RESUMO
Permethrin (Per) is a widely used and frequently detected pyrethroid pesticide in agricultural products and the environment. It may pose potential toxicity to non-target organisms. Per has been reported to affect lipid homeostasis, although the mechanism is undefined. This study aims to explore the characteristic transcriptomic profiles and clarify the underlying signaling pathways of Per-induced lipid metabolism disorder in zebrafish liver. The results showed that environmental exposure to Per caused changes in the liver index, histopathology, and oxidative stress in zebrafish. Moreover, transcriptome results showed that Per heavily altered the pathways involved in metabolism, the immune system, and the endocrine system. We conducted a more in-depth analysis of the genes associated with lipid metabolism. Our findings revealed that exposure to Per led to a disruption in lipid metabolism by activating the KRAS-PPAR-GLUT signaling pathways through oxidative stress. The disruption of lipid homeostasis caused by exposure to Per may also contribute to obesity, hepatitis, and other diseases. The results may provide new insights for the risk of Permethrin to aquatic organisms and new horizons for the pathogenesis of hepatotoxicity.
Assuntos
Metabolismo dos Lipídeos , Estresse Oxidativo , Permetrina , Transdução de Sinais , Poluentes Químicos da Água , Peixe-Zebra , Animais , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Permetrina/toxicidade , Transdução de Sinais/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Inseticidas/toxicidade , Transcriptoma/efeitos dos fármacosRESUMO
Certain insecticides are known to have estrogenic effects by activating estrogen receptors through genomic transcription. This has led researchers to associate specific insecticide use with an increased breast cancer risk. However, it is unclear if estrogen receptor-dependent pathways are the only way in which these compounds induce carcinogenic effects. The objective of this study was to determine the impact of the pyrethroid insecticide permethrin on the growth of estrogen receptor negative breast cancer cells MDA-MB-231. Using tandem mass spectrometric techniques, the effect of permethrin on cellular protein expression was investigated, and gene ontology and pathway function enrichment analyses were performed on the deregulated proteins. Finally, molecular docking simulations of permethrin with the candidate target protein was performed and the functionality of the protein was confirmed through gene knockdown experiments. Our findings demonstrate that exposure to 10-40⯵M permethrin for 48â¯h enhanced cell proliferation and cell cycle progression in MDA-MB-231. We observed deregulated expression in 83 upregulated proteins and 34 downregulated proteins due to permethrin exposure. These deregulated proteins are primarily linked to transmembrane signaling and chemical carcinogenesis. Molecular docking simulations revealed that the overexpressed transmembrane signaling protein, G protein-coupled receptor 39 (GPR39), has the potential to bind to permethrin. Knockdown of GPR39 partially impeded permethrin-induced cellular proliferation and altered the expression of proliferation marker protein PCNA and cell cycle-associated protein cyclin D1 via the ERK1/2 signaling pathway. These findings offer novel evidence for permethrin as an environmental breast cancer risk factor, displaying its potential to impact breast cancer cell proliferation via an estrogen receptor-independent pathway.
Assuntos
Proliferação de Células , Receptor alfa de Estrogênio , Inseticidas , Simulação de Acoplamento Molecular , Permetrina , Receptores Acoplados a Proteínas G , Permetrina/toxicidade , Humanos , Proliferação de Células/efeitos dos fármacos , Inseticidas/toxicidade , Linhagem Celular Tumoral , Receptor alfa de Estrogênio/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neoplasias da Mama/patologia , Feminino , Transdução de Sinais/efeitos dos fármacosRESUMO
In this study, the toxic effects of permethrin on Allium cepa L. and the protective role of Zingiber officinale rhizome extract (Zoex) were investigated. In this context, 6 different groups were formed. While the control group was treated with tap water, the groups II and III were treated with 10 µg/mL and 20 µg/mL Zoex, respectively, and the group IV was treated with 100 µg/L permethrin. The protective effect of Zoex against permethrin toxicity was studied as a function of dose, and groups V and VI formed for this purpose were treated with 10 µg/mL Zoex + 100 µg/L permethrin and 20 µg/mL Zoex + 100 µg/L permethrin, respectively. After 72 h of germination, cytogenetic, biochemical, physiological, and anatomical changes in meristematic cells of A. cepa were studied. As a result, permethrin application decreased the mitotic index (MI) and increased the frequency of micronuclei (MN), and chromosomal abnormalities. The increase in malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) and the decrease in glutathione (GSH) indicate that permethrin causes oxidative damage. Compared to the control group, a 68.5% decrease in root elongation (p < 0.05) and an 81.8% decrease (p < 0.05) in weight gain were observed in the permethrin-treated group. It was found that the application of Zoex together with permethrin resulted in regression of all detected abnormalities, reduction in the incidence of anatomical damage, MN and chromosomal aberrations, and improvement in MI rates. The most significant improvement was observed in group VI treated with 20 µg/mL Zoex, and Zoex was also found to provide dose-dependent protection. The toxicity mechanism of permethrin was also elucidated by molecular docking and spectral studies. From the data obtained during the study, it was found that permethrin has toxic effects on A. cepa, a non-target organism, while Zoex plays a protective role by reducing these effects.
