and clinical settings. Due to its extensive use, there is potential for humans in all age groups to receive lifetime exposures to triclosan, yet data on the chronic dermal toxicity/carcinogenicity of triclosan are still lacking. We evaluated the toxicity/carcinogenicity of triclosan administered dermally to B6C3F1 mice for 104 weeks. Groups of 48 male and 48 female B6C3F1 mice received dermal applications of 0, 1.25, 2.7, 5.8, or 12.5 mg triclosan/kg body weight (bw)/day in 95% ethanol, 7 days/week for 104 weeks. Vehicle control animals received 95% ethanol only; untreated, naïve control mice did not receive any treatment. There were no significant differences in survival among the groups. The highest dose of triclosan significantly decreased the body weight of mice in both sexes, but the decrease was ≤ 9%. Minimal-to-mild epidermal hyperplasia, suppurative inflammation (males only), and ulceration (males only) were observed at the application site in the treated groups, with the highest incidence occurring in the 12.5 mg triclosan/kg bw/day group. No tumors were identified at the application site. Female mice had a positive trend in the incidence of pancreatic islet adenoma. In male mice, there were positive trends in the incidences of hepatocellular carcinoma and hepatocellular adenoma or carcinoma (combined), with the increase of carcinoma being significant in the 5.8 and 12.5 mg/kg/day groups and the increase in hepatocellular adenoma or carcinoma (combined) being significant in the 2.7, 5.8, and 12.5 mg/kg/day groups.


Assuntos
Adenoma de Células Hepáticas , Carcinoma Hepatocelular , Neoplasias Hepáticas , Triclosan , Ratos , Humanos , Camundongos , Masculino , Feminino , Animais , Triclosan/toxicidade , Ratos Endogâmicos F344 , Testes de Carcinogenicidade , Camundongos Endogâmicos , Etanol , Peso Corporal
7.
Toxicol Lett ; 390: 1-4, 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-37923025

RESUMO

The Tumorigenic dose 50 (TD50) is a widely used measure of carcinogenic potency representing the dosage at which 50 % of animals exposed to a compound will develop tumours. The popularity of the TD50 is in part due to the large amount of publicly available data. TD50s were calculated for a large number of compounds in the Carcinogenic Potency Database, which has since been extended in the freely available Lhasa Carcinogenicity database, containing TD50s from over 7500 studies and 1700 compounds. However, due to the age of these studies many are of low quality, often comprising only a single test dosage, therefore raising questions about the applicability of such TD50 sfor toxicological risk assessment. We investigate whether the lower 99 % confidence interval is sufficient to produce conservative TD50 estimates for these studies.


Assuntos
Neoplasias , Roedores , Animais , Carcinógenos/toxicidade , Neoplasias/induzido quimicamente , Medição de Risco , Carcinogênese , Testes de Carcinogenicidade
8.
Regul Toxicol Pharmacol ; 145: 105522, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37879513

RESUMO

For a pharmaceutical drug, carcinogenicity testing occurs in rodents to identify its tumorigenic potential to allow assessment of the risk from its use in humans. Testing takes the form of 2-year studies in mice and rats and/or more recently, a 6-month study in transgenic mice. This paper examines the process of regulatory interaction regarding carcinogenicity testing, notably through the United States (US) Food and Drug Administration (FDA) Special Protocol Assessment (SPA) process to seek Executive Carcinogenicity Assessment Committee (ECAC) approval. The content of 37 submissions to CAC were examined. The paper also examines the outcome from such agency engagement, notably around study dose level selection as well as looking at the design of proposed carcinogenicity study protocols used in submissions (including numbers of animals, control group aspects and toxicokinetic [TK] evaluation). Overall, it was shown that the current process of regulatory interaction allows for studies acceptable to support eventual drug approval and marketing. However, it was established that areas exist to improve the content of submission documents and study design aspects.


