RESUMO
Phthalates are extensively used in the production of plastics products and have been verified to induce lung injury. Lycopene (LYC) has proved an effective preventive and can be utilized to prevent phthalates-induced toxicity. However, the role of phthalate in pathogenesis of lung injury remain poorly researched, and little work has been devoted whether LYC could alleviate phthalate-induced lung toxicity via modulating nuclear xenobiotic receptors (NXRs) response. Here, di (2-ethylhexyl) phthalate (DEHP) is used as the representative of phthalates for further studies on toxicity of phthalates and the antagonistic role of LYC in phthalates-induced lung injury. We found that DEHP exposure caused alveoli destruction and alveolar epithelial cells type II damage. Mechanistically, DEHP exposure increased nuclear accumulation of aryl hydrocarbon receptor (AHR) and its downstream genes level, including cytochrome P450-dependent monooxygenase (CYP) 1A1 and CYP1B1. Constitutive androstane receptor (CAR) and their downstream gene level, including CYP2E1 are also increased after phthalates exposure. Significantly, LYC supplementation relieves lung injury from DEHP exposure by inhibiting the activation of NXRs. We confirm that NXRs plays a key role in phthalates-induced lung injury. Our study showed that LYC may have a positive role in alleviating the toxicity effects of phthalates, which provides an effective strategy for revising phthalates-induced injury.
Assuntos
Dietilexilftalato , Lesão Pulmonar , Ácidos Ftálicos , Humanos , Dietilexilftalato/toxicidade , Lesão Pulmonar/induzido quimicamente , Licopeno/farmacologia , Ácidos Ftálicos/toxicidade , Receptores Citoplasmáticos e Nucleares/metabolismo , Xenobióticos/toxicidade , Aminoácidos/metabolismoRESUMO
Early human life is considered a critical window of susceptibility to external exposures. Infants are exposed to a multitude of environmental factors, collectively referred to as the exposome. The chemical exposome can be summarized as the sum of all xenobiotics that humans are exposed to throughout a lifetime. We review different exposure classes and routes that impact fetal and infant metabolism and the potential toxicological role of mixture effects. We also discuss the progress in human biomonitoring and present possiblemodels for studying maternal-fetal transfer. Data gaps on prenatal and infant exposure to xenobiotic mixtures are identified and include natural biotoxins, in addition to commonly reported synthetic toxicants, to obtain a more holistic assessment of the chemical exposome. We highlight the lack of large-scale studies covering a broad range of xenobiotics. Several recommendations to advance our understanding of the early-life chemical exposome and the subsequent impact on health outcomes are proposed.
Assuntos
Exposição Ambiental , Expossoma , Gravidez , Lactente , Feminino , Humanos , Pré-Escolar , Exposição Ambiental/efeitos adversos , Xenobióticos/toxicidade , Desenvolvimento FetalRESUMO
The liver is a highly metabolic organ and plays a crucial role in the transportation, storage, and/or detoxication of xenobiotics. Liver damage induced by xenobiotics (e.g., heavy metal, endocrine disrupting chemicals, Chinese herbal medicine, or nanoparticles) has become a pivotal reason for liver diseases, leading to great clinical challenge and much attention for the past decades. Given that endoplasmic reticulum (ER) is the prominent organelle involved in hepatic metabolism, ER dysfunction, namely, ER stress, is clearly observed in various liver diseases. In response to ER stress, a conserved adaptive signaling pathway known as unfolded protein response (UPR) is activated to restore ER homeostasis. However, the prolonged ER stress with UPR eventually leads to the death of hepatocytes, which is a pathogenic event in many hepatic diseases. Therefore, analyzing the perturbation in the activation or inhibition of ER stress and the UPR signaling pathway is likely an effective marker for investigating the molecular mechanisms behind the toxic effects of xenobiotics on the liver. We review the role of ER stress in hepatic diseases and xenobiotic-induced hepatotoxicity, which not only provides a theoretical basis for further understanding the pathogenesis of liver diseases and the mechanisms of hepatotoxicity induced by xenobiotics but also presents a potential target for the prevention and treatment of xenobiotic-related liver diseases.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Hepatopatias , Humanos , Xenobióticos/toxicidade , Estresse do Retículo Endoplasmático/fisiologia , Hepatopatias/etiologia , Resposta a Proteínas não DobradasRESUMO
In an in vivo rat model of human exposure to cadmium (Cd; 5 and 50 mg/L, 6 months), whether the supplementation with zinc (Zn; 30 and 60 mg/L, increasing its daily intake by 79% and 151%, respectively) protects against the unfavourable impact of this xenobiotic on the vascular tissue of the abdominal aorta was investigated. The treatment with Cd led to oxidative stress and increased the concentrations of pro-inflammatory interleukin 1ß (IL-1ß), total cholesterol (TC), triglycerides (TG), and endothelial nitric oxide synthase (eNOS) and decreased the concentration of anti-inflammatory interleukin 10 (IL-10) in the vascular tissue. Cd decreased the expression of intercellular adhesion molecule-1 (ICAM-1), platelet endothelial cell adhesion molecule-1 (PECAM-1), and L-selectin on the endothelial cells. The administration of Zn prevented most of the Cd-induced alterations or at least weakened them (except for the expression of adhesive molecules). In conclusion, Zn supplementation may protect from the toxic impact of Cd on the blood vessels and thus exert a beneficial influence on the cardiovascular system. The increase in the intake of Zn by 79% may be sufficient to provide this protection and the effect is related to the antioxidative, anti-inflammatory, and antiatherogenic properties of this essential element.