Assuntos
Permetrina , Zingiber officinale , Permetrina/toxicidade , Raízes de Plantas , Simulação de Acoplamento Molecular , Meristema , Cebolas , Aberrações Cromossômicas , Glutationa/farmacologia , Malondialdeído/farmacologiaRESUMO
The evidence supporting the biological plausibility of the association of permethrin and malathion with hematological cancer is limited and contradictory; thus, further studies are needed. This study aimed to investigate whether in vitro exposure to 0.1 µM permethrin and malathion at 0, 24, 48 and 72 h after cell culture initiation induced changes in the gene expression and DNA methylation in mononuclear cells from bone marrow and peripheral blood (BMMCs, PBMCs). Both pesticides induced several gene expression modifications in both tissues. Through gene ontology analysis, we found that permethrin deregulates ion channels in PBMCs and BMMCs and that malathion alters genes coding proteins with nucleic acid binding capacity, which was also observed in PBMCs exposed to permethrin. Additionally, we found that both insecticides deregulate genes coding proteins with chemotaxis functions, ion channels, and cytokines. Several genes deregulated in this study are potentially associated with cancer onset and development, and some of them have been reported to be deregulated in hematological cancer. We found that permethrin does not induce DNA hypermethylation but can induce hypomethylation, and that malathion generated both types of events. Our results suggest that these pesticides have the potential to modify gene expression through changes in promoter DNA methylation and potentially through other mechanisms that should be investigated.
Assuntos
Células da Medula Óssea , Metilação de DNA , Expressão Gênica , Inseticidas , Malation , Organofosfatos , Permetrina , Expressão Gênica/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Hematopoese/efeitos dos fármacos , Hematopoese/genética , Permetrina/toxicidade , Malation/toxicidade , Inseticidas/toxicidade , Organofosfatos/toxicidade , Células da Medula Óssea/efeitos dos fármacos , Células Sanguíneas/efeitos dos fármacos , Humanos , Masculino , Adulto Jovem , Células CultivadasRESUMO
Pyrethroids are among the most widely used insecticides. Permethrin and tetramethrin, which are synthetic pyrethroids, are generally used to control insects in agricultural areas and household applications. Due to broad use areas, they contaminate aquatic ecosystems and cause adverse effects to the non-target aquatic organisms. Even though permethrin and tetramethrin are known to alter the oxidative stress parameters of in vivo aquatic animal model organisms, there are limited studies in vitro. This study aims to determine the adverse effects of permethrin and tetramethrin in the in vitro models of freshwater mussels exposed to 1 mg/L, 10 µg/L, 100 ng/L and 1 ng/L concentrations of chemicals for 24 h. For this purpose, reduced glutathione activities were evaluated as biomarkers of the primary gill and digestive gland cell cultures. In both cell cultures, reduced glutathione values increased in the exposed groups, compared to the control group. Even though the results showed that reduced glutathione activities had not significantly changed concentration-dependently (p > 0.05), significant differences were observed in the reduced glutathione activities of both cell cultures (p < 0.05). This study showed that permethrin and tetramethrin had highly toxic effects in the in vitro models of mussels even at low concentrations.