Assuntos
Aprovação de Drogas , Roedores , Humanos , Estados Unidos , Camundongos , Ratos , Animais , Preparações Farmacêuticas , Testes de Carcinogenicidade/métodos , Camundongos Transgênicos , United States Food and Drug Administration
9.
Toxicol Lett ; 389: 11-18, 2023 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-37813191

RESUMO

To date, long-term rodent carcinogenesis assays are the only assays recognized by regulators to assess non-genotoxic carcinogens, but their reliability has been questioned. In vitro cell transformation assays (CTAs) could represent an interesting alternative to animal models as it has the advantage of detecting both genotoxic and non-genotoxic transforming chemicals. Among them, Bhas 42 CTA uses a cell line that has been transfected with the oncogenic sequence v-Ha-ras. This sequence confers an "initiated" status to these cells and makes them particularly sensitive to non-genotoxic agents. In a previous work, transcriptomic analysis revealed that the treatment of Bhas 42 cells with transforming silica (nano)particles and 12-O-tetradecanoylphorbol-13-acetate (TPA) commonly modified the expression of 12 genes involved in cell proliferation and adhesion. In the present study, we assess whether this signature would be the same for four other soluble transforming agents, i.e. mezerein, methylarsonic acid, cholic acid and quercetin. The treatment of Bhas 42 cells for 48 h with mezerein modified the expression of the 12 genes of the signature according to the same profile as that of the TPA. However, methylarsonic acid and cholic acid gave an incomplete signature with changes in the expression of only 7 and 5 genes, respectively. Finally, quercetin treatment induced no change in the expression of all genes but exhibited higher cytotoxicty. These results suggest that among the transforming agents tested, some may share similar mechanisms of action leading to cell transformation while others may activate different additional pathways involved in such cellular process. More transforming and non-transforming agents and gene markers should be tested in order to try to identify a relevant gene signature to predict the transforming potential of non-genotoxic agents.


Assuntos
Hidroxianisol Butilado , Transcriptoma , Animais , Camundongos , Hidroxianisol Butilado/toxicidade , Reprodutibilidade dos Testes , Quercetina , Testes de Carcinogenicidade/métodos , Células 3T3 BALB , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/induzido quimicamente , Carcinógenos/toxicidade , Acetato de Tetradecanoilforbol/farmacologia , Ácido Cólico/toxicidade
10.
Int J Mol Sci ; 24(16)2023 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-37629136

RESUMO

Mesenchymal stromal cells (MSCs) have been considered a therapeutic strategy in regenerative medicine because of their regenerative and immunomodulatory properties. The translation of MSC-based products has some challenges, such as regulatory and scientific issues. Quality control should be standardized and optimized to guarantee the reproducibility, safety, and efficacy of MSC-based products to be administered to patients. The aim of this study was to develop MSC-based products for use in clinical practice. Quality control assays include cell characterization, cell viability, immunogenicity, and cell differentiation; safety tests such as procoagulant tissue factor (TF), microbiological, mycoplasma, endotoxin, genomic stability, and tumorigenicity tests; and potency tests. The results confirm that the cells express MSC markers; an average cell viability of 96.9%; a low expression of HLA-DR and costimulatory molecules; differentiation potential; a high expression of TF/CD142; an absence of pathogenic microorganisms; negative endotoxins; an absence of chromosomal abnormalities; an absence of genotoxicity and tumorigenicity; and T-lymphocyte proliferation inhibition potential. This study shows the relevance of standardizing the manufacturing process and quality controls to reduce variability due to the heterogeneity between donors. The results might also be useful for the implementation and optimization of new analytical techniques and automated methods to improve safety, which are the major concerns related to MSC-based therapy.