Assuntos
Aorta Abdominal , Cádmio , Zinco , Animais , Aorta Abdominal/efeitos dos fármacos , Cádmio/toxicidade , Colesterol/metabolismo , Suplementos Nutricionais , Células Endoteliais/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Selectina L/metabolismo , Modelos Teóricos , Óxido Nítrico Sintase Tipo III/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Ratos , Ratos Wistar , Triglicerídeos/metabolismo , Xenobióticos/toxicidade , Zinco/farmacologiaRESUMO
Small molecule tyrosine kinase inhibitors (TKIs) are widely used as anticancer drugs approved by U.S. FDA. However, the toxicities of TKIs to multiple organs have greatly limited their clinical applications. The metabolism of TKIs generates several potentially toxic metabolites in vivo, that can disturb the endogenous metabolism as well as cellular function, leading to organ damage. Therefore, it is essential to identify the toxic metabolites and elucidate the underlying mechanism of TKI-induced toxicity. Metabolomics is a powerful tool for the identification of the xenobiotic metabolites and metabolic derangement associated with xenobiotic exposure, that is helpful to understand the toxicity of TKIs. The study using metabolomics approach has revealed that the reactive metabolites/intermediates (e.g., N-oxide metabolite, primary amine metabolite, 1,4-benzoquinone intermediate) and adducts with glutathione, cysteine and mercapturic acid can be derived from TKIs. Fourteen metabolic pathways could be affected following the TKI treatment, including lipid metabolism, bile acid metabolism, and gut microbiota-related pathway. Modulation of xenobiotic receptor signaling, inhibition of xenobiotic metabolism, and supplementation of endogenous metabolites are potential strategies to protect against TKI-induced toxicity. In this review, studies on the metabolism of TKIs and the alterations of endogenous metabolism are discussed, and the potential preventions against TKI-induced toxicity are summarized.
Assuntos
Antineoplásicos , Inibidores de Proteínas Quinases , Antineoplásicos/toxicidade , Humanos , Inibidores de Proteínas Quinases/toxicidade , Xenobióticos/toxicidadeRESUMO
A high-fat diet (HFD) induces changes in gut microbiota leading to activation of pro-inflammatory pathways, and obesity, as a consequence of overnutrition, exacerbates inflammation, a known risk factor not only for cancer. However, experimental data showed that the composition of dietary fat has a greater impact on the pathogenesis of cancer than the total fat content in isocaloric diets. Similarly, human studies did not prove that a decrease in total fat intake is an effective strategy to combat cancer. Saturated fat has long been considered as harmful, but the current consensus is that moderate intake of saturated fatty acids (SFAs), including palmitic acid (PA), does not pose a health risk within a balanced diet. In regard to monounsaturated fat, plant sources are recommended. The consumption of plant monounsaturated fatty acids (MUFAs), particularly from olive oil, has been associated with lower cancer risk. Similarly, the replacement of animal MUFAs with plant MUFAs decreased cancer mortality. The impact of polyunsaturated fatty acids (PUFAs) on cancer risk depends on the ratio between ω-6 and ω-3 PUFAs. In vivo data showed stimulatory effects of ω-6 PUFAs on tumour growth while ω-3 PUFAs were protective, but the results of human studies were not as promising as indicated in preclinical reports. As for trans FAs (TFAs), experimental data mostly showed opposite effects of industrially produced and natural TFAs, with the latter being protective against cancer progression, but human data are mixed, and no clear conclusion can be made. Further studies are warranted to establish the role of FAs in the control of cell growth in order to find an effective strategy for cancer prevention/treatment.
