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PubMedDate not supplied

Toxicoproteomics: proteomics applied to toxicology and pathology.

Global measurement of proteins and their many attributes in tissues and biofluids defines the field of proteomics. Toxicoproteomics, as part of the larger field of toxicogenomics. seeks to identify critical proteins and pathways in biological systems that are affected by and respond to adverse chemical and environmental exposures using global protein expression technologies. Toxicoproteomics integrates 3 disciplinary areas: traditional toxicology and pathology, differential protein and gene expression analysis, and systems biology. Key topics to be reviewed are the evolution of proteomics, proteomic technology platforms and their capabilities with exemplary studies from biology and medicine, a review of over 50 recent studies applying proteomic analysis to toxicological research, and the recent development of databases designed to integrate -Omics technologies with toxicology and pathology. Proteomics is examined for its potential in discovery of new biomarkers and toxicity signatures, in mapping serum,plasma. and other biofluid proteomes, and in parallel proteomic and transcriptomic studies. The new field of toxicoproteomics is uniquely positioned toward an expanded understanding of protein expression during toxicity and environmental disease for the advancement of public health.

Animals↗
PubMed2006

Toxicoproteomics in liver injury and inflammation.

Toxicoproteomics, in applying proteomics to toxicology, seeks to identify critical proteins and pathways in biological systems responding to adverse chemical exposures and environmental stressors using global protein expression technologies. Toxicoproteomics is being exploited for the discovery of new biomarkers and toxicity signatures in target organs, such as liver, in major biological processes, such as inflammation, in mapping serum, plasma, and other biofluid proteomes, and in parallel proteomic and transcriptomic studies. The new field of toxicoproteomics is uniquely positioned toward discovery of new biomarkers and signatures of tissue injury and a better understanding of protein expression responses during toxicity and environmental disease.

Chemical and Drug Induced Liver Injury↗
PubMed2026

Toxicoproteomic analysis reveals arsenic-induced alterations in eye lens proteins of Labeo rohita.

Arsenic occurs extensively in the environment and is classified as a potent carcinogenic substance in humans. Prolonged intake of water contaminated with arsenic results in the development of arsenicosis. In the present study, a toxicoproteomic approach was employed to elucidate arsenic-induced alterations in lens proteins using a fish model. Juveniles of Labeo rohita were exposed to sodium meta-arsenite (NaAsO2) at concentrations of 5, 10, 15, and 20&#xa0;ppm for a period of 10&#xa0;days in triplicate experimental groups. Soluble lens proteins were analyzed using one- and two-dimensional gel electrophoresis, immunoblotting of &#x3b1;A-crystallin and MALDI-TOF mass spectrometry. Cataract development was observed at arsenic concentrations&#x2009;&#x2265;&#x2009;15&#xa0;ppm. Proteomic analyses revealed concentration-dependent alterations in lens protein abundance, including significant reductions in &#x3b2;B1, &#x3b2;B2, and &#x3b2;A2b-crystallin, small heat shock protein and skeletal &#x3b1;-actin (p&#x2009;<&#x2009;0.05). In addition, &#x3b1;A, &#x3b2;A2, and &#x3b2;A2a-crystallin exhibited reduced abundance trends, although these changes were not statistically significant. Two-dimensional immunoblotting revealed 15 distinct &#x3b1;A-crystallin isoforms in control lenses, several of which showed a progressive decrease with increasing arsenic exposure, culminating in complete degradation at 20&#xa0;ppm. These findings demonstrate that arsenic exposure is associated with substantial alterations in lens crystallins and other proteins involved in structural organization and protein homeostasis, coinciding with cataract development at higher exposure concentrations. The identified proteins may serve as potential toxicoproteomic biomarkers of lens damage in aquatic organisms and provide a foundation for future studies investigating the molecular mechanisms of arsenic-induced lens toxicity.

Animals↗
PubMed2026

Comparative toxicoproteomics reveals distinct proteostasis and ribosomal stress signatures of CMIT and PHMG.