Assuntos
Bivalves , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Inseticidas , Piretrinas , Animais , Permetrina/toxicidade , Permetrina/análise , Ecossistema , Piretrinas/toxicidade , Inseticidas/toxicidade , Inseticidas/análise , Estresse Oxidativo , Glutationa , Técnicas de Cultura de CélulasRESUMO
Permethrin (PER) is a pyrethroid pesticide that is extensively used as an insecticide in world because of its high activity and its low mammalian toxicity. The current study was conducted to investigate the protective action of Fumaria officinalis against PER-induced liver injury in male rats. However, HPLC-DAD showed the richness of 6 components in F. officinalis (F) including quercetin, ferulic acid, and naringenin which were the most abundant. Total polyphenols, total flavonoids, and condensed tannins were studied by phytochemical screening. In vitro, antioxidant properties showed that F. officinalis exhibited the highest DPPH radical, FRAP, and H2 O2 tests and total antioxidant capacity. Wistar rats were divided into four groups: negative control group (C), positive control group (F) (200 mg F. officinalis/kg BW), PER group (34.05 mg permethrin/kg BW), and PER + F group (34.05 mg permethrin/kg BW and 200 mg F. officinalis/kg BW). Oral administration of PER led to promote a decrease of body weight and Ca2+ -ATPases and Mg2+ -ATPases activities and an increase of plasma C-reactive protein level, transaminases, and hepatic Ï-GT activities as well as hepatic and mitochondrial oxidative stress. An increase in plasma lactate-to pyruvate ratio and a reduction in complexes enzymes I, III, and IV activities were also observed. In addition, histoarchitecture of liver in PER-treated rats showed apoptosis and necrosis as confirmed by DNA fragmentation. F. officinalis significantly exerted hepatoprotective effect by modulating hepatic alteration and mitochondrial dysfunction as well as genotoxicity. This effect could be attributed to phenolics compounds such as polyphenols, condensed tannins, and flavonoids.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Fumaria , Inseticidas , Permetrina , Proantocianidinas , Adenosina Trifosfatases/metabolismo , Animais , Antioxidantes/metabolismo , Apoptose , Proteína C-Reativa/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Dano ao DNA , Flavonoides/farmacologia , Fumaria/química , Inseticidas/toxicidade , Lactatos/metabolismo , Fígado/metabolismo , Masculino , Mamíferos/metabolismo , Mitocôndrias/metabolismo , Estresse Oxidativo , Permetrina/toxicidade , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Proantocianidinas/farmacologia , Piruvatos/farmacologia , Quercetina/farmacologia , Ratos , Ratos Wistar , TransaminasesRESUMO
The non-genotoxic synthetic pyrethroid insecticide permethrin produced hepatocellular adenomas and bronchiolo-alveolar adenomas in female CD-1 mice, but not in male CD-1 mice or in female or male Wistar rats. Studies were performed to evaluate possible modes of action (MOAs) for permethrin-induced female CD-1 mouse liver and lung tumor formation. The MOA for liver tumor formation by permethrin involves activation of the peroxisome proliferator-activated receptor alpha (PPARα), increased hepatocellular proliferation, development of altered hepatic foci, and ultimately liver tumors. This MOA is similar to that established for other PPARα activators and is considered to be qualitatively not plausible for humans. The MOA for lung tumor formation by permethrin involves interaction with Club cells, followed by a mitogenic effect resulting in Club cell proliferation, with prolonged administration producing Club cell hyperplasia and subsequently formation of bronchiolo-alveolar adenomas. Although the possibility that permethrin exposure may potentially result in enhancement of Club cell proliferation in humans cannot be completely excluded, there is sufficient information on differences in basic lung anatomy, physiology, metabolism, and biologic behavior of tumors in the general literature to conclude that humans are quantitatively less sensitive to agents that increase Club cell proliferation and lead to tumor formation in mice. The evidence strongly indicates that Club cell mitogens are not likely to lead to increased susceptibility to lung tumor development in humans. Overall, based on MOA evaluation it is concluded that permethrin does not pose a tumorigenic hazard for humans, this conclusion being supported by negative data from permethrin epidemiological studies.
