Person: Martínez Caballero, María Aranzazu
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First Name
María Aranzazu
Last Name
Martínez Caballero
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Veterinaria
Department
Farmacología y Toxicología
Area
Toxicología
Identifiers
13 results
Search Results
Now showing 1 - 10 of 13
Item Mycotoxins modify the barrier function of Caco-2 cells through differential gene expression of specific claudin isoforms: Protective effect of illite mineral clay(Toxicology, 2016) Romero Martínez, Manuel Alejandro; Ares Lombán, Irma; Ramos Alonso, Eva; Castellano Santos, Víctor Jesús; Martínez Caballero, Marta; Martínez Larrañaga, María Rosa; Anadón Navarro, Arturo Ramón; Martínez Caballero, María AranzazuAflatoxin B1 (AFB1), fumonisin B1 (FB1), ochratoxin A (OTA) and T-2 toxin (T2) are mycotoxins that commonly contaminate the food chain and cause various toxicological effects. Their global occurrence is regarded as an important risk factor for human and animal health. In this study, the results demonstrate that, in human Caco-2 cells, AFB1, FB1, OTA and T2 origin cytotoxic effects, determining cell viability through MTT assay and LDH leakage, and decrease trans-epithelial electrical resistance (TEER). The decrease in barrier properties is concomitant with a reduction in the expression levels of the tight junction constituents claudin-3, claudin-4 and occludin. The protective effect of mineral clays (diosmectite, montmorillonite and illite) on alterations in cell viability and epithelial barrier function induced by the mycotoxins was also evaluated. Illite was the best clay to prevent the mycotoxin effects. Illite plus mycotoxin co-treatment completely abolished AFB1 and FB1-induced cytotoxicity. Also, the decreases in the gene expression of claudins and the reduction of TEER induced by mycotoxins were reversed by the illite plus mycotoxin co-treatment. In conclusion, these results demonstrated that mycotoxins AFB1, FB1, T2 and OTA disrupt the intestinal barrier permeability by a mechanism involving reduction of claudin isoform expressions, and illite counteracts this disruption.Item Brown marine algae Gongolaria baccata extract protects Caco-2 cells from oxidative stress induced by tert-butyl hydroperoxide(Food and Chemical Toxicology, 2021) Martínez Caballero, María Aranzazu; Ares Lombán, Irma; Martínez Caballero, Marta; López Torres, Bernardo; Maximiliano Guerra, Jorge Enrique; Rodriguez, J.L; Martínez Larrañaga, María Rosa; Anadón Navarro, Arturo Ramón; Peteiro, C.; Rubiño, S; Hortos, MGongolaria baccata (S.G. Gmelin) is marine brown seaweed mainly found on the coasts of the Baltic Sea south to the Mediterranean Sea, Canary Islands, Mauritania and Western Sahara. Herein, we report the cell viability and protective effects attributed to molecular mechanisms underlying antioxidant response to survive oxidative stress injuries. Caco-2 cells were submitted to oxidative stress by treatment with tert-butylhydroperoxide (tert-BOOH). The extract prevented cell damage and enhanced activity of antioxidant defenses (NQO1 and GST activities and GSH levels) reduced by treatment with tert-BOOH. The increases of MDA levels, the amount of intracellular ROS and caspase 3/7 activity induced by tert-BOOH were prevented when cells were treated with the G. baccata extract. Moreover, G. baccata extract caused up-regulation of GSTM2, Nrf2, and AKT1 gene expressions, as well as G. baccata extract reduced significantly Bax, BNIP3, APAF1, ERK1, JNK1, MAPK1, P38, P53, NFκB1, TNFα, IL-6, IL-1β and HO-1 gene expressions related to apoptosis, proinflammation and oxidative stress induced by tert-BOOH. These results suggest that G.baccata extract protected the cells against oxidative damage and inflammation; protective effects that could be linked to their bioactive constituents. Hence, this brown seaweed G. baccata extract could be used for