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1.
Arch Toxicol ; 98(2): 425-469, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38147116

RESUMEN

Fungi of the genus Alternaria are ubiquitous plant pathogens and saprophytes which are able to grow under varying temperature and moisture conditions as well as on a large range of substrates. A spectrum of structurally diverse secondary metabolites with toxic potential has been identified, but occurrence and relative proportion of the different metabolites in complex mixtures depend on strain, substrate, and growth conditions. This review compiles the available knowledge on hazard identification and characterization of Alternaria toxins. Alternariol (AOH), its monomethylether AME and the perylene quinones altertoxin I (ATX-I), ATX-II, ATX-III, alterperylenol (ALP), and stemphyltoxin III (STTX-III) showed in vitro genotoxic and mutagenic properties. Of all identified Alternaria toxins, the epoxide-bearing analogs ATX-II, ATX-III, and STTX-III show the highest cytotoxic, genotoxic, and mutagenic potential in vitro. Under hormone-sensitive conditions, AOH and AME act as moderate xenoestrogens, but in silico modeling predicts further Alternaria toxins as potential estrogenic factors. Recent studies indicate also an immunosuppressive role of AOH and ATX-II; however, no data are available for the majority of Alternaria toxins. Overall, hazard characterization of Alternaria toxins focused, so far, primarily on the commercially available dibenzo-α-pyrones AOH and AME and tenuazonic acid (TeA). Limited data sets are available for altersetin (ALS), altenuene (ALT), and tentoxin (TEN). The occurrence and toxicological relevance of perylene quinone-based Alternaria toxins still remain to be fully elucidated. We identified data gaps on hazard identification and characterization crucial to improve risk assessment of Alternaria mycotoxins for consumers and occupationally exposed workers.


Asunto(s)
Micotoxinas , Perileno , Humanos , Alternaria/metabolismo , Micotoxinas/toxicidad , Micotoxinas/análisis , Mutágenos/toxicidad , Mutágenos/metabolismo , Lactonas/toxicidad , Lactonas/metabolismo , Medición de Riesgo , Contaminación de Alimentos/análisis
3.
J Hazard Mater ; 474: 134721, 2024 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-38843629

RESUMEN

The new challenges in toxicology demand novel and innovative in vitro approaches for deriving points of departure (PODs) and determining the mode of action (MOA) of chemicals. Therefore, the aim of this original study was to couple in vitro studies with untargeted metabolomics to model the concentration-response of extra- and intracellular metabolome data on human HepaRG cells treated for 48 h with three pyrrolizidine alkaloids (PAs): heliotrine, retrorsine and lasiocarpine. Modeling revealed that the three PAs induced various monotonic and, importantly, biphasic curves of metabolite content. Based on unannotated metabolites, the endometabolome was more sensitive than the exometabolome in terms of metabolomic effects, and benchmark concentrations (BMCs) confirmed that lasiocarpine was the most hepatotoxic PA. Regarding its MOA, impairment of lipid metabolism was highlighted at a very low BMC (first quartile, 0.003 µM). Moreover, results confirmed that lasiocarpine targets bile acids, as well as amino acid and steroid metabolisms. Analysis of the endometabolome, based on coupling concentration-response and PODs, gave encouraging results for ranking toxins according to their hepatotoxic effects. Therefore, this novel approach is a promising tool for next-generation risk assessment, readily applicable to a broad range of compounds and toxic endpoints.