Assuntos
Bioensaio , Células-Tronco Mesenquimais , Humanos , Reprodutibilidade dos Testes , Testes de Carcinogenicidade , Endotoxinas , Controle de Qualidade
11.
Int J Toxicol ; 42(6): 489-503, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37480334

RESUMO

Enarodustat (JTZ-951) is an oral hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor for the treatment of anemia with chronic kidney disease. Carcinogenicity of enarodustat was evaluated in a 26-week repeated oral dose study in Transgenic rasH2 (Tg.rasH2) mice and a 2-year repeated oral dose study in Sprague-Dawley (SD) rats. The highest dose levels were set at 6 mg/kg in the Tg.rasH2 mouse study and at 1 mg/kg in the SD rat study based on the maximum tolerated doses in the 3-month and 6-month dose-range finding studies, respectively. Enarodustat did not increase the incidence of any tumors or affect survival in these carcinogenicity studies. Pharmacology-related findings including increases in blood RBC parameters were observed at the highest dose levels for each study. The AUC-based exposure margins as protein-unbound drug base are 16.3-/26.0-fold multiple (males/females) for Tg.rasH2 mice and 1.6-/1.1-fold multiple for SD rats when compared with the estimated exposure in human with chronic kidney disease at 8 mg/day (maximum recommended human dose). In conclusion, enarodustat was considered to have no carcinogenic potential at the clinical dose.


Assuntos
Inibidores de Prolil-Hidrolase , Insuficiência Renal Crônica , Camundongos , Ratos , Animais , Masculino , Humanos , Feminino , Camundongos Transgênicos , Ratos Sprague-Dawley , Prolil Hidroxilases , Carcinógenos , Inibidores de Prolil-Hidrolase/farmacologia , Carcinogênese , Hipóxia , Testes de Carcinogenicidade
13.
Chem Res Toxicol ; 36(6): 805-817, 2023 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-37156502

RESUMO

Nongenotoxic (NGTX) carcinogens induce cancer via other mechanisms than direct DNA damage. A recognized mode of action for NGTX carcinogens is induction of oxidative stress, a state in which the amount of oxidants in a cell exceeds its antioxidant capacity, leading to regenerative proliferation. Currently, carcinogenicity assessment of environmental chemicals primarily relies on genetic toxicity end points. Since NGTX carcinogens lack genotoxic potential, these chemicals may remain undetected in such evaluations. To enhance the predictivity of test strategies for carcinogenicity assessment, a shift toward mechanism-based approaches is required. Here, we present an adverse outcome pathway (AOP) network for chemically induced oxidative stress leading to (NGTX) carcinogenesis. To develop this AOP network, we first investigated the role of oxidative stress in the various cancer hallmarks. Next, possible mechanisms for chemical induction of oxidative stress and the biological effects of oxidative damage to macromolecules were considered. This resulted in an AOP network, of which associated uncertainties were explored. Ultimately, development of AOP networks relevant for carcinogenesis in humans will aid the transition to a mechanism-based, human relevant carcinogenicity assessment that involves a substantially lower number of laboratory animals.


Assuntos
Rotas de Resultados Adversos , Neoplasias , Animais , Humanos , Carcinógenos/toxicidade , Carcinógenos/metabolismo , Carcinogênese/induzido quimicamente , Neoplasias/induzido quimicamente , Estresse Oxidativo , Dano ao DNA , Testes de Carcinogenicidade
14.
Altern Lab Anim ; 51(3): 188-203, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37125451

RESUMO

The induction of vasculature formation is proposed to be a significant mechanism behind the non-genotoxic carcinogenicity of a chemical. The vasculature formation model used in this study is based on the coculture of human primary HUVECs and hASCs. This model was used to develop an assay to assess the induction of vasculature formation. Three assay protocols, based on different conditions, were developed and compared in order to identify the optimal conditions required. Some serum supplements and growth factors were observed to be essential for initiating vasculature formation. Of the studied putative positive reference chemicals, aspartame, sodium nitrite, bisphenol A and nicotine treatment led to a clear induction of vasculature formation, but arsenic and cadmium treatment only led to a slight increase. This human cell-based assay has the potential to be used as one test within a next generation testing battery, to assess the non-genotoxic carcinogenicity of a chemical through the mechanism of vasculature formation induction.