the development of functional foods and/or nutraceuticals.Item Toxicologic evidence of developmental neurotoxicity of type II pyrethroids cyfluthrin and alpha-cypermethrin in SH-SY5Y cells(Food and Chemical Toxicology, 2020) Martínez Caballero, María Aranzazu; López Torres, Bernardo; Rodriguez, J.L.; Martínez Caballero, Marta; Maximiliano Guerra, Jorge Enrique; Martínez Larrañaga, María Rosa; Anadón Navarro, Arturo Ramón; Ares Lombán, IrmaWe attempted to identify cellular mechanisms as an approach to screen chemicals for the potential to cause developmental neurotoxicity. We examine, in SH-SY5Y cells, whether apoptosis and oxidative stress via reactive oxygen species (ROS) generation, caspase 3/7 activation, gene expression (Bax, Bcl-2, Casp-3, BNIP3, p53 and Nrf2) alterations and necrosis by release of cytosolic adenylate kinase (AK), underlie direct effects of the pyrethroids cyfluthrin and alpha-cypermethrin. We also determined transcriptional alterations of genes (TUBB3, NEFL, NEFH, GAP43, CAMK2A, CAMK2B, WNT3A, WNT5A, WNT7A, SYN1 and PIK3C3) linked to neuronal development and maturation. Our results indicate that cyfluthrin and alpha-cypermethrin have the ability to elicit concentration-dependent increases in AK release, cellular ROS production, caspase 3/7 activity and gene expression of apoptosis and oxidative stress mediators. Both pyrethroids caused changes in mRNA expression of key target genes linked to neuronal development. These changes might reflect in a subsequent neuronal dysfunction. Our study shows that SH-SY5Y cell line is a valuable in vitro model for predicting development neurotoxicity. Our research provides evidence that cyfluthrin and alpha-cypermethrin have the potential to act as developmental neurotoxic compounds. Additional information is needed to improve the utility of this in vitro model and/or better understand its predictive capability.Item Effects of exposure to pyrethroid cyfluthrin on serotonin and dopamine levels in brain regions of male rats(Environmental Research, 2016) Rodriguez, J.L.; Ares Lombán, Irma; Castellano Santos, Víctor Jesús; Martínez Caballero, Marta; Martínez Larrañaga, María Rosa; Anadón Navarro, Arturo Ramón; Martínez Caballero, María AranzazuThe effects of cyfluthrin oral exposure (1, 5, 10 and 20mg/kg bw, 6 days) on brain region monoamine levels of male rats were examined. Cyfluthrin-treated rats (1, 5 and 10mg/kg bw, orally 6 days), had no visible injury, i.e., no clinical signs of dysfunction were observed. However, rats treated with cyfluthrin at the highest dose (20mg/kg bw, orally 6 days) showed skeletal muscle contraction in the hind limbs, slight movement incoordination without any signs of dyskinesia and tremor after 1-2h of treatment. These signs were reversible at 6h after dose. After last dose of cyfluthrin, dopamine (DA) and serotonin (5-HT) and its metabolites levels were determined in brain regions hypothalamus, midbrain, hippocampus, striatum and prefrontal cortex by HPLC. Cyfluthrin (1mg/kg bw, orally 6 days) did not affect the DA, 5-HT and metabolites levels in the brain regions studied. Cyfluthrin (5, 10 and 20mg/kg bw, orally 6 days) caused a statistically significant decrease in DA and its metabolites DOPAC and HVA levels and in 5-HT and its metabolite 5-HIAA levels in a brain region- and dose-related manner. Moreover, cyfluthrin (20mg/kg bw, orally 6 days) evoked a statistically significant increase in 5-HT turnover in striatum and midbrain, and in DA turnover in striatum and prefrontal cortex. These findings indicate that serotoninergic and dopaminergic neurotransmission is affected by exposure to cyfluthrin and may contribute to the overall spectrum of neurotoxicity caused by this pyrethroidItem Use of human neuroblastoma SH-SY5Y cells to evaluate glyphosate-induced effects on oxidative stress, neuronal development and cell death signaling pathways(Environment