Methylchloroisothiazolinone (CMIT) and polyhexamethylene guanidine (PHMG) are antimicrobial biocides associated with pulmonary toxicity, although their comparative cellular stress mechanisms remain unclear. Here, we investigated how CMIT and PHMG differentially alter the proteome of human alveolar epithelial A549 cells under subcytotoxic conditions. Cells were exposed to CMIT or PHMG, and global proteomic profiling was performed using label-free liquid chromatography-tandem mass spectrometry. Differentially expressed proteins (DEPs) were identified at a 1% false discovery rate with an absolute log2 fold change &#x2265;1. Functional analyses were conducted using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Ingenuity Pathway Analysis, and selected proteins were validated by western blotting. Comparative toxicoproteomics revealed distinct stress-response signatures induced by the two biocides. CMIT preferentially altered proteins associated with proteostasis, oxidative stress, and protein quality control, whereas PHMG was characterized by coordinated depletion of ribosome-associated and translation-related proteins. A total of 73 and 155 DEPs were identified in CMIT- and PHMG-treated cells, respectively, with 22 proteins shared between treatments. Western blotting confirmed PSMD3, TUBB2A, and GLRX1 as CMIT-responsive proteins and THRAP3, DHX15, and RPL4 as PHMG-responsive markers. These findings provide comparative mechanistic insight into how CMIT and PHMG induce distinct epithelial stress responses and identify candidate protein markers that may support future in vitro assessment of biocide-induced pulmonary toxicity.

CMIT↗
PubMed2006

Toxicoproteomic investigation of the molecular mechanisms of cycloheximide-induced hepatocellular apoptosis in rat liver.

C/EBP homologous protein (CHOP) is a transcriptional factor and is induced under conditions such as the unfolded protein response or amino acid starvation. A previous study showed that the transcriptional level of CHOP was highly increased in rat liver in which hepatocellular apoptosis was induced by cycloheximide (CHX) treatment. Here, we investigated the relationship between hepatocellular apoptosis and CHOP-mediated apoptotic pathway, and studied the mechanisms of induction of CHOP gene in the liver of rats treated with CHX. Male F344 rats were treated intravenously with 6mg/kg CHX, and sacrificed at 1, 2 and 6h after the treatment. In the gene expression assay using quantitative RT-PCR, the genes related to CHOP-mediated apoptosis such as the C/EBPbeta, ATF3 and ATF4 genes were significantly increased corresponding to the induction of hepatocellular apoptosis in rats treated with CHX. However the GRP78/Bip gene, which serves as a representative marker for the unfolded protein response, did not change after the treatment. Toxicoproteomics using two-dimensional difference gel electrophoresis and mass spectrometry indicated that GRP78/Bip was inactivated by the CHX treatment. Furthermore, the CHX-treated animals exhibited a significant decrease of phosphorylated Akt/PKB (protein kinase B). These results indicate that the protein synthesis inhibition by CHX induces the CHOP gene through a pathway similar to that of amino acid starvation, and that Akt/PKB inactivation enhances the CHOP-mediated hepatocellular apoptosis.

Animals↗
PubMed2002

Toxicoproteomics -- a new preclinical tool.

The publication of the human genome has presented the scientific community with an unprecedented amount of genetic information with the potential to revolutionize the drug discovery process. This information could be used to identify novel drug targets and disease markers or could aid in the development of personalized medicines. The realization that genetic changes must ultimately influence protein function has pushed the field of proteomics further into the limelight. In this review the applications of proteomics to the field of toxicology will be discussed. It is anticipated that, in the future, toxicologists will apply a range of genomic and proteomic techniques to address issues in toxicity.

Animals↗
PubMedDate not supplied

Toxicoproteomics: serum proteomic pattern diagnostics for early detection of drug induced cardiac toxicities and cardioprotection.

Proteomics is more than just generating lists of proteins that increase or decrease in expression as a cause or consequence of pathology. The goal should be to characterize the information flow through the intercellular protein circuitry which communicates with the extracellular microenvironment and then ultimately to the serum/plasma macroenvironment. The nature of this information can be a cause, or a consequence, of disease and toxicity based processes as cascades of reinforcing information percolate through the system and become reflected in changing proteomic information content of the circulation. Serum Proteomic Pattern Diagnostics is a new type of proteomic platform in which patterns of proteomic signatures from high dimensional mass spectrometry data are used as a diagnostic classifier. While this approach has shown tremendous promise in early detection of cancers, detection of drug-induced toxicity may also be possible with this same technology. Analysis of serum from rat models of anthracycline and anthracenedione induced cardiotoxicity indicate the potential clinical utility of diagnostic proteomic patterns where low molecular weight peptides and protein fragments may have higher accuracy than traditional biomarkers of cardiotoxicity such as troponins. These fragments may one day be harvested by circulating nanoparticles designed to absorb, enrich and amplify the diagnostic biomarker repertoire generated even at the critical initial stages of toxicity.