Asunto(s)
Metaboloma , Alcaloides de Pirrolicidina , Alcaloides de Pirrolicidina/toxicidad , Alcaloides de Pirrolicidina/metabolismo , Humanos , Metaboloma/efectos de los fármacos , Línea Celular , Metabolómica , Metabolismo de los Lípidos/efectos de los fármacos
4.
Artículo en Inglés | MEDLINE | ID: mdl-34043493

RESUMEN

A qualitative and quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the sensitive and exhaustive analysis of residues from triarylmethane dyes, triarylmethane-derivative dyes, phenothiazines, phenoxazines and xanthenes in aquaculture samples. For a wider and more robust detection of dye misuse on farms, other residue markers were also included the leuco forms of brilliant green, crystal violet and malachite green; one direct metabolite of Victoria pure blue BO and methylene blue and three bile acids, which are endogenous markers of the effects of dye contamination in fish. We optimised the extraction method by comparing several extraction solvents and sample solvents reported in the literature to have the best extraction efficiency. The residues were determined using a positive electrospray ionisation source. We assessed the parameters of this LC-MS/MS method by evaluating the matrix effects, identification and quantitative parameters according to the criteria stipulated in the European Commission Decision No. 2002/657/EC. A study on the applicability of the method was conducted on various aquaculture species and on a positive catfish.


Asunto(s)
Acuicultura/métodos , Colorantes/análisis , Abuso de Medicamentos/prevención & control , Residuos de Medicamentos/análisis , Contaminación de Alimentos/análisis , Contaminantes Químicos del Agua/análisis , Animales , Ácidos y Sales Biliares/análisis , Bagres , Cromatografía Líquida de Alta Presión , Colorantes/efectos adversos , Violeta de Genciana/análisis , Humanos , Músculos/química , Compuestos de Amonio Cuaternario/análisis , Colorantes de Rosanilina/análisis , Espectrometría de Masas en Tándem , Extractos de Tejidos/química
5.
Chemosphere ; 262: 127636, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32750594

RESUMEN

Victoria Pure Blue BO is a dye that bears some therapeutic activity and that can be retrieved in effluent or may be used in aquaculture as a prohibited drug. In this study, the metabolism and tissue distribution during uptake and depuration of VPBO were investigated in order to propose a residue marker of illegal treatment in fish. The dye was administered to rainbow trout (oncorhynchus mykiss) for one day by water bath at a dose of 0.1 mg.L-1. The concentrations of VPBO in all tissues increased rapidly during the treatment period, reaching a Cmax of 567 ± 301 µg.L-1 in plasma and 1846 µg kg-1 ±517 for liver after 2 h. After placing the rainbow trout in a clean water bath for a 64 day-period of depuration, the concentrations in the tissues and plasma decreased to reach comparable levels for muscle and for skin after 33 days. The concentrations measured were still above the LOQ at 2.26 ± 0.48 µg kg-1 for muscle and 2.85 ± 1.99 µg kg-1 for skin at the end of the depuration period. The results indicated the existence of 14 phase I metabolites and one glucuronide conjugated metabolite. Non-compartmental analysis was applied to assess the pharmacokinetic parameters. The half-life in edible muscle of the main metabolite detected, deethyl-leuco-VPBO, was found to be 22.5 days compared to a half-life of 19.7 days for the parent VPBO. This study provides new information to predict a VPBO drug treatment of aquacultured species via a proposed new residue marker.


Asunto(s)
Oncorhynchus mykiss/metabolismo , Compuestos de Amonio Cuaternario/metabolismo , Animales , Acuicultura , Músculos/metabolismo , Distribución Tisular
6.
Chemosphere ; 238: 124538, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31454745

RESUMEN

Although banned, dyes, such as Victoria pure blue BO (VPBO), are illicitly used in aquaculture to treat or prevent infections due to their therapeutic activities. The present study examined the formation of phase I and phase II metabolites derived from VPBO using trout liver microsomes and S9 proteins. The well-known malachite green (MG) dye was also studied as a positive control and to compare its metabolism with that of VPBO. First, we optimised the incubation conditions for the detection of VPBO and MG metabolites by studying the formation of cytochrome P450 (CYP) substrates. Using the determined conditions (2 h at 20 °C), we incubated VPBO with trout microsomal and S9 fractions induced with ß-naphtoflavone, and analysed the supernatant in a LC-LTQ-Orbitrap-HRMS system. The in vitro assays led to the detection of 16 VPBO metabolites from Phase I reactions, arising in particular from reactions with CYP1A. No metabolites were detected from Phase II reactions. The main metabolite detected, deethyl-VPBO, was CID-fragmented to determine its chemical structure, and thus recommend a potential biomarker for the control of VPBO in farmed fish foodstuffs.