Assuntos
Gorduras na Dieta/efeitos adversos , Gorduras na Dieta/farmacologia , Inflamação/etiologia , Neoplasias/etiologia , Animais , Dieta Hiperlipídica/efeitos adversos , Dieta Mediterrânea , Gorduras/química , Ácidos Graxos Insaturados/química , Ácidos Graxos Insaturados/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Inflamação/microbiologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Obesidade/complicações , Estresse Oxidativo , Xenobióticos/toxicidadeRESUMO
Sarcocornia perennis subsp. perennis is an edible halophyte with reported potential health benefits. To disclose the potential contribution of its polysaccharides to health benefits, in this work, hot water extracts were prepared and a holistic approach was performed, relating the simultaneous effects on different organs and molecular components administered orally, using the extract and the purified polysaccharides. The material rich in polysaccharides extracted with hot water was separated into two fractions by dialysis, allowing to obtain the pectic polysaccharides and the low molecular weight compounds. Oral administration of the extract and its fractions (120 mg/kg/day, 30 days) in mice was evaluated by histopathological analysis of liver, lymphoid (thymus and spleen) and reproductive organs (testis and epididymis). Extract and purified polysaccharides promoted a megakaryocytes increase in spleen, while low molecular weight compounds affected the reproductive organs (vacuolation and germ cells release in lumen), causing hydropic change in liver and degeneration of seminiferous tubules. This is the first study on polysaccharides from Sarcocornia. These pectic polysaccharides were shown to protect the immune and reproductive systems against toxic chemicals inducers of oxidation reactions. Their purification is a fundamental step, since the low molecular weight compounds of the edible parts may contribute to lesions in reproductive organs.
Assuntos
Amaranthaceae/química , Pectinas/química , Polissacarídeos/química , Polissacarídeos/farmacologia , Xenobióticos/toxicidade , Administração Oral , Animais , Peso Corporal/efeitos dos fármacos , Histologia , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Polissacarídeos/administração & dosagem , Solubilidade , Água/químicaRESUMO
The environment receives about 2.7â¯kg.ha-1 annually of pesticides, used in crop production. Pesticides may have a negative impact on environmental biodiversity and potentially induce physiological effects on non-target species. Advances in technology and nanocarrier systems for agrochemicals led to new alternatives to minimize these impacts, such as nanopesticides, considered more efficient, safe and sustainable. However, it is important to evaluate the risk potential, action and toxicity of nanopesticides in aquatic and terrestrial organisms. This study aims to evaluate genotoxic and hematological biomarkers in bullfrog tadpoles (Lithobates catesbeianus) submitted to acute exposure (48â¯h) to pyrethrum extract (PYR) and solid lipid nanoparticles loaded with PYR. Results showed increased number of leukocytes during acute exposure, specifically eosinophils in nanoparticle-exposed groups, and basophil in PYR-exposed group. Hematological analysis showed that PYR encapsulated in nanoparticles significantly increased the erythrocyte number compared to the other exposed groups. Data from the comet assay indicated an increase in frequency of the classes that correspond to more severe DNA damages in exposed groups, being that the PYR-exposed group showed a high frequency of class-4 DNA damage. Moreover, erythrocyte nuclear abnormalities were triggered by short-time exposure in all treatments, which showed effects significantly higher than the control group. These results showed genotoxic responses in tadpoles, which could trigger cell death pathways. Concluding, these analyses are important for applications in assessment of contaminated aquatic environments and their biomonitoring, which will evaluate the potential toxicity of xenobiotics, for example, the nanoparticles and pyrethrum extract in frog species. However, further studies are needed to better understand the effects of nanopesticides and botanical insecticides on non-target organisms, in order to contribute to regulatory aspects of future uses for these systems.