Assuntos
Adenoma , Neoplasias Hepáticas , Neoplasias Pulmonares , Adenoma/metabolismo , Animais , Feminino , Humanos , Fígado , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , PPAR alfa/metabolismo , PPAR alfa/farmacologia , Permetrina/toxicidade , Ratos , Ratos WistarRESUMO
Permethrin has been shown to increase lung adenomas in female CD-1 mice, but not in male mice or Wistar rats. The proposed mode of action (MOA) for permethrin-induced female mouse lung tumor formation involves morphological changes in Club cells; increased Club cell proliferation; increased Club cell hyperplasia, and lung tumor formation. In this study, the treatment of female CD-1 mice with tumorigenic doses (2500 and 5000 ppm) of permethrin, but not with a nontumorigenic dose (20 ppm), for 14 and/or 28 days increased Club cell replicative DNA synthesis. Global gene expression analysis of female mouse lung samples demonstrated that permethrin treatment up-regulated 3 genes associated with cell proliferation, namely aldehyde dehydrogenase 3a1 (Aldh3a1), oxidative stress-induced growth inhibitor 1, and thioredoxin reductase 1. Treatment with 2500 and 5000 ppm, but not 20 ppm, permethrin for 7 days produced significant increases in mRNA levels of these 3 genes. Immunohistochemical analysis demonstrated that Club cell secretory protein, CYP2F2, and ALDH3A1 colocalized in Club cells; confirmed by flow cytometry analysis of lung cells employing KI67 as a cell proliferation marker. Overall, the present data extend the proposed MOA by demonstrating that Club cells are the primary initial target of permethrin administration in female mouse lungs. As humans are quantitatively much less sensitive to agents that increase Club cell proliferation and lung tumor formation in mice, it is most likely that permethrin could not produce lung tumors in humans. This conclusion is supported by available negative epidemiological data from several studies.
Assuntos
Neoplasias Pulmonares , Permetrina , Animais , Bronquíolos/patologia , Células Epiteliais/metabolismo , Feminino , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Permetrina/toxicidade , Ratos , Ratos WistarRESUMO
This study is the first to examine the possible mechanism by which long-term exposure to permethrin (PER) can promote arterial retention of proatherogenic lipid and lipoproteins and related vascular dysfunction in rats. Experimental animals were administered two doses of oral PER, PER-1 (2.5 mg/kg/bw) and PER-2 (5 mg/kg/bw), for 90 consecutive days. The results indicated that both PER-1 and PER-2 increased plasmatic and aortic total cholesterol, low-density lipoprotein cholesterol (LDL-C), apo B-100, and oxidized LDL together with arterial scavenger LDL receptors (CD36) but markedly reduced plasmatic and hepatic high-density lipoprotein cholesterol and native LDL receptors in aortic and hepatic tissue. The levels of malondialdehyde, protein carbonyl, and reactive oxygen species were significantly higher, and glutathione content as well as catalase, superoxide dismutase, and glutathione peroxidase activities were suppressed in the aorta of the PER-1 and PER-2 groups. The arterial oxidative damage possibly caused by PER was clearly demonstrated by hematoxylin and eosin histological analysis. Moreover, PER treatment aggravated the inflammatory responses through enhancement of the production of proinflammatory cytokines (tumor necrosis factor-α, interleukin-2, and interleukin-6) in both plasma and aorta. Furthermore, PER-1 and PER-2 potentiated the dysregulation of the aortic extracellular matrix (ECM) content by increasing mRNA activation of collagens I and III. The abundant histological collagen deposition observed in the media and adventitia of intoxicated rats using Masson's trichrome staining corroborates the observed change in ECM. These data showed that oxidative stress related to PER exposure increases the arterial accumulation of lipoprotein biomarkers, likely by actions on both LDL and CD36 receptors, together with the disruption of the aortic ECM.
Assuntos
Colágeno/genética , Inseticidas/toxicidade , Lipoproteínas LDL/sangue , Estresse Oxidativo/fisiologia , Permetrina/toxicidade , Animais , Aorta/metabolismo , Aorta/patologia , Apolipoproteína B-100/metabolismo , Antígenos CD36/metabolismo , Inflamação/metabolismo , Lipídeos/sangue , Masculino , Malondialdeído/metabolismo , Oxirredução , Ratos , Espécies Reativas de Oxigênio/metabolismo , Receptores de LDL/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
In 2-year studies, the nongenotoxic pyrethroid insecticide permethrin produced hepatocellular tumors in CD-1 mice but not in Wistar rats. Recently, we demonstrated that the mode of action (MOA) for mouse liver tumor formation by permethrin involves activation of the peroxisome proliferator-activated receptor alpha (PPARα), resulting in a mitogenic effect. In the present study, the effects of permethrin and 2 major permethrin metabolites, namely 3-phenoxybenzoic acid and trans-dichlorochrysanthemic acid, on cytochrome P450 mRNA levels and cell proliferation (determined as replicative DNA synthesis) were evaluated in cultured CD-1 mouse, Wistar rat, and human hepatocytes. Permethrin and 3-phenoxybenzoic acid induced CYP4A mRNA levels in both mouse and human hepatocytes, with trans-dichlorochrysanthemic acid also increasing CYP4A mRNA levels in mouse hepatocytes. 3-Phenoxybenzoic acid induced CYP4A mRNA levels in rat hepatocytes, with trans-dichlorochrysanthemic acid increasing both CYP4A mRNA levels and replicative DNA synthesis. Permethrin, 3-phenoxybenzoic acid, and trans-dichlorochrysanthemic acid stimulated replicative DNA synthesis in mouse hepatocytes but not in human hepatocytes, demonstrating that human hepatocytes are refractory to the mitogenic effects of permethrin and these 2 metabolites. Thus, although some of the key (eg, PPARα activation) and associative (eg, CYP4A induction) events in the established MOA for permethrin-induced mouse liver tumor formation could occur in human hepatocytes at high doses of permethrin, 3-phenoxybenzoic acid, and/or trans-dichlorochrysanthemic acid, increased cell proliferation (an essential step in carcinogenesis by nongenotoxic PPARα activators) was not observed. These results provide additional evidence that the established MOA for permethrin-induced mouse liver tumor formation is not plausible for humans.