Animals↗
PubMed2004

[Toxicoproteomics: first experiences in a BMBF-study].

The rapid development of molecular toxicology is providing innovative approaches to an improved investigation and recognition of toxic substances. Proteome analysis offers, with 2DE/MS (two-dimensional gel electrophoresis and mass spectrometry) and SELDI (surface enhanced laser desorption/ionisation), a promising discipline to classify molecular changes caused by toxic exposure. The Rat Liver Foci Bioassay (RLFB) is a detailed, well-described model for the investigation of liver carcinogenesis induced by chemical substances. Based on this model, we examined whether proteomic methods of molecular toxicology can be used for the early recognition of toxic and/or carcinogenic characteristics of toxic substances. In addition, identification and subsequent prevalidation of new hepatocellular biomarkers was performed, enabling better prediction of toxic and/or carcinogenic effects. This could lead to a more meaningful RLFB and thus to an improved risk assessment of chemicals. 2DE analysis in this study showed that deregulated proteins are assigned to mainly anabolic and catabolic metabolism pathways in the cell. Beyond this, individual proteins were identified which play a key role in the carcinogenic process. A comparison of the differentially expressed proteins in tissue from tumour-bearing animals and tissue derived from the start of the study revealed that protein expression changes (biomarkers) were already detectable shortly after exposure. In addition, analysis by SELDI clearly showed several differentially expressed proteins and/or derived masses. The spectra represented specific differences in tissues, which could be assigned to the same histopathological endpoints. With bioinformatics analysis it was possible to identify individual discriminating mass peaks, which were indicative of tumour formation. Group specific changes can be illustrated and/or represented in more detail with further cluster analysis methods. These results give hope for an improved prediction of hepatotoxicity and carcinogenicity by means of protein markers, which could in the future lead to a shortening of carcinogenicity studies and to a reduction in the use of experimental animals.

Animals↗
PubMed2002

Proteomic evaluation of cell preparation methods in primary hepatocyte cell culture.

In vitro liver preparations are being used increasingly to study various aspects of chemical hepatotoxicity and thus have become powerful alternatives to in vivo toxicologic models. Primary hepatocyte culture systems are especially useful in screening cytotoxic and genotoxic compounds and assessing biochemical lesions associated with chemical exposure. We have begun to use this approach in combination with proteomic analysis to construct a molecular "toxicoproteomic" test system for a broad range of relevant and potentially toxic chemicals. Using a highly parallel two-dimensional electrophoretic (2-DE) protein separation system to analyze cells from culture systems, we previously observed significant variations in protein expression that were unrelated to chemical exposure. We hypothesized these artifactual protein alterations were the result of the variations in the culture conditions or cell manipulations, or both. Therefore, we conducted a study to assess the expression of hepatocyte proteins cultured on 6-well plates and recovered for analysis either by scraping/pelleting or direct in-well solubilization. Following incubation of 1.2 x 10(6) hepatocytes in six-well plate, recovery and solubilization of the cells and 2-DE of the solubilized lysates of 100 000 cells, we detected 1388 proteins in the in-well solubilized samples compared to 899 proteins in the washed/scraped/pelleted cell samples, a loss of 35%. Based on protein identification by peptide mass fingerprinting, the subcellular location of nearly all of the proteins whose abundance decreased were cytosolic and those few that increased were either microsomal, mitochondrial, or cytoskeletal proteins. These results emphasize the variation introduced by cell-handling during recovery of hepatocytes from culture plates and may explain at least some of the artifactual differences observed in earlier in vitro experiments.

Animals↗
PubMed2026

Proteomics in environmental pollution research: Advances, challenges, and future directions.