Asunto(s)
Colorantes/metabolismo , Peces/metabolismo , Contaminación de Alimentos/análisis , Compuestos de Amonio Cuaternario/metabolismo , Alimentos Marinos , Animales , Acuicultura , Sistema Enzimático del Citocromo P-450/metabolismo , Metabolómica , Microsomas Hepáticos/metabolismo
7.
Sci Rep ; 9(1): 10548, 2019 07 22.
Artículo en Inglés | MEDLINE | ID: mdl-31332230

RESUMEN

Many efforts have been made in the last 30 years to develop more relevant in vitro models to study genotoxic responses of drugs and environmental contaminants. While 2D HepaRG cells are one of the most promising models for liver toxicology, a switch to 3D cultures that integrate both in vivo architecture and cell-cell interactions has occurred to achieve even more predictive models. Preliminary studies have indicated that 3D HepaRG cells are suitable for liver toxicity screening. Our study aimed to evaluate the response of HepaRG spheroids exposed to various genotoxic compounds using the single cell gel electrophoresis assay. HepaRG spheroids were used at 10 days after seeding and exposed for 24 and 48 hours to certain selected chemical compounds (methylmethansulfonate (MMS), etoposide, benzo[a]pyrene (B[a]P), cyclophosphamide (CPA), 7,12-dimethylbenz[a]anthracene (DMBA), 2-acetylaminofluorene (2-AAF), 4-nitroquinoline (4-NQO), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3-methylimidazo[4,5-f]quinolone (IQ), acrylamide, and 2-4-diaminotoluene (2,4-DAT)). After treatment, the comet assay was performed on single cell suspensions and cytotoxicity was determined by the ATP assay. Comet formation was observed for all compounds except IQ, etoposide and 2,4-DAT. Treatment of spheroids with rifampicin increased CYP3A4 activity, demonstrating the metabolic capacity of HepaRG spheroids. These data on genotoxicity in 3D HepaRG spheroids are promising, but further experiments are required to prove that this model can improve the predictivity of in vitro models to detect human carcinogens.


Asunto(s)
Ensayo Cometa/métodos , Hepatocitos/citología , Hepatocitos/efectos de los fármacos , Mutágenos/toxicidad , Esferoides Celulares/citología , Esferoides Celulares/efectos de los fármacos , Activación Metabólica , Línea Celular , Sistema Enzimático del Citocromo P-450/metabolismo , Daño del ADN , Hepatocitos/metabolismo , Humanos , Mutágenos/farmacocinética , Esferoides Celulares/metabolismo
8.
Toxicol Lett ; 307: 17-25, 2019 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-30825503

RESUMEN

13-Desmethylspirolide C (13-SPX-C) is a phycotoxin produced by dinoflagellates which can accumulate in shellfish. 13-SPX-C induces neurotoxic effects in rodents through blockade of nicotinic acetylcholine receptors. As no human intoxication has been to date attributed to the consumption of 13-SPX-C-contaminated seafood, this toxin is not regulated according to the Codex Alimentarius. Nevertheless, shellfish consumers can be exposed to 13-SPX-C via shellfish consumption. In order to follow the fate of the toxin after ingestion and to verify whether metabolic detoxification could explain the lack of human intoxications, we assessed the metabolism of 13-SPX-C using several in vitro liver systems. First, both phase I and II reactions occurring with rat and human liver S9 fractions were screened. Our results indicated that 13-SPX-C was almost completely metabolized with both rat and human liver S9. Using a receptor binding assay towards nicotinic acetylcholine receptors we demonstrated that the resulting metabolites showed less affinity towards nicotinic acetylcholine receptors than 13-SPX-C. Finally, we showed that 13-SPX-C induced a pronounced increase of gene expression of the drug-metabolizing enzyme cytochrome P450 (CYP) CYP1A2. The role of this CYP in 13-SPX-C metabolism was clarified using an innovative in vitro tool, CYP1A2-Silensomes™. In summary, this study highlights that liver first-pass metabolism can contribute to the detoxification of 13-SPX-C.