Assuntos
Transformação Celular Neoplásica/induzido quimicamente , Hepatócitos/efeitos dos fármacos , Inseticidas/toxicidade , Neoplasias Hepáticas/induzido quimicamente , Permetrina/toxicidade , Animais , Benzoatos/toxicidade , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Células Cultivadas , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Feminino , Regulação Enzimológica da Expressão Gênica , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , PPAR alfa/agonistas , PPAR alfa/metabolismo , Ratos Wistar , Medição de Risco , Fatores Sexuais , Especificidade da EspécieRESUMO
Chemicals that are highly prevalent in our environment, such as phthalates and pesticides, have been linked to problems associated with reproductive health. However, rapid assessment of their impact on reproductive health and understanding how they cause such deleterious effects, remain challenging due to their fast-growing numbers and the limitations of various current toxicity assessment model systems. Here, we performed a high-throughput screen in C. elegans to identify chemicals inducing aneuploidy as a result of impaired germline function. We screened 46 chemicals that are widely present in our environment, but for which effects in the germline remain poorly understood. These included pesticides, phthalates, and chemicals used in hydraulic fracturing and crude oil processing. Of the 46 chemicals tested, 41% exhibited levels of aneuploidy higher than those detected for bisphenol A (BPA), an endocrine disruptor shown to affect meiosis, at concentrations correlating well with mammalian reproductive endpoints. We further examined three candidates eliciting aneuploidy: dibutyl phthalate (DBP), a likely endocrine disruptor and frequently used plasticizer, and the pesticides 2-(thiocyanomethylthio) benzothiazole (TCMTB) and permethrin. Exposure to these chemicals resulted in increased embryonic lethality, elevated DNA double-strand break (DSB) formation, activation of p53/CEP-1-dependent germ cell apoptosis, chromosomal abnormalities in oocytes at diakinesis, impaired chromosome segregation during early embryogenesis, and germline-specific alterations in gene expression. This study indicates that this high-throughput screening system is highly reliable for the identification of environmental chemicals inducing aneuploidy, and provides new insights into the impact of exposure to three widely used chemicals on meiosis and germline function.
Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Poluentes Ambientais/toxicidade , Células Germinativas/efeitos dos fármacos , Ensaios de Triagem em Larga Escala/métodos , Aneugênicos/toxicidade , Aneuploidia , Animais , Animais Geneticamente Modificados , Benzotiazóis/toxicidade , Caenorhabditis elegans/embriologia , Caenorhabditis elegans/genética , Quebras de DNA de Cadeia Dupla , Dibutilftalato/toxicidade , Exposição Ambiental , Inseticidas/toxicidade , Meiose/efeitos dos fármacos , Permetrina/toxicidade , Plastificantes/toxicidade , Tiocianatos/toxicidadeRESUMO
The nongenotoxic pyrethroid insecticide permethrin produced hepatocellular tumors in CD-1 mice but not in Wistar rats. Recently, based on findings of a Pathology Working Group involving an expert panel of pathologists, it was concluded that permethrin increased liver tumors at 2500 and 5000 ppm in female mice, but no treatment-related tumorigenic response occurred in male mice at dose levels examined in the 2-year bioassay. To evaluate a possible mode of action (MOA) for the permethrin female CD-1 mouse hepatocellular tumors, a number of investigative studies were conducted. In time-course studies in female CD-1 mice, permethrin increased relative liver weight and enhanced hepatocyte proliferation within 1 week. Treatment with permethrin resulted in marked increases in CYP4A enzyme activities and mRNA levels, but only slightly increased CYP2B markers, suggesting that permethrin primarily activates the peroxisome proliferator-activated receptor alpha (PPARα) and to a much lesser extent the constitutive androstane receptor. The effects of permethrin on relative liver weight, hepatocyte proliferation and CYP4A enzyme activities and mRNA levels were dose-dependent and were reversible within 5 weeks after cessation of treatment. The hepatic effects of permethrin observed in wild-type female mice were markedly reduced in PPARα knockout female mice. These results demonstrate that the MOA for hepatocellular tumor formation by permethrin in female mice involves activation of PPARα resulting in a mitogenic effect. The MOA for permethrin-induced mouse liver tumor formation due to PPARα activation is considered to be not plausible for humans. This conclusion is strongly supported by available epidemiological data for permethrin.