Environmental proteomics has emerged as a powerful approach for elucidating the molecular mechanisms underlying pollutant-induced biological effects. Although this field has developed rapidly, the systematic review of recent proteomics applications in environmental pollution research remains limited. This review explored the emerging roles of toxicoproteomics in biomarker discovery and mechanistic elucidation, as well as ecotoxicoproteomics in ecological risk assessment and bioremediation strategies. Here, we review the field, highlighting recent trends such as the integration of proteomics with genomics, transcriptomics, and metabolomics to provide a comprehensive view of biological responses to environmental stressors. We further discuss the growing application of artificial intelligence in improving proteomics data interpretation and accelerating biomarker discovery. In addition, recent technological advances in environmental proteomics are highlighted, including next-generation tissue microarray proteomics, nanoscale proteomics, single-cell proteomics, and spatial proteomics. Despite its potential, proteomics faces challenges, such as high operational costs, computational complexity in analysis, and technical limitations in low-abundance protein detection. We propose that the convergence of proteomics with artificial intelligence and multi-omics approaches offers promising solutions to these challenges, enhancing the practical application of proteomics in environmental monitoring and risk assessment.

Proteomics↗
PubMed2002

An EU perspective on the use of in vitro methods in regulatory pharmaceutical toxicology.

Some in vitro methods such as those used in the assessment of genotoxicity, receptor-binding and QT-prolongation are well established in regulatory pharmaceutical toxicology. In vitro systems to study metabolic profiles, P450 isoforms, drug interactions, etc. or to provide metabolic activation in genotoxicity assays are extremely useful, but are subject to a number of important limitations. In vitro models are also employed on an ad-hoc basis for other purposes, for example, to help investigate mechanisms underlying in vivo findings. At the current stage of technical development of alternative methods, rapid replacement of the pivotal animal studies used in drug safety assessment seems unlikely. The existing in vivo models have good predictive ability regarding toxic effects in humans, are underpinned by an extensive literature and form the basis of most regulatory toxicology guidelines. Integrated in vitro testing strategies, meant to replace conventional repeated-dose studies, are still relatively undeveloped. Emerging technologies such as transgenics, toxicogenomics and toxicoproteomics, although they rely on the continued use of animals, have considerable potential in terms of reduction and refinement of in vivo methods.

Animals↗
PubMed2005

Identification of oxidative stress-related proteins for predictive screening of hepatotoxicity using a proteomic approach.

We investigated the effects of three hepatotoxicants, acetaminophen (APAP), amiodarone (AD) and tetracycline (TC), on protein expression in primary cultured rat hepatocytes with toxicoproteomic approach, which is two-dimensional gel electrophoresis (2DE) and mass spectrometry. The objectives of this study were to search for alternative toxicity biomarkers which could be detected with high sensitivity prior to the appearance of morphological changes or alterations of analytical conventional biomarkers. The related proteins in the process of cell degeneration/necrosis such as cell death, lipid metabolism and lipid/carbohydrate metabolism were mainly affected under exposure to APAP, AD and TC, respectively. Among the differentially expressed proteins, several oxidative stress-related proteins were clearly identified after 24-hr exposure, even though they were not affected for 6-hr exposure. They were glutathione peroxidase (GPX) as a down-regulated protein as well as peroxiredoxin 1 (PRX1) and peroxiredoxin 2 (PRX2) as up-regulated proteins, which are known to serve as antioxidative enzymes in cells. These findings suggested that the focused proteins, GPX and PRXs, could be utilized as biomarkers of hepatotoxicity, and they were useful for setting high throughput screening methods to assess hepatotoxicity in the early stage of drug discovery.

Acetaminophen↗
PubMed2004

[Toxicogenomics. New perspectives for the molecular toxicology].

Gene expression in the cellular genome is subject to changes caused by internal and external factors. Due to different expression of gene sets (polymorphism), cells show different morphological and functional characteristics. Environmental and occupational toxic agents may influence cells at the level of transcription and translation. The functional toxicogenomics attempts to explain those influences. Due to recent developments in molecular biology and bioinformatics, it has become possible to analyze protein transcript (toxicogenomics) and profile (toxicoproteomics). This work reports new opportunities to study gene sequencing and expression by means of the DNA chip technique (rapid analysis of the genetic polymorphism) and the microarrays technique (simultaneous analysis of hundreds or thousands of genes). The authors report examples of some practical applications of toxicogenomics in the assessment of the effects of pathological exposures to environmental and occupational toxic (carcinogenic, hepatotoxic and/or neurotoxic) agents, due to the development of new groups of biomarkers, such as biomarkers of individual susceptibility, biomarkers of toxic effects combined with the assay of the relationship between a toxic agent and its dose, and the effect measured at the level of the cellular genome and results of histopathological and biochemical tests.

Carcinogens, Environmental↗