Assuntos
Carcinógenos , Humanos , Projetos Piloto , Testes de Carcinogenicidade/métodos
15.
J Toxicol Sci ; 48(5): 227-241, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37121738

RESUMO

We conducted a two-year inhalation study of butyl methacrylate using F344/DuCrlCrlj rats and B6D2F1/Crl mice. Rats were exposed to 0, 30, 125 and 500 ppm (v/v) and mice were exposed to 0, 8, 30 and 125 ppm (v/v) using whole-body inhalation chambers. Non-neoplastic lesions developed in the nasal cavities of both rats and mice, but neoplastic lesions were not found. There was also a positive trend in the incidence of large granular lymphocytic (LGL) leukemia in the spleen of male rats. No changes were observed in female rats. Overall, there is some evidence of carcinogenicity in male rats, but there is no evidence of carcinogenicity in female rats. In male mice, there was a positive trend by Peto's test in the incidence of hepatocellular adenomas, and the incidence of hepatocellular adenomas and hepatocellular carcinomas combined was significantly increased compared to the controls by Fisher's exact test in the 30 ppm exposed male group. In female mice, the incidence of hemangiosarcoma in all organs combined showed a positive trend by Peto's test. Therefore, there is some evidence of carcinogenicity in male mice, and there is equivocal evidence of carcinogenicity in female mice.


Assuntos
Adenoma de Células Hepáticas , Neoplasias Hepáticas , Ratos , Camundongos , Masculino , Feminino , Animais , Ratos Endogâmicos F344 , Camundongos Endogâmicos , Neoplasias Hepáticas/patologia , Testes de Carcinogenicidade
16.
Int J Mol Sci ; 24(6)2023 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-36982734

RESUMO

The history of the development of the cell transformation assays (CTAs) is described, providing an overview of in vitro cell transformation from its origin to the new transcriptomic-based CTAs. Application of this knowledge is utilized to address how the different types of CTAs, variously addressing initiation and promotion, can be included on a mechanistic basis within the integrated approach to testing and assessment (IATA) for non-genotoxic carcinogens. Building upon assay assessments targeting the key events in the IATA, we identify how the different CTA models can appropriately fit, following preceding steps in the IATA. The preceding steps are the prescreening transcriptomic approaches, and assessment within the earlier key events of inflammation, immune disruption, mitotic signaling and cell injury. The CTA models address the later key events of (sustained) proliferation and change in morphology leading to tumor formation. The complementary key biomarkers with respect to the precursor key events and respective CTAs are mapped, providing a structured mechanistic approach to represent the complexity of the (non-genotoxic) carcinogenesis process, and specifically their capacity to identify non-genotoxic carcinogenic chemicals in a human relevant IATA.


Assuntos
Carcinógenos , Neoplasias , Humanos , Carcinógenos/toxicidade , Testes de Carcinogenicidade/métodos , Transformação Celular Neoplásica/genética , Carcinogênese/genética
18.
Arch Toxicol ; 97(6): 1739-1751, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36941454

RESUMO

Validated in vitro assays for testing non-genotoxic carcinogenic potential of chemicals are currently not available. Consequently, the two-year rodent bioassay remains the gold standard method for the identification of these chemicals. Transcriptomic and proteomic analyses have provided a comprehensive understanding of the non-genotoxic carcinogenic processes, however, functional changes induced by effects at transcriptional and translational levels have not been addressed. The present study was set up to test a number of proposed in vitro biomarkers of non-genotoxic hepatocarcinogenicity at the functional level using a translational 3-dimensional model. Spheroid cultures of human hepatocytes and stellate cells were exposed to 5 genotoxic carcinogenic, 5 non-genotoxic carcinogenic, and 5 non-carcinogenic chemical compounds and assessed for oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, apoptosis, and inflammation. The spheroid model could capture many of these events triggered by the genotoxic carcinogenic chemicals, particularly aflatoxin B1 and hydroquinone. Nonetheless, no clear distinction could be made between genotoxic and non-genotoxic hepatocarcinogenicity. Therefore, spheroid cultures of human liver cells may be appropriate in vitro tools for mechanistic investigation of chemical-induced hepatocarcinogenicity, however, these mechanisms and their read-outs do not seem to be eligible biomarkers for detecting non-genotoxic carcinogenic chemicals.