Assuntos
Carcinógenos/toxicidade , Hepatócitos/efeitos dos fármacos , Neoplasias Hepáticas/induzido quimicamente , Fígado/efeitos dos fármacos , PPAR alfa/metabolismo , Permetrina/toxicidade , Animais , Proliferação de Células/efeitos dos fármacos , Citocromo P-450 CYP4A/metabolismo , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Feminino , Hepatócitos/patologia , Fígado/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Knockout , PPAR alfa/genéticaRESUMO
A 24-month oral carcinogenicity study of permethrin was conducted by feeding male and female CD-1 mice diets containing concentrations of 0, 20, 500, and 2,000 ppm of permethrin (males) or 0, 20, 2,500, and 5,000 ppm of permethrin (females). After approximately two years on study, surviving mice were sacrificed for the evaluation of chronic toxicity and/or carcinogenicity. An expert panel of pathologists was convened as a Pathology Working Group (PWG) to review coded liver histology sections from male and female mice and to classify all liver neoplasms according to current nomenclature and diagnostic criteria guidelines. The PWG results indicate that permethrin induced a significant dose-dependent increase in the incidence of hepatocellular neoplasms in treated female mice ( p < .01) as well as a nonstatistically significant increase in the incidence of hepatocellular tumors in treated male mice. Given the continuum of the diagnoses of adenoma and carcinoma, and the difficulty in distinguishing some of the lesions, it is appropriate to consider only the combined incidences of hepatocellular tumors (adenoma and/or carcinoma) for biological significance and risk assessment.
Assuntos
Carcinógenos/toxicidade , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas/induzido quimicamente , Permetrina/toxicidade , Administração Oral , Animais , Testes de Carcinogenicidade , Relação Dose-Resposta a Droga , Feminino , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas Experimentais/patologia , Masculino , Camundongos Endogâmicos , Fatores SexuaisRESUMO
Gulf War Illness (GWI) is a chronic multisymptom disorder affecting veterans of the 1990-91 Gulf war. GWI was linked with exposure to chemicals including the nerve gas prophylactic drug pyridostigmine-bromide (PB) and pesticides (DEET, permethrin). Veterans with GWI exhibit prolonged, low-level systemic inflammation, though whether this impacts the liver is unknown. While no evidence exists that GWI-related chemicals are hepatotoxic, the prolonged inflammation may alter the liver's response to insults such as cholestatic injury. We assessed the effects of GWI-related chemicals on macrophage infiltration and its subsequent influence on hepatic cholestasis. Sprague Dawley rats were treated daily with PB, DEET and permethrin followed by 15 minutes of restraint stress for 28 days. Ten weeks afterward, GWI rats or naïve age-matched controls underwent bile duct ligation (BDL) or sham surgeries. Exposure to GWI-related chemicals alone increased IL-6, and CD11b+F4/80- macrophages in the liver, with no effect on biliary mass or hepatic fibrosis. However, pre-exposure to GWI-related chemicals enhanced biliary hyperplasia and fibrogenesis caused by BDL, compared to naïve rats undergoing the same surgery. These data suggest that GWI patients could be predisposed to developing worse liver pathology due to sustained low-level inflammation of the liver when compared to patients without GWI.