International, 2020) Martínez Caballero, María Aranzazu; Rodríguez, José Luis; López Torres, Bernardo; Martínez Caballero, Marta; Martínez Larrañaga, María Rosa; Maximiliano Guerra, Jorge Enrique; Anadón Navarro, Arturo Ramón; Ares Lombán, IrmaGlyphosate-containing herbicides are the most used agrochemicals in the world. Their indiscriminate application raises some concerns regarding the possible health and environmental hazards. In this study, we investigated in human neuroblastoma cell line SH-SY5Y if oxidative stress, altered neurodevelopment and cell death pathways are involved in response to glyphosate and its metabolite aminomethylphosphonic acid (AMPA) exposures. MTT and LDH assays were carried out to assess the glyphosate and AMPA cytotoxicity. Lipid peroxides measured as malondialdehyde (MDA), nitric oxide (NO) and reactive oxygen species (ROS) production, and caspase-Glo 3/7 activity were evaluated. The neuroprotective role of melatonin (MEL), Trolox, N-acetylcysteine (NAC) and Sylibin against glyphosate- and AMPA-induced oxidative stress was examined. Glyphosate and AMPA effects on neuronal development related gene transcriptions, and gene expression profiling of cell death pathways by Real-Time PCR array were also investigated. Glyphosate (5 mM) and AMPA (10 mM) induced a significant increase in MDA levels, NO and ROS production and caspase 3/7 activity. Glyphosate exposure induced up-regulation of Wnt3a, Wnt5a, Wnt7a, CAMK2A, CAMK2B and down-regulation of GAP43 and TUBB3 mRNA expression involved in normal neural cell development. In relation to gene expression profiling of cell death pathways, of the 84 genes examined in cells a greater than 2-fold change was observed for APAF1, BAX, BCL2, CASP3, CASP7, CASP9, SYCP2, TNF, TP53, CTSB, NFκB1, PIK3C3, SNCA, SQSTMT, HSPBAP1 and KCNIPI mRNA expression for glyphosate and AMPA exposures. These gene expression data can help to define neurotoxic mechanisms of glyphosate and AMPA. Our results demonstrated that glyphosate and AMPA induced cytotoxic effects on neuronal development, oxidative stress and cell death via apoptotic, autophagy and necrotic pathways and confirmed that glyphosate environmental exposure becomes a concern. This study demonstrates that SH-SY5Y cell line could be considered an in vitro system for pesticide screening.Item Oral bioavailability, tissue distribution and depletion of flumequine in the food producing animal, chicken for fattening(Food and Chemical Toxicology, 2008) Anadón Navarro, Arturo Ramón; Martínez Caballero, María Aranzazu; Martínez Caballero, Marta; De la Cruz, C; Diaz, M.J.; Martínez Larrañaga, María RosaChickens were used to investigate kinetic properties including metabolism of flumequine after single IV and oral dose, and to study tissue depletion of flumequine after multiple oral doses. Plasma and tissue (muscle, kidney, liver and skin plus fat) concentrations of flumequine and its metabolite 7-hydroxyflumequine were determined using a HPLC method. After IV and oral administration (single-dose of 12 mg flumequine/kg bw), plasma concentration-time curves were best described by a two-compartment open model. Elimination half-life and mean residence time of flumequine in plasma were 6.91 and 5.90 h, respectively, after IV administration and 10.32 and 8.95 h after oral administration. Maximum plasma concentration was 3.62 microg/ml and interval from oral administration until maximum concentration was 1.43 h. Oral bioavailability was found to be 57%. Flumequine was converted to 7-hydroxyflumequine. After oral administration (24 mg/kg bw every 24 h for 5 days), renal and hepatic concentrations of flumequine (18-25 microg/kg) persisted for 4 days; however, at that time, flumequine residues were not detected in skin plus fat and muscle tissues. Flumequine administered at a dosage of 24 mg/kg bw every 24h for 5 days, with a withdrawal time of 2d ays, resulted in