Toxicometabolomics: Small Molecules to Answer Big Toxicological Questions

Araújo, Ana Margarida; Carvalho, Félix; Pinho, Paula Guedes de; Carvalho, Márcia

doi:10.3390/metabo11100692

Cited by 32 publications

(24 citation statements)

References 157 publications

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“…The cross-validation results were R 2 = 0.98, Q 2 = 0.92, which shows an adequate fit of the data to the model, and therefore it is considered a highly accurate model. Usual values for biological experiments are Q 2 > 0.4 and R 2 > 0.7 [ 26 , 27 ].…”

Section: Resultsmentioning

confidence: 99%

An Exploratory Study of the Metabolite Profiling from Pesticides Exposed Workers

et al. 2023

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Pesticides constitute a category of chemical products intended specifically for the control and mitigation of pests. With their constant increase in use, the risk to human health and the environment has increased proportionally due to occupational and environmental exposure to these compounds. The use of these chemicals is associated with several toxic effects related to acute and chronic toxicity, such as infertility, hormonal disorders and cancer. The present work aimed to study the metabolic profile of individuals occupationally exposed to pesticides, using a metabolomics tool to identify potential new biomarkers. Metabolomics analysis was carried out on plasma and urine samples from individuals exposed and non-exposed occupationally, using liquid chromatography coupled with mass spectrometry (UPLC-MS). Non-targeted metabolomics analysis, using principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA) or partial least squares discriminant orthogonal analysis (OPLS-DA), demonstrated good separation of the samples and identified 21 discriminating metabolites in plasma and 17 in urine. The analysis of the ROC curve indicated the compounds with the greatest potential for biomarkers. Comprehensive analysis of the metabolic pathways influenced by exposure to pesticides revealed alterations, mainly in lipid and amino acid metabolism. This study indicates that the use of metabolomics provides important information about complex biological responses.

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Section: Resultsmentioning

confidence: 99%

An Exploratory Study of the Metabolite Profiling from Pesticides Exposed Workers

et al. 2023

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“…Metabolomics based on liquid chromatography coupled to mass spectrometry can be successfully used to profile toxic response in vitro and in vivo [ 56 , 57 ]. We have analyzed the cell extracts of HepG2 and diHLC-T incubated with reference hepatotoxicants to obtain a predictive model of toxicity caused by these drugs in both cell models.…”

Section: Discussionmentioning

confidence: 99%

A robust reprogramming strategy for generating hepatocyte-like cells usable in pharmaco-toxicological studies

et al. 2023

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Background High-throughput pharmaco-toxicological testing frequently relies on the use of established liver-derived cell lines, such as HepG2 cells. However, these cells often display limited hepatic phenotype and features of neoplastic transformation that may bias the interpretation of the results. Alternate models based on primary cultures or differentiated pluripotent stem cells are costly to handle and difficult to implement in high-throughput screening platforms. Thus, cells without malignant traits, optimal differentiation pattern, producible in large and homogeneous amounts and with patient-specific phenotypes would be desirable. Methods We have designed and implemented a novel and robust approach to obtain hepatocytes from individuals by direct reprogramming, which is based on a combination of a single doxycycline-inducible polycistronic vector system expressing HNF4A, HNF1A and FOXA3, introduced in human fibroblasts previously transduced with human telomerase reverse transcriptase (hTERT). These cells can be maintained in fibroblast culture media, under standard cell culture conditions. Results Clonal hTERT-transduced human fibroblast cell lines can be expanded at least to 110 population doublings without signs of transformation or senescence. They can be easily differentiated at any cell passage number to hepatocyte-like cells with the simple addition of doxycycline to culture media. Acquisition of a hepatocyte phenotype is achieved in just 10 days and requires a simple and non-expensive cell culture media and standard 2D culture conditions. Hepatocytes reprogrammed from low and high passage hTERT-transduced fibroblasts display very similar transcriptomic profiles, biotransformation activities and show analogous pattern behavior in toxicometabolomic studies. Results indicate that this cell model outperforms HepG2 in toxicological screening. The procedure also allows generation of hepatocyte-like cells from patients with given pathological phenotypes. In fact, we succeeded in generating hepatocyte-like cells from a patient with alpha-1 antitrypsin deficiency, which recapitulated accumulation of intracellular alpha-1 antitrypsin polymers and deregulation of unfolded protein response and inflammatory networks. Conclusion Our strategy allows the generation of an unlimited source of clonal, homogeneous, non-transformed induced hepatocyte-like cells, capable of performing typical hepatic functions and suitable for pharmaco-toxicological high-throughput testing. Moreover, as far as hepatocyte-like cells derived from fibroblasts isolated from patients suffering hepatic dysfunctions, retain the disease traits, as demonstrated for alpha-1-antitrypsin deficiency, this strategy can be applied to the study of other cases of anomalous hepatocyte functionality.

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“…Metabolomics using liquid chromatography hyphenated to high-resolution mass spectrometry (LC-HRMS) have been suggested as an emerging approach to clarify the mechanisms of toxicity and identify prognostic biomarkers [ 21 , 22 , 23 , 24 , 25 ]. This strategy relies on targeted analyses quantifying well-known molecules [ 21 , 22 ] and additionally involves challenging untargeted analyses to detect and quantify hundreds of other metabolites [ 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

Life-Threatening Cardiogenic Shock Related to Venlafaxine Poisoning—A Case Report with Metabolomic Approach

et al. 2023

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Metabolomics in clinical toxicology aim at reliably identifying and semi-quantifying a broad array of endogenous and exogenous metabolites using dedicated analytical methods. Here, we developed a three-step-based workflow to investigate the metabolic impact of the antidepressant drug venlafaxine in a poisoned patient who developed life-threatening cardiac failure managed with extracorporeal membrane oxygenation. Both targeted quantitative and untargeted semi-quantitative metabolomic analyses using liquid chromatography hyphenated to high-resolution tandem mass spectrometry were performed to determine the plasma kinetics of venlafaxine, O-desmethyl-venlafaxine, and N-desmethyl-venlafaxine and to identify sixteen different venlafaxine-derived metabolites including one unknown (i.e., venlafaxine conjugated to a hexosyl-radical), respectively. Correlations between the quantitative metabolomic data and annotated endogenous metabolites suggested impaired amino acid and lipid metabolism, Krebs cycle, and kynurenine pathway. This preliminary study represents a first step towards a more extensive application of toxicometabolomics in clinical toxicology and a useful workflow to identify the biomarkers of toxicity.

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Toxicometabolomics: Small Molecules to Answer Big Toxicological Questions

Cited by 32 publications

References 157 publications

An Exploratory Study of the Metabolite Profiling from Pesticides Exposed Workers

An Exploratory Study of the Metabolite Profiling from Pesticides Exposed Workers

A robust reprogramming strategy for generating hepatocyte-like cells usable in pharmaco-toxicological studies

Life-Threatening Cardiogenic Shock Related to Venlafaxine Poisoning—A Case Report with Metabolomic Approach

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