Assuntos
Colestase/imunologia , DEET/toxicidade , Permetrina/toxicidade , Síndrome do Golfo Pérsico/imunologia , Brometo de Piridostigmina/toxicidade , Estresse Psicológico/imunologia , Animais , Ductos Biliares/efeitos dos fármacos , Ductos Biliares/imunologia , Ductos Biliares/patologia , Ductos Biliares/cirurgia , Antígeno CD11b/genética , Antígeno CD11b/imunologia , Movimento Celular/efeitos dos fármacos , Colestase/genética , Colestase/psicologia , Colestase/cirurgia , Modelos Animais de Doenças , Expressão Gênica , Humanos , Imobilização , Inflamação , Interleucina-6/genética , Interleucina-6/imunologia , Ligadura , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/patologia , Masculino , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/patologia , Síndrome do Golfo Pérsico/induzido quimicamente , Síndrome do Golfo Pérsico/genética , Síndrome do Golfo Pérsico/psicologia , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/genética , Estresse Psicológico/patologiaRESUMO
ãToxicity prediction based on stem cells and tissue derived from stem cells plays a very important role in the fields of biomedicine and pharmacology. Here we report on qRT-PCR data obtained by exposing 20 compounds to human embryonic stem (ES) cells. The data are intended to improve toxicity prediction, per category, of various compounds through the use of support vector machines, and by applying gene networks. The accuracy of our system was 97.5-100% in three toxicity categories: neurotoxins (NTs), genotoxic carcinogens (GCs), and non-genotoxic carcinogens (NGCs). We predicted that two uncategorized compounds (bisphenol-A and permethrin) should be classified as follows: bisphenol-A as a non-genotoxic carcinogen, and permethrin as a neurotoxin. These predictions are supported by recent reports, and as such constitute a good outcome. Our results include two important features: 1) The accuracy of prediction was higher when machine learning was carried out using gene networks and activity, rather than the normal quantitative structure-activity relationship (QSAR); and 2) By using undifferentiated ES cells, the late effect of chemical substances was predicted. From these results, we succeeded in constructing a highly effective and highly accurate system to predict the toxicity of compounds using stem cells.
Assuntos
Células-Tronco Embrionárias/efeitos dos fármacos , Máquina de Vetores de Suporte , Testes de Toxicidade/métodos , Compostos Benzidrílicos/toxicidade , Carcinógenos/toxicidade , Humanos , Neurotoxinas/toxicidade , Permetrina/toxicidade , Fenóis/toxicidade , Relação Quantitativa Estrutura-AtividadeRESUMO
Pesticides are commonly used worldwide and almost every human is potentially exposed to these chemicals. Exposure to pesticides such as permethrin and malathion has been associated with hematological malignancies in epidemiological studies. However, biological evidence showing if these chemicals induce genetic aberrations involved in the etiology of leukemia and lymphoma is missing. In our previous work, we have shown that a single high exposure (200 µm, 24 hours) of permethrin and malathion induce damage in genes associated with hematological malignancies in peripheral blood mononuclear cells analyzed by interphase fluorescence in situ hybridization (FISH). In the present study, we assessed by FISH whether exposure to low concentrations (0.1 µm, 72 hours) of permethrin and malathion induce aberrations in KMT2A and IGH genes, which are involved in the etiology of leukemia and lymphoma. Peripheral blood mononuclear cells were exposed to the chemicals, and damage in these genes was assessed on interphases and metaphases. We observed that both chemicals at low concentration induced structural aberrations in KMT2A and IGH genes. A higher level of damage was observed in KMT2A gene with malathion treatment and in IGH gene with permethrin exposure. We also observed numerical aberrations induced by these chemicals. The most frequent aberrations detected on interphase FISH were also observed on metaphases. Our results show that permethrin and malathion induce genetic damage in genes associated with hematological cancer, at concentrations biologically relevant. In addition, damage was observed on dividing cells, which suggests that these cells maintain their proliferation capacity in spite of the genetic damage they possess.