Assuntos
Chrysanthemum cinerariifolium , Larva/fisiologia , Nanopartículas/toxicidade , Extratos Vegetais/toxicidade , Rana catesbeiana/fisiologia , Xenobióticos/toxicidade , Animais , Dano ao DNA , Larva/efeitos dos fármacosRESUMO
The increased incidence of diabetes to the magnitude of a global epidemic is attributed to non-traditional risk factors, including exposure to environmental chemicals. However, the contribution of xenobiotic exposure during the development of an organism to the etiology of diabetes is not fully addressed. Developing stages are more susceptible to chemical insult, but knowledge on the consequence of the same to the onset of diabetes is residual. In this context, by using Drosophila melanogaster having conserved Insulin/Insulin growth factor-like signaling (IIS) as well as glucose homeostasis as a model, we evaluated the potential of developmental exposure to dichlorvos (DDVP, an organophosphorus pesticide) or atrazine (herbicide) to cause diabetes in exposed organisms. Flies exposed to DDVP during their development display insulin deficiency or type 1 diabetes (T1D) while those exposed to atrazine show insulin resistance or type 2 diabetes (T2D), suggesting that exposure to these xenobiotics during organismal development can result in diabetes and that different mechanisms underlie pesticide mediated diabetes. We show that oxidative stress-mediated c-Jun N-terminal kinase (JNK) signaling activation underlies insulin resistance in flies exposed to atrazine during their development while DDVP-mediated T1D involves activation of caspase-mediated cell death pathway. Mitigation of oxidative stress through over-expression of SOD2 in atrazine (20µg/ml) exposed flies, revealed significantly decreased oxidative stress levels and reduced phosphorylation of JNK. Moreover, glucose and Akt phosphorylation levels in SOD2 over-expression flies exposed to atrazine were comparable to those in controls, suggesting restoration in insulin sensitivity. Therefore, exposure to xenobiotics during development is a common risk factor for the development of type 1 or type 2 diabetes. Accordingly, the present study cautions against the use of such diabetogenic pesticides. Also, mitigation of oxidative stress or anti-oxidant supplementation could be a potential therapy for xenobiotic mediated type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/genética , Resistência à Insulina/genética , Estresse Oxidativo/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Atrazina/toxicidade , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Diclorvós/toxicidade , Modelos Animais de Doenças , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/genética , Expressão Gênica/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Humanos , Insulina/genética , Proteínas Quinases JNK Ativadas por Mitógeno , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/genética , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/genética , Xenobióticos/toxicidadeRESUMO
Metagenomics is a powerful approach to study microorganisms present in any given environment and their potential to maintain and improve ecosystem health without the need of cultivating these microorganisms in the laboratory. In this study, we combined a cultivation-independent metagenomics approach with functional assays to identify the detoxification potential of microbial genes evaluating their potential to contribute to xenobiotics resistance in oil-impacted mangrove sediments. A metagenomic fosmid library containing 12,960 clones from highly contaminated mangrove sediment was used in this study. For assessment of metal resistance, clones were grown in culture medium with increasing concentrations of mercury. The analyses metagenomic library sequences revealed the presence of genes related to heavy metals and antibiotics resistance in the oil-impacted mangrove microbiome. The taxonomic profiling of these sequences suggests that at the genus level, Geobacter was the most abundant genus in our dataset. A functional screening assessment of the metagenomic library successfully detected 24 potential heavy metal tolerant clones, six of which were capable of growing with increased concentrations of mercury. The genetic characterization of selected clones allowed the detection of genes related to detoxification processes, such as chromate transport protein ChrA, haloacid dehalogenase-like hydrolase, lipopolysaccharide transport system, and 3-oxoacyl-[acyl-carrier-protein] reductase. Clones were capable of growing in medium containing increased concentrations of metals and antibiotics, but none manifested strong mercury removal from culture medium characteristic of mercuric reductase activity. These results suggest that resistance to xenobiotic stress varies greatly and that additional studies to elucidate the potential of metal biotransformation need to be carried out with the goal of improving bioremediation application.
