Suchergebnisse

In toxicogenomics, functional annotation is an important step to gain additional insights into genes with aberrant expression that drive pathophysiological mechanisms. Nevertheless, there exists a gap on annotation of these genes which often hampers the interpretation of results and limits their applicability in translational medicine. In this study, we evaluated the coverage of functional annotations of differentially expressed genes (DEGs) induced by 10 selected compounds from the TG-GATEs database identified as high- or no-risk in causing drug-induced liver injury (most-DILI or no-DILI, respectively) using in vitro human data. Functional roles of DEGs not present in the most common biological annotation databases - termed "dark genes" - were unveiled via literature mining and via the identification of shared regulatory transcription factors or signaling pathways. Our results demonstrated that there were approximately 13% of dark genes induced by these compounds in vitro and we were able to obtain additional relevant information for up to 76% of those. Using interactome data from several sources, we have uncovered genes such as LRBA, and WDR26 as highly connected in the protein network that play roles in drug response. Genes such as MALAT1, H19, and MIR29C - whose links to hepatotoxicity have been confirmed - were identified as markers for the most-DILI group and appeared as top hits across all literature-based mining methods. Furthermore, we investigated the potential impact of dark genes on liver toxicity by identifying their rat orthologs in combination with their correlation to drug-induced liver pathologies observed in vivo following chemical exposure. We identified a set of important regulatory transcription factors of dark genes for all most-DILI compounds including E2F1 and JUND with supporting evidences in literature and we found Magee1 correlated with chemically induced bile duct hyperplasia and adverse responses at 29 days in rats in vivo. In conclusion, in this study we show the potential role of these poorly annotated genes in mechanisms underlying hepatotoxicity and offer a number of computational approaches that may help to minimize current gaps in gene annotation and highlight their values as potential biomarkers in toxicological studies. ; This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no. 116030 (TransQST). This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA.

Traffic-related air pollution (TRAP) is a complex mixture of compounds that contributes to the pathogenesis of many diseases including several types of cancer, pulmonary, cardiovascular and neurodegenerative diseases, and more recently also diabetes mellitus. In search of an early diagnostic biomarker for improved environmental health risk assessment, recent human studies have shown that certain extracellular miRNAs are altered upon exposure to TRAP. Here, we present a global circulating miRNA analysis in a human population exposed to different levels of TRAP. The cross-over study, with sampling taking place during resting and physical activity in two different exposure scenarios, included for each subject personal exposure measurements of PM10,PM2.5, NO, NO2, CO, CO2, BC and UFP. Next-generation sequencing technology was used to identify global circulating miRNA levels across all subjects. We identified 8 miRNAs to be associated with the mixture of TRAP and 27 miRNAs that were associated with the individual pollutants NO, NO2, CO, CO2, BC and UFP. We did not find significant associations between miRNA levels and PM10 or PM2.5. Integrated network analysis revealed that these circulating miRNAs are potentially involved in processes that are implicated in the development of air pollution-induced diseases. Altogether, this study demonstrates that signatures consisting of circulating miRNAs present a potential novel biomarker to be used in health risk assessment. ; This work has been supported by the European Union within the frame of the Exposomics (226756) project.

EXPOsOMICS is a European Union funded project that aims to develop a novel approach to the assessment of exposure to high priority environmental pollutants, by characterizing the external and the internal components of the exposome. It focuses on air and water contaminants during critical periods of life. To this end, the project centres on 1) exposure assessment at the personal and population levels within existing European short and long-term population studies, exploiting available tools and methods which have been developed for personal exposure monitoring (PEM); and 2) multiple "omic" technologies for the analysis of biological samples (internal markers of external exposures). The search for the relationships between external exposures and global profiles of molecular features in the same individuals constitutes a novel advancement towards the development of "next generation exposure assessment" for environmental chemicals and their mixtures. The linkage with disease risks opens the way to what are defined here as 'exposome-wide association studies' (EWAS).

Background: Acrylamide is a common dietary exposure that crosses the human placenta. It is classified as a probable human carcinogen, and developmental toxicity has been observed in rodents. Objectives: We examined the associations between prenatal exposure to acrylamide and birth outcomes in a prospective European mother–child study. Methods: Hemoglobin (Hb) adducts of acrylamide and its metabolite glycidamide were measured in cord blood (reflecting cumulated exposure in the last months of pregnancy) from 1,101 singleton pregnant women recruited in Denmark, England, Greece, Norway, and Spain during 2006–2010. Maternal diet was estimated through food-frequency questionnaires. Results: Both acrylamide and glycidamide Hb adducts were associated with a statistically significant reduction in birth weight and head circumference. The estimated difference in birth weight for infants in the highest versus lowest quartile of acrylamide Hb adduct levels after adjusting for gestational age and country was –132 g (95% CI: –207, –56); the corresponding difference for head circumference was –0.33 cm (95% CI: –0.61, –0.06). Findings were similar in infants of nonsmokers, were consistent across countries, and remained after adjustment for factors associated with reduced birth weight. Maternal consumption of foods rich in acrylamide, such as fried potatoes, was associated with cord blood acrylamide adduct levels and with reduced birth weight. Conclusions: Dietary exposure to acrylamide was associated with reduced birth weight and head circumference. Consumption of specific foods during pregnancy was associated with higher acrylamide exposure in utero. If confirmed, these findings suggest that dietary intake of acrylamide should be reduced among pregnant women. ; The NewGeneris (Newborns and Genotoxic exposure risks) study was funded by the European Union (EU Contract FOOD-CT-2005-016320). The study was also supported by grants obtained locally, including the Swedish Cancer and Allergy Foundation and the Swedish Research Council Formas, the National Institute for Health Research, UK (programme grant RP-PG-0407-10044), the Norwegian Ministry of Health, the Norwegian Ministry of Education and Research, the Norwegian Research Council/FUGE (grant 151918/S10), the EU funded HiWATE (contract Food-CT-2006-036224), the U.S. National Institutes of Health (NIH)/National Institute of Environmental Health Sciences (contract NO-ES-75558), and the U.S. NIH/National Institute of Neurological Disorders and Stroke (grant 1 UO1 NS 047537-01). M.P. holds a Juan de la Cierva postdoctoral fellowship awarded from the Spanish Ministry of Science and Innovation (JCI-2011-09479)