Assuntos
Carcinógenos , Proteômica , Humanos , Técnicas de Cocultura , Carcinógenos/toxicidade , Fígado , Hepatócitos , Testes de Carcinogenicidade/métodos
19.
Reprod Toxicol ; 118: 108366, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36958465

RESUMO

Corn oil, sodium carboxymethyl cellulose (CMC-Na), and dimethyl sulfoxide (DMSO) are widely used as solvents or suspensions in animal experiments, but the effects of prenatal exposure to them on fetal development have not been reported. In this study, Kunming mice were given a conventional dose of corn oil (9.2 g/kg·d), CMC-Na (0.05 g/kg·d) or DMSO (0.088 g/kg·d) during gestation days 10-18, and the pregnancy outcome, fetal physical development, serum phenotype, and multi-organ function changes were observed. The results showed that corn oil decreased serum triglyceride level in males but increased their serum testosterone and CORT levels, and affected female placenta and female/male multi-organ functions (mainly bone, liver, kidney). CMC-Na increased female/male body lengths and tail lengths, decreased serum glucose and total cholesterol levels in males as well as increased their serum LDL-C/HDL-C ratio and testosterone level, decreased female serum bile acid level, and affected male/female placenta and multi-organ functions (mainly bone, liver, hippocampus). DMSO decreased male body weight and serum glucose level, decreased male/female serum bile acid levels, and affected male/female placenta and multi-organs functions (mainly bone, hippocampus, adrenal gland). In conclusion, prenatal exposure to a conventional dose of corn oil, CMC-Na or DMSO could affect fetal physical development and multi-organ functions, and has the characteristics of "multi-pathway, multi-organ and multi-target". This study provides the experimental basis for the rational selection of solvents or suspensions in pharmacology and toxicology studies.


Assuntos
Dimetil Sulfóxido , Efeitos Tardios da Exposição Pré-Natal , Camundongos , Ratos , Humanos , Feminino , Masculino , Gravidez , Animais , Dimetil Sulfóxido/toxicidade , Camundongos Endogâmicos , Óleo de Milho/toxicidade , Ratos Endogâmicos F344 , Testes de Carcinogenicidade , Solventes , Testosterona , Ácidos e Sais Biliares , Glucose
20.
J Occup Health ; 65(1): e12388, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36756793

RESUMO

OBJECTIVE: The purpose of this study was to investigate the carcinogenicity of 2-bromopropane (2-BP) in rats. METHODS: Male and female F344 rats were exposed by whole body inhalation to 2-BP vapor at concentrations of 0, 67, 200, and 600 ppm for 6 h/day, 5 days/week for 2 years. RESULTS: All rats of both sexes exposed to 600 ppm died or became moribund within 85 weeks. Death/moribundity was caused by 2-BP induced tumors. In males, significantly increased tumors were malignant Zymbal's gland tumors; sebaceous adenoma and basal cell carcinoma of the skin/appendage; adenocarcinoma of the small/large intestine; follicular cell adenoma of the thyroid; fibroma of the subcutis, and malignant lymphoma of the lymph node. In addition, an increased trend in tumor incidence was found in the preputial gland, lung, forestomach, pancreas islet, brain, and spleen. In females, significantly increased tumors were adenocarcinoma and fibroadenoma of the mammary gland, squamous cell papilloma of the vagina, and large granular lymphocytic leukemia of the spleen. In addition, an increased trend in tumor incidence was found in Zymbal's gland, the clitoral gland, skin, large intestine, pancreas islet, uterus, and subcutis. Particularly, malignant Zymbal's gland tumors were induced even in males exposed to the lowest concentration, 67 ppm. CONCLUSION: Two-year inhalation exposure to 2-BP resulted in multi-organ carcinogenicity in rats. Based on sufficient evidence of carcinogenicity in this study, 2-BP has the potential to be a human carcinogen.


Assuntos
Adenocarcinoma , Adenoma , Humanos , Camundongos , Ratos , Animais , Masculino , Feminino , Ratos Endogâmicos F344 , Camundongos Endogâmicos , Testes de Carcinogenicidade , Exposição por Inalação/efeitos adversos , Adenocarcinoma/induzido quimicamente , Adenoma/induzido quimicamente
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