Assuntos
Sedimentos Geológicos , Metagenômica/métodos , Metais Pesados/análise , Microbiota/genética , Áreas Alagadas , Xenobióticos/análise , Biodegradação Ambiental , Resistência Microbiana a Medicamentos/genética , Biblioteca Gênica , Sedimentos Geológicos/química , Sedimentos Geológicos/microbiologia , Hidrolases/genética , Metais Pesados/toxicidade , Microbiota/efeitos dos fármacos , Petróleo/análise , Petróleo/toxicidade , Xenobióticos/toxicidadeRESUMO
A mathematical model has been developed to assist with the development of a hollow fibre bioreactor (HFB) for hepatotoxicity testing of xenobiotics; specifically, to inform the HFB operating set-up, interpret data from HFB outputs and aid in optimizing HFB design to mimic certain hepatic physiological conditions. Additionally, the mathematical model has been used to identify the key HFB and compound parameters that will affect xenobiotic clearance. The analysis of this model has produced novel results that allow the operating set-up to be calculated, and predictions of compound clearance to be generated. The mathematical model predicts the inlet oxygen concentration and volumetric flow rate that gives a physiological oxygen gradient in the HFB to mimic a liver sinusoid. It has also been used to predict the concentration gradients and clearance of a test drug and paradigm hepatotoxin, paracetamol (APAP). The effect of altering the HFB dimensions and fibre properties on APAP clearance under the condition of a physiological oxygen gradient is analysed. These theoretical predictions can be used to design the most appropriate experimental set up and data analysis to quantitatively compare the functionality of cell types that are cultured within the HFB to those in other systems.
Assuntos
Reatores Biológicos , Avaliação Pré-Clínica de Medicamentos/métodos , Fígado/efeitos dos fármacos , Modelos Biológicos , Xenobióticos/toxicidade , Acetaminofen/farmacocinética , Acetaminofen/toxicidade , Animais , Técnicas de Cultura de Células/métodos , Hepatócitos/efeitos dos fármacos , Humanos , Fígado/metabolismo , Modelos Teóricos , Consumo de Oxigênio/fisiologia , RatosRESUMO
Honey bee (Apis mellifera) health has been severely impacted by multiple environmental stressors including parasitic infection, pesticide exposure, and poor nutrition. The decline in bee health is therefore a complex multifactorial problem which requires a holistic investigative approach. Within the exposome paradigm, the combined exposure to the environment, drugs, food, and individuals' internal biochemistry affects health in positive and negative ways. In the context of the exposome, honey bee hive infection with parasites such as Nosema ceranae is also a form of environmental exposure. In this study, we hypothesized that exposure to xenobiotic pesticides and other environmental chemicals increases susceptibility to N. ceranae infection upon incidental exposure to the parasite. We further queried whether these exposures could be linked to changes in conserved metabolic biological pathways. From 30 hives sampled across 10 sites, a total of 2,352 chemical features were found via gas chromatography-time of flight mass spectrometry (GC-TOF) in extracts of honey bees collected from each hive. Of these, 20 pesticides were identified and annotated, and found to be significantly associated with N. ceranae infection. We further determined that infected hives were linked to a greater number of xenobiotic exposures, and the relative concentration of the exposures were not linked to the presence of a N. ceranae infection. In the exposome profiles of the bees, we also found chemicals inherent to known biological metabolic pathways of Apis mellifera and identified 9 dysregulated pathways. These findings have led us to posit that for hives exposed to similar chemicals, those that incur multiple, simultaneous xenobiotic stressors have a greater incidence of infection with N. ceranae. Mechanistically, our results suggests the overwhelming nature of these exposures negatively affects the biological functioning of the bee, and could explain how the decline in bee populations is associated with pesticide exposures.
Assuntos
Abelhas/metabolismo , Biomarcadores/metabolismo , Exposição Ambiental/efeitos adversos , Redes e Vias Metabólicas/efeitos dos fármacos , Nosema/efeitos dos fármacos , Xenobióticos/toxicidade , Animais , Abelhas/efeitos dos fármacos , Abelhas/microbiologia , Interações Hospedeiro-Patógeno , Metaboloma , Nosema/fisiologiaRESUMO
CYP20A1 is a member of the cytochrome P450 (CYP) superfamily, identified as an orphan P450 without any assigned biological function; hence, its continued status as an "orphan" gene. In order to address this shortcoming in our understanding of this superfamily, we sought to characterize the CYP20A1 gene in the copepods Tigriopus japonicus (Tj-CYP20A1) and Paracyclopina nana (Pn-CYP20A1) at their mRNA transcriptional level. We assessed the response of this gene's expression in various developmental stages and in response to treatment with bisphenol A (BPA), 2, 2', 4, 4'-tetrabromodiphenyl ether (BDE-47), and water accommodated fractions (WAFs) of crude oil. As shown in the vertebrate CYP20A1, both Tj-CYP20A1 and Pn-CYP20A1 contained characteristic conserved motifs and domain regions (I helix, K helix and heme-binding motifs) with unusual amino acid sequences apparent in their gene structure. Also molecular characterization of the putative responsive elements in the promoter regions was performed. We observed transcriptional up-regulation of these genes during post-embryonic developmental stages including sex-specific up-regulation in adults. In addition, concentration- and time-dependent mRNA transcripts in response to xenobiotics (BPA, BDE-47, and WAFs) were seen. This study focuses on the molecular elucidation of CYP20A1 genes and their interactions with xenobiotics in the copepods T. japonicus and P. nana that provides important insight into the biological importance of CYP20A1 in invertebrates.