Asunto(s)
Hígado/metabolismo , Toxinas Marinas/metabolismo , Compuestos de Espiro/metabolismo , Animales , Citocromo P-450 CYP1A2/metabolismo , Cromatografía de Gases y Espectrometría de Masas , Humanos , Técnicas In Vitro , Hígado/efectos de los fármacos , Ratas , Reacción en Cadena en Tiempo Real de la Polimerasa
9.
Artículo en Inglés | MEDLINE | ID: mdl-27585601

RESUMEN

An approach is described to validate a fast and simple targeted screening method for antibiotic analysis in meat and aquaculture products by LC-MS/MS. The strategy of validation was applied for a panel of 75 antibiotics belonging to different families, i.e., penicillins, cephalosporins, sulfonamides, macrolides, quinolones and phenicols. The samples were extracted once with acetonitrile, concentrated by evaporation and injected into the LC-MS/MS system. The approach chosen for the validation was based on the Community Reference Laboratory (CRL) guidelines for the validation of screening qualitative methods. The aim of the validation was to prove sufficient sensitivity of the method to detect all the targeted antibiotics at the level of interest, generally the maximum residue limit (MRL). A robustness study was also performed to test the influence of different factors. The validation showed that the method is valid to detect and identify 73 antibiotics of the 75 antibiotics studied in meat and aquaculture products at the validation levels.


Asunto(s)
Antibacterianos/análisis , Cromatografía Liquida/normas , Residuos de Medicamentos/análisis , Contaminación de Alimentos/análisis , Carne/análisis , Espectrometría de Masas en Tándem/normas , Animales , Acuicultura , Bovinos , Cefalosporinas/análisis , Cabras , Guías como Asunto , Humanos , Macrólidos/análisis , Músculos/química , Penicilinas/análisis , Aves de Corral , Quinolonas/análisis , Salmón , Sensibilidad y Especificidad , Ovinos , Sulfonamidas/análisis , Porcinos
10.
Toxins (Basel) ; 9(7)2017 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-28678150

RESUMEN

PTX-2 is a marine biotoxin frequently found in shellfish that can lead to food intoxication in humans. Information regarding PTX-2 metabolism is scarce, and little is known of its effect on xenobiotic-metabolizing enzymes (XME) or its molecular pathways. The aim of this study was consequently to examine PTX-2 Phase I metabolism using rat and human liver S9 fractions, and also to assess the capability of PTX-2: (i) to modulate the gene expression of a panel of Phase I (CYP450) and II (UGT, SULT, NAT, and GST) enzymes, as well as the Phase III or 0 (ABC and SLCO) transporters in the human hepatic HepaRG cell line using qPCR; (ii) to induce specific CYP450 in HepaRG cells measured by immunolabeling detection and the measurement of the cells' activities; and (iii) to activate nuclear receptors and induce CYP promoter activities in HEK-T and HepG2 transfected cell lines using transactivation and reporter gene assay, respectively. Our results indicate that PTX-2 hydroxylation occurred with both rat and human S9 fractions. Whereas PTX-2 mostly upregulated the gene expression of CYP1A1 and 1A2, no induction of these two CYP activities was observed. Lastly, PTX-2 did not act as an agonist of CAR or PXR. Due to its effects on some key XME, more attention should be paid to possible drug-drug interactions with phycotoxins, especially as shellfish can accumulate several phycotoxins as well as other kinds of contaminants.