Assuntos
Dano ao DNA , Genes de Cadeia Pesada de Imunoglobulina , Histona-Lisina N-Metiltransferase/genética , Inseticidas/toxicidade , Leucemia/induzido quimicamente , Leucócitos Mononucleares/efeitos dos fármacos , Linfoma/induzido quimicamente , Malation/toxicidade , Proteína de Leucina Linfoide-Mieloide/genética , Permetrina/toxicidade , Proliferação de Células , Sobrevivência Celular , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Hibridização in Situ Fluorescente , Interfase , Leucemia/enzimologia , Leucemia/genética , Leucemia/patologia , Leucócitos Mononucleares/enzimologia , Leucócitos Mononucleares/patologia , Linfoma/enzimologia , Linfoma/genética , Linfoma/patologia , Masculino , Metáfase , Índice Mitótico , Medição de RiscoRESUMO
No systematic reviews are available on data from humans on cancer risk from exposure to permethrin, a widely used insecticide for which some animal studies have reported positive findings based on mechanisms that may not be relevant to humans. We identified potentially relevant articles through a search of electronic databases which included all studies of pesticide exposure and human cancer. A total of 18 articles were selected, including six identified from the list of references of other articles. Most articles were based on analyzes of the Agriculture Health Study (AHS); they provided no evidence of an increased risk of cancers of colon, rectum, pancreas, lung, melanoma, female breast, prostate, urinary bladder, as well as non-Hodgkin lymphoma (including its main subtypes), and leukemia. An increased risk of multiple myeloma was reported among AHS members with the highest tertile of estimated permethrin exposure (odds ratio 5.01; 95% confidence interval 2.41-10.42; p for trend <0.01). A subsequent analysis with a larger number of cases found a less pronounced association between permethrin exposure and risk of multiple myeloma; no exposed cases were reported in a separate study. Two case-control studies of childhood leukemia reported an association with biological markers of permethrin metabolites; in another study self-reported exposure to permethrin was associated with risk in children below 1 year of age, but not in older children. In conclusion, permethrin exposure does not seem to entail a risk of cancer in humans. Results on multiple myeloma and childhood leukemia are weak and inconsistent, and require replication in independent populations.
Assuntos
Inseticidas/toxicidade , Neoplasias/induzido quimicamente , Permetrina/toxicidade , Carcinógenos/toxicidade , Exposição Ambiental/efeitos adversos , Feminino , Humanos , Masculino , Neoplasias/epidemiologia , RiscoRESUMO
Mounting an immune response consumes resources, which should lead to increased feeding. However, activating the immune system reduces feeding (i.e. illness-induced anorexia) in both vertebrates and invertebrates, suggesting that it may be beneficial. We suggest that illness-induced anorexia may be an adaptive response to conflicts between immune defense and food detoxification. We found that activating an immune response in the caterpillar Manduca sexta increased its susceptibility to the toxin permethrin. Conversely, a sublethal dose of permethrin reduced resistance to the bacterium Serratia marcescens, demonstrating a negative interaction between detoxification and immune defense. Immune system activation and toxin challenge each depleted the amount of glutathione in the hemolymph. Increasing glutathione concentration in the hemolymph increased survival for both toxin- and immune+toxin-challenged groups. The results of this rescue experiment suggest that decreased glutathione availability, such as occurs during an immune response, impairs detoxification. We also found that the expression of some detoxification genes were not upregulated during a combined immune-toxin challenge, although they were when animals received a toxin challenge alone. These results suggest that immune defense reduces food detoxification capacity. Illness-induced anorexia may protect animals by decreasing exposure to food toxins when detoxification is impaired.
Assuntos
Antibiose , Imunidade Inata , Inseticidas/toxicidade , Manduca/imunologia , Manduca/microbiologia , Permetrina/toxicidade , Serratia marcescens/fisiologia , Animais , Ingestão de Alimentos , Larva/imunologia , Larva/microbiologia , Manduca/crescimento & desenvolvimento , Desintoxicação Metabólica Fase IRESUMO
The mechanisms associated to the development of neurodegeneration due to pesticide exposure are not clear yet. In this study we evaluated how permethrin pesticide (PERM) can influence the Nurr1 gene and protein expression, and if a pro-oxidant activity of the pesticide contributes to up-regulation of Nurr1 in a dopaminergic cell line. Incubation of PC12 cells with 1µM PERM for 72h, leads to over expression of Nurr1 gene. This effect occurs with both corn oil and extra virgin olive oil (EVO) used to solubilize the toxicant. In order to investigate if the Nurr1 up-regulation induced by PERM, was associated to the pro-oxidant activity of the pesticide, anti-oxidants as glutathione (GSH), tocotrienols (TOC) and Electrolyzed Reduced Water (ERW) were tested. RT-PCR of Nurr1 showed that its up-regulation was significantly reduced in the presence of antioxidants, especially by addition of ERW. Western-blot analysis reveals that ERW was able to counterbalance the up-regulation of Nurr1 protein induced by permethrin exposure.