Assuntos
Compostos Benzidrílicos/toxicidade , Copépodes/efeitos dos fármacos , Copépodes/genética , Sistema Enzimático do Citocromo P-450/genética , Éteres Difenil Halogenados/toxicidade , Fenóis/toxicidade , Poluentes Químicos da Água/toxicidade , Sequência de Aminoácidos , Animais , Sequência de Bases , Regulação da Expressão Gênica/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Petróleo/toxicidade , Regiões Promotoras Genéticas/efeitos dos fármacos , RNA Mensageiro/genética , Transcrição Gênica/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Xenobióticos/toxicidadeRESUMO
Organ toxicity, particularly liver toxicity, remains one of the major reasons for the termination of drug candidates in the development pipeline as well as withdrawal or restrictions of marketed drugs. A screening-amenable alternative in vivo model such as zebrafish would, therefore, find immediate application in the early prediction of unacceptable organ toxicity. To identify highly upregulated genes as biomarkers of toxic responses in the zebrafish model, a set of well-characterized reference drugs that cause drug-induced liver injury (DILI) in the clinic were applied to zebrafish larvae and adults. Transcriptome microarray analysis was performed on whole larvae or dissected adult livers. Integration of data sets from different drug treatments at different stages identified common upregulated detoxification pathways. Within these were candidate biomarkers which recurred in multiple treatments. We prioritized 4 highly upregulated genes encoding enzymes acting in distinct phases of the drug metabolism pathway. Through promoter isolation and fosmid recombineering, eGFP reporter transgenic zebrafish lines were generated and evaluated for their response to DILI drugs. Three of the 4 generated reporter lines showed a dose and time-dependent induction in endodermal organs to reference drugs and an expanded drug set. In conclusion, through integrated transcriptomics and transgenic approaches, we have developed parallel independent zebrafish in vivo screening platforms able to predict organ toxicities of preclinical drugs.
Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Drogas em Investigação/efeitos adversos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Genes Reporter/efeitos dos fármacos , Fígado/efeitos dos fármacos , Testes de Toxicidade/métodos , Xenobióticos/toxicidade , Animais , Animais Geneticamente Modificados , Biomarcadores/metabolismo , Relação Dose-Resposta a Droga , Drogas em Investigação/administração & dosagem , Endoderma/efeitos dos fármacos , Endoderma/crescimento & desenvolvimento , Endoderma/metabolismo , Feminino , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Perfilação da Expressão Gênica , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Larva/efeitos dos fármacos , Larva/genética , Larva/crescimento & desenvolvimento , Larva/metabolismo , Fígado/crescimento & desenvolvimento , Fígado/metabolismo , Masculino , Organogênese/efeitos dos fármacos , Proteínas Recombinantes/metabolismo , Teratogênicos/toxicidade , Xenobióticos/administração & dosagem , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento , Peixe-Zebra/metabolismoRESUMO
Drug-induced liver injury (DILI) is a major concern for drug developers, regulators and clinicians. It is triggered by drug and xenobiotic insults leading to liver impairment or damage, in the worst-case liver failure. In contrast to acute "intrinsic" hepatotoxicity, DILI typically manifests in a very small subset of the population under treatment with no clear dose relationship and inconsistent temporal patterns and is therefore termed an idiosyncratic event. Involved are multifactorial, compound-dependent mechanisms and host-specific factors, making the prediction in preclinical test systems very challenging. While preclinical safety studies in animals usually are able to capture direct, acute liver toxicities, they are less predictive for human DILI, where specific, human-derived in vitro models can potentially close the gap. On one hand, mechanistic approaches addressing key mechanisms involved in DILI in well-characterized and standardized in vitro test systems have been developed. On the other hand, co-cultures of different cell types, including patient- and/or stem cell-derived cells, in a three-dimensional setup allow for prolonged incubations and multiplexed readouts. Such complex setups might better reflect multifactorial human DILI. One major challenge is that for many compounds with human DILI the underlying mechanisms are not yet fully understood, complicating establishment and validation of predictive cellular tools. A tiered approach including rapid mechanism-based in vitro screens followed by confirmatory tests in more physiologically relevant models might allow minimizing DILI risk early on in vitro. Such complex, integrated approaches will gain from larger collaborations in multidisciplinary groups bringing existing knowledge and state-of-the-art technology together.