Asunto(s)
Sistema Enzimático del Citocromo P-450/metabolismo , Furanos/metabolismo , Hígado/metabolismo , Toxinas Marinas/metabolismo , Piranos/metabolismo , Animales , Línea Celular , Línea Celular Tumoral , Sistema Enzimático del Citocromo P-450/genética , Expresión Génica , Humanos , Macrólidos , Proteínas de Transporte de Membrana/genética , Ratas , Receptores de Hidrocarburo de Aril/genética , Transferasas/genética , Xenobióticos/metabolismo
11.
J Chromatogr A ; 1497: 9-18, 2017 May 12.
Artículo en Inglés | MEDLINE | ID: mdl-28366563

RESUMEN

Starting from a critical analysis of a first "proof of concept" study on the utility of the liver volatolome for detecting livestock exposure to environmental micropollutants (Berge et al., 2011), the primary aim of this paper is to improve extraction conditions so as to obtain more representative extracts by using an extraction temperature closer to livestock physiological conditions while minimizing analytical variability and maximizing Volatile Organic Compound (VOC) abundancies. Levers related to extraction conditions and sample preparation were assessed in the light of both abundance and coefficient of variation of 22 candidate VOC markers identified in earlier volatolomic studies. Starting with a CAR/PDMS fiber and a 30min extraction, the reduction of SPME temperature to 40°C resulted in a significant decrease in the area of 14 candidate VOC markers (p<0.05), mainly carbonyls and alcohols but also a reduction in the coefficient of variation for 17 of them. In order to restore VOC abundances and to minimize variability, two approaches dealing with sample preparation were investigated. By increasing sample defrosting time at 4°C from 0 to 24h yielded higher abundances and lower variabilities for 15 and 13 compounds, respectively. Lastly, by using additives favouring the release of VOCs (1.2g of NaCl) the sensitivity of the analysis was improved with a significant increase in VOC abundances of more than 50% for 13 out of the 22 candidate markers. The modified SPME parameters significantly enhanced the abundances while decreasing the analytical variability for most candidate VOC markers. The second step was to validate the ability of the revised SPME protocol to discriminate intentionally contaminated broiler chickens from controls, under case/control animal testing conditions. After verification of the contamination levels of the animals by national reference laboratories, data analysis by a multivariate chemometric method (Common Components and Specific Weights Analysis - ComDim) showed that the liver volatolome could reveal dietary exposure of broilers to a group of environmental pollutants (PCBs), a veterinary treatment (monensin), and a pesticide (deltamethrin), thus confirming the usefulness of this analytical set-up.


Asunto(s)
Contaminantes Ambientales/análisis , Hígado/química , Ganado/metabolismo , Microextracción en Fase Sólida/métodos , Compuestos Orgánicos Volátiles/análisis , Alcoholes/análisis , Animales , Pollos/metabolismo , Monensina/análisis , Nitrilos/análisis , Plaguicidas/análisis , Piretrinas/análisis , Temperatura
12.
Food Chem ; 232: 218-228, 2017 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-28490068

RESUMEN

The chemical contamination levels of both conventional and organic meats were assessed. The objective was to provide occurrence data in a context of chronic exposure. Environmental contaminants (17 polychlorinated dibenzodioxins/dibenzofurans, 18 polychlorinated biphenyls (PCBs), 3 hexabromocyclododecane (HBCD) isomers, 6 mycotoxins, 6 inorganic compounds) together with chemical residues arising from production inputs (75 antimicrobials, 10 coccidiostats and 121 pesticides) have been selected as relevant compounds. A dedicated sampling strategy, representative of the French production allowed quantification of a large sample set (n=266) including both conventional (n=139) and organic (n=127) raw meat from three animal species (bovine, porcine, poultry). While contamination levels below regulatory limits were measured in all the samples, significant differences were observed between both species and types of farming. Several environmental contaminants (Dioxins, PCBs, HBCD, Zn, Cu, Cd, Pb, As) were measured at significantly higher levels in organic samples.


Asunto(s)
Carne , Animales , Bovinos , Dioxinas , Contaminación de Alimentos , Alimentos Orgánicos , Plaguicidas , Bifenilos Policlorados , Dibenzodioxinas Policloradas , Porcinos
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