flumequine concentrations in target tissues that were less than the European Union maximal residue limits.Item Toxicokinetics of glyphosate and its metabolite aminomethyl phosphonic acid in rats(Toxicology Letters, 2009) Anadón Navarro, Arturo Ramón; Martínez Larrañaga, María Rosa; Martínez Caballero, María Aranzazu; Castellano Santos, Víctor Jesús; Martínez Caballero, Marta; Martín, M.T.; Nozal, M.J.; Bernal, J.L.The toxicokinetics of glyphosate after single 100 mg kg−1 intravenous (i.v.) and 400 mg kg−1 oral doses were studied in rats. Serial blood samples were obtained after i.v. and oral administration. Plasma concentrations of glyphosate and its metabolite amiomethyl phosphonic acid (AMPA) were determined by HPLC method. After i.v. and oral administration, plasma concentration–time curves were best described by a two-compartment open model. For glyphosate, the elimination half-lives (T1/2β) from plasma were 9.99 h after i.v. and 14.38 h after oral administration. The total plasma clearance was not influenced by dose concentration or route and reached a value of 0.995 l h−1 kg−1. After i.v. administration, the apparent volume of distribution in the second compartment (V2) and volume of distribution at steady state (Vss) were 2.39 and 2.99 l kg−1, respectively, suggesting a considerable diffusion of the herbicide into tissues. After oral administration, glyphosate was partially and slowly absorbed with a Tmax of 5.16 h. The oral bioavailability of glyphosate was found to be 23.21%. Glyphosate was converted to AMPA. The metabolite AMPA represented 6.49% of the parent drug plasma concentrations. The maximum plasma concentrations of glyphosate and AMPA were 4.62 and 0.416 μg ml−1, respectively. The maximum plasma concentration of AMPA was achieved at 2.42 h. For AMPA, the elimination half-life (T1/2β) was 15.08 h after oral administration of glyphosate parent compound.Item Toxicokinetics of lambda-cyhalothrin in rats(Toxicology Letters, 2006) Anadón Navarro, Arturo Ramón; Martínez Caballero, Marta; Martínez Caballero, María Aranzazu; Diaz, M.J.; Martínez Larrañaga, María RosaThe toxicokinetics of lambda-cyhalothrin after single 20 mg kg(-1) oral and 3 mg kg(-1) intravenous doses were studied in rats. Serial blood samples were obtained after oral and intravenous administration. Liver, brain, spinal cord, sciatic nerve, vas deferens, anococcygeus and myenteric plexus tissue samples were also collected. Plasma, liver, hypothalamus, cerebellum, medulla oblongata, frontal cortex, striatum, hippocampus, midbrain, spinal cord, vas deferens, anococcygeus, myenteric plexus and sciatic nerve concentrations of lambda-cyhalothrin were determined by HPLC. The plasma and tissue concentration-time data for lambda-cyhalothrin were found to fit a two-compartment open model. For lambda-cyhalothrin, the elimination half-life (T1/2beta) and the mean residence time from plasma were 7.55 and 8.55 h after i.v. and 10.27 and 14.43 h after oral administration. The total plasma clearance was not influenced by dose concentration or route and reached a value of 0.060l h(-1)kg(-1). After i.v. administration, the apparent volume of distribution and at steady state were 0.68 and 0.53l kg(-1), suggesting a diffusion of the pyrethroid into tissue. After oral administration, lambda-cyhalothrin was extensively but slowly absorbed (Tmax, 2.69 h). The oral bioavailability was found to be 67.37%. Significant differences in the kinetic parameters between nervous tissues and plasma was observed. The maximum concentrations in hypothalamus (Cmax, 24.12 microg g(-1)) and myenteric plexus (Cmax, 25.12 microg g(-1)) were about 1.5 times higher than in plasma (Cmax, 15.65 microg ml(-1)) and 1.3 times higher than in liver (Cmax, 18.42 microg ml(-1)). Nervous tissue accumulation of lambda-cyhalothrin was also reflected by the area under the concentration curve ratios of tissue/plasma (liver). The