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Avaliação Pré-Clínica de Medicamentos , Drogas em Investigação/efeitos adversos , Modelos Biológicos , Xenobióticos/toxicidade , Alternativas aos Testes com Animais/tendências , Animais , Linhagem Celular , Células Cultivadas , Técnicas de Cocultura , Biologia Computacional , Avaliação Pré-Clínica de Medicamentos/tendências , Drogas em Investigação/metabolismo , Sistemas Inteligentes , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Reconhecimento Automatizado de Padrão/tendências , Reprodutibilidade dos Testes , Pesquisa Translacional Biomédica/tendências , Xenobióticos/metabolismoRESUMO
One of the goals of the Critical Path Institute's Predictive Safety Testing Consortium (PSTC) is to promote best practices for evaluating novel markers of drug induced injury. This includes the use of sound statistical methods. For rat studies, these practices have centered around comparing the area under the receiver-operator characteristic curve for each novel injury biomarker to those for the standard markers. In addition, the PSTC has previously used the net reclassification index (NRI) and integrated discrimination index (IDI) to assess the increased certainty provided by each novel injury biomarker when added to the information already provided by the standard markers. Due to their relatively simple interpretations, NRI and IDI have generally been popular measures of predictive performance. However recent literature suggests that significance tests for NRI and IDI can have inflated false positive rates and thus, tests based on these metrics should not be relied upon. Instead, when parametric models are employed to assess the added predictive value of a new marker, following (Pepe, M. S., Kerr, K. F., Longton, G., and Wang, Z. (2013). Testing for improvement in prediction model performance. Stat. Med. 32, 1467-1482), the PSTC recommends that likelihood based methods be used for significance testing.
Assuntos
Biomarcadores/metabolismo , Avaliação Pré-Clínica de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Drogas em Investigação/efeitos adversos , Modelos Estatísticos , Testes de Toxicidade , Xenobióticos/toxicidade , Animais , Biomarcadores/sangue , Biomarcadores/urina , Avaliação Pré-Clínica de Medicamentos/tendências , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/sangue , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/metabolismo , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/urina , Drogas em Investigação/classificação , Reações Falso-Positivas , Humanos , Doenças Musculares/induzido quimicamente , Doenças Musculares/diagnóstico , Doenças Musculares/metabolismo , Organizações sem Fins Lucrativos , Valor Preditivo dos Testes , Curva ROC , Insuficiência Renal/induzido quimicamente , Insuficiência Renal/diagnóstico , Insuficiência Renal/metabolismo , Testes de Toxicidade/tendências , Estados Unidos , Xenobióticos/classificaçãoRESUMO
Daily rhythms in physiology significantly modulate drug pharmacokinetics and pharmacodynamics according to the time-of-day, a finding that has led to the concept of chronopharmacology. The importance of biological clocks for xenobiotic metabolism has gained increased attention with the discovery of the molecular circadian clockwork. Mechanistic understanding of the cell-autonomous molecular circadian oscillator and the circadian timing system as a whole has opened new conceptual and methodological lines of investigation to understand first, the clock's impact on a specific drug's daily variations or the effects/side effects of environmental substances, and second, how clock-controlled pathways are coordinated within a given tissue or organism. Today, there is an increased understanding of the circadian modulation of drug effects. Moreover, several molecular strategies are being developed to treat disease-dependent and drug-induced clock disruptions in humans.
Assuntos
Relógios Circadianos , Cronofarmacoterapia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/metabolismo , Xenobióticos/metabolismo , Xenobióticos/toxicidade , Animais , Relógios Biológicos , Cronofarmacocinética , Ritmo Circadiano , HumanosRESUMO
Pesticides are omnipresent in environment, water, fruits, and vegetables and are considered as risk factors for human health. Consumers are mainly exposed to pesticides through diet, and the main question to be answered concerns the impact of such exposure on health. In this study, we developed a mouse model to mimic consumer exposure. During gestation and lactation periods, the experimental mouse dams (M) received one of the following treatments: (a) diet-free of pesticides; (b) diet enriched with chlorpyrifos (CPF; 44.0 µg kg(-1)); c) diet + oral vitamin E (vit. E; α-tocopherol; 200 mg/kg/mouse); and (d) diet enriched with CPF (44.0 µg/kg + oral vit. E (200 mg/kg/mouse). At weaning, pups (P) and dams were killed, and organs as well as blood samples were collected. Compared with control results, CPF induced alteration of measured parameters (e.g. organ weight, alkaline phosphatase, urea, malondialdehyde, superoxide dismutase, and cholinesterase) either in mouse dams or in their offspring. Also, CPF induced histological impairment in kidney, liver, and ovary. Administration of vit. E in conjunction with CPF clearly alleviated deviation of these parameters than those of control ones. In conclusion, a dietary exposure of mice during gestation and lactation to low dose of CPF led to significant changes in the mother but also in the weaned animals that have not been directly exposed to this pesticide. These biological and histological modifications could be reversed by an oral supplementation of vit. E.
Assuntos
Clorpirifos/toxicidade , Inibidores da Colinesterase/toxicidade , Inseticidas/toxicidade , Exposição Materna , alfa-Tocoferol/farmacologia , Fosfatase Alcalina/sangue , Animais , Colinesterases/sangue , Dieta , Relação Dose-Resposta a Droga , Feminino , Rim/efeitos dos fármacos , Rim/metabolismo , Lactação , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Malondialdeído/sangue , Camundongos , Camundongos Endogâmicos C57BL , Nível de Efeito Adverso não Observado , Tamanho do Órgão/efeitos dos fármacos , Ovário/efeitos dos fármacos , Ovário/metabolismo , Superóxido Dismutase/sangue , Ureia/sangue , Desmame , Xenobióticos/toxicidadeRESUMO
When reactive centers are formed in chemical conversions, intermolecular reactions tend to dominate over intramolecular alternatives whenever both alternatives are possible. Hence, when reactive metabolites are formed from xenobiotics, intramolecular quenching by moieties adjacent to a toxicophore may play an important role in reducing toxicity related to reactive intermediates. The phenomenon is likely to be particularly noticeable for toxicophores that are readily associated with a type of toxicity that is rarely caused by other structural motives. In two demonstrative investigations, it is concluded that nitrobenzenes for which the expected nitrosyl metabolite is likely to react with adjacent groups are less toxic than what is rationally expected, and that among aryl amine drugs allowing for the immediate quenching of the corresponding N-aryl hydroxylamine metabolite, the typical erythrocyte toxicity often seen with aryl amines is absent. The deliberate introduction of effective quenching groups nearby a toxicophoric moiety may present a potential strategy for reducing toxicity in the design of drugs and other man-made xenobiotics.
Assuntos
Desenho de Fármacos , Xenobióticos/toxicidade , Animais , Avaliação Pré-Clínica de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Eritrócitos/efeitos dos fármacos , Furosemida/química , Furosemida/toxicidade , Humanos , Nitrobenzenos/química , Nitrobenzenos/toxicidade , Tetrahymena pyriformis/efeitos dos fármacos , Tetrahymena pyriformis/metabolismo , Testes de Toxicidade , Xenobióticos/químicaRESUMO
The kidney is a major target for xenobiotics, which include drugs, industrial chemicals, environmental toxicants and other compounds. Accurate methods for screening large numbers of potentially nephrotoxic xenobiotics with diverse chemical structures are currently not available. Here, we describe an approach for nephrotoxicity prediction that combines high-throughput imaging of cultured human renal proximal tubular cells (PTCs), quantitative phenotypic profiling, and machine learning methods. We automatically quantified 129 image-based phenotypic features, and identified chromatin and cytoskeletal features that can predict the human in vivo PTC toxicity of 44 reference compounds with ~82 % (primary PTCs) or 89 % (immortalized PTCs) test balanced accuracies. Surprisingly, our results also revealed that a DNA damage response is commonly induced by different PTC toxicants that have diverse chemical structures and injury mechanisms. Together, our results show that human nephrotoxicity can be predicted with high efficiency and accuracy by combining cell-based and computational methods that are suitable for automation.