T1/2beta for lambda-cyhalothrin was significantly greater for the nerve tissues, including neuromuscular fibres, (range 12-26 and 15-34 h, after i.v. and oral doses) than for plasma (7.55 and 10.27 h, respectively).Item Neurotransmitter changes in rat brain regions following glyphosate exposure(Environmental Research, 2018) Martínez Caballero, María Aranzazu; Ares Lombán, Irma; Rodríguez, José Luis; Martínez Caballero, Marta; Martínez Larrañaga, María Rosa; Anadón Navarro, Arturo RamónThe effects of glyphosate oral exposure (35, 75, 150 and 800 mg/kg bw, 6 days) on brain region monoamine levels of male Wistar rats were examined. Glyphosate-treated rats (35, 75, 150 and 800 mg/kg bw, 6 days), had no visible injury, i.e., no clinical signs of dysfunction were observed. After last dose of glyphosate, serotonin (5-HT), dopamine (DA) and norepinephrine (NE) and its metabolites levels were determined in the brain regions striatum, hippocampus, prefrontal, cortex, hypothalamus and midbrain, by HPLC. Glyphosate caused statistically significant changes in the 5-HT and its metabolite 5-hydroxy-3-indolacetic acid (5-HIAA), DA and its metabolites 3,4-hydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and NE and its metabolite 3-metoxy-4-hydroxyphenylethyleneglycol (MHPG) levels in a brain regional- and dose-related manner. Moreover, glyphosate, dose-dependent, evoked a statistically significant increase in 5-HT turnover in striatum and hypothalamus and in DA turnover in prefrontal cortex and hippocampus, and a statistically significant decrease in NE turnover in prefrontal cortex and hypothalamus. The present findings indicate that glyphosate significantly altered central nervous system (CNS) monoaminergic neurotransmitters in a brain regional- and dose-related manner, effects that may contribute to the overall spectrum of neurotoxicity caused by this herbicide.Item Oxidative stress and gene expression profiling of cell death pathways in alpha-cypermethrin-treated SH-SY5Y cells(Archives of Toxicology, 2017) Romero Martínez, Manuel Alejandro; Ramos Alonso, Eva; Ares Lombán, Irma; Castellano Santos, Víctor Jesús; Martínez Caballero, Marta; Martínez Larrañaga, María Rosa; Anadón Navarro, Arturo Ramón; Martínez Caballero, María AranzazuIn this study, we investigated the induction of oxidative stress and apoptosis in human neuroblastoma cell line SH-SY5Y in response to alpha-cypermethrin (α-CYPER) exposure. MTT and LDH assays were carried out to assess the α-CYPER cytotoxicity. The IC50 value for α-CYPER was calculated to be 78.3 ± 2.98 µM for the MTT assay and 71.5 ± 3.94 µM for LDH assay. The pyrethroid α-CYPER (1-100 µM), in a dose-dependent manner, induced a significant increase in lipid peroxides measured as malondialdehyde (MDA) and in the levels of nitric oxide (NO). The neuroprotective role of three antioxidants, melatonin (MEL), Trolox and N-acetylcysteine (NAC) against α-CYPER-induced oxidative stress was examined. Compared to other antioxidants, MEL (1 µM) treatment showed the most effective protection against α-CYPER-induced lipid peroxidation and NO production. The effects of α-CYPER on gene expression profiling of cell death pathway in human neuroblastoma SH-SY5Y cells were also investigated. Of the 84 genes examined (P < 0.001; fold change >1.5), changes in mRNA levels were detected in 39 genes: 36 were up-regulated and 3 were down-regulated. A greater fold change reversion than 3.5-fold was observed on the up-regulated ATP6V1G2, BCL2, CASP9, FAS, GADD45A, SPATA2, SYCP2, ATG7, NFKB1, SNCA, ULK1 and JPH3 genes. The results demonstrated that α-CYPER alters the expression of apoptosis-, autophagy- and necrosis genes as well as induces oxidative stress which may lead to DNA damage. The detailed knowledge of the changes in gene expression obtained will provide a basis for further elucidating the molecular mechanisms of the α-CYPER-induced toxicity.