Browsing by Subject "TOXICOLOGY"

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  • Kohonen, Pekka; Parkkinen, Juuso A.; Willighagen, Egon L.; Ceder, Rebecca; Wennerberg, Krister; Kaski, Samuel; Grafstrom, Roland C. (2017)
    Predicting unanticipated harmful effects of chemicals and drug molecules is a difficult and costly task. Here we utilize a 'big data compacting and data fusion'-concept to capture diverse adverse outcomes on cellular and organismal levels. The approach generates from transcriptomics data set a 'predictive toxicogenomics space' (PTGS) tool composed of 1,331 genes distributed over 14 overlapping cytotoxicity-related gene space components. Involving similar to 2.5 x 10(8) data points and 1,300 compounds to construct and validate the PTGS, the tool serves to: explain dose-dependent cytotoxicity effects, provide a virtual cytotoxicity probability estimate intrinsic to omics data, predict chemically-induced pathological states in liver resulting from repeated dosing of rats, and furthermore, predict human drug-induced liver injury (DILI) from hepatocyte experiments. Analysing 68 DILI-annotated drugs, the PTGS tool outperforms and complements existing tests, leading to a hereto-unseen level of DILI prediction accuracy.
  • Iesce, Maria Rosaria; Lavorgna, Margherita; Russo, Chiara; Piscitelli, Concetta; Passananti, Monica; Temussi, Fabio; DellaGreca, Marina; Cermola, Flavio; Isidori, Marina (2019)
    Loratadine and desloratadine are second-generation antihistaminic drugs. Because of human administration, they are continuously released via excreta into wastewater treatment plants and occur in surface waters as residues and transformation products (TPs). Loratadine and desloratadine residues have been found at very low concentrations (ng/L) in the aquatic environment but their toxic effects are still not well known. Both drugs are light-sensitive even under environmentally simulated conditions and some of the photoproducts have been isolated and characterized. The aim of the present study was to investigate the acute and chronic ecotoxicity of loratadine, desloratadine and their light-induced transformation products in organisms of the aquatic trophic chain. Bioassays were performed in the alga Pseudokirchneriella subcapitata, the rotifer Brachionus calyciflorus and in two crustaceans, Thamnocephalus platyurus and Ceriodaphnia dubia. Loratadine exerted its acute and chronic toxicity especially on Ceriodaphnia dubia (LC50: 600 mu g/L, EC50: 28.14 mu g/L) while desloratadine showed similar acute toxicity among the organisms tested and it was the most chronically effective compound in Ceriodaphnia dubia and Pseudokirchneriella subcapitata. Generally, transformation products were less active in both acute and chronic assays.
  • Legehar, Ashenafi; Xhaard, Henri; Ghemtio, Leo (2016)
    Background: The disposition of a pharmaceutical compound within an organism, i.e. its Absorption, Distribution, Metabolism, Excretion, Toxicity (ADMET) properties and adverse effects, critically affects late stage failure of drug candidates and has led to the withdrawal of approved drugs. Computational methods are effective approaches to reduce the number of safety issues by analyzing possible links between chemical structures and ADMET or adverse effects, but this is limited by the size, quality, and heterogeneity of the data available from individual sources. Thus, large, clean and integrated databases of approved drug data, associated with fast and efficient predictive tools are desirable early in the drug discovery process. Description: We have built a relational database (IDAAPM) to integrate available approved drug data such as drug approval information, ADMET and adverse effects, chemical structures and molecular descriptors, targets, bioactivity and related references. The database has been coupled with a searchable web interface and modern data analytics platform (KNIME) to allow data access, data transformation, initial analysis and further predictive modeling. Data were extracted from FDA resources and supplemented from other publicly available databases. Currently, the database contains information regarding about 19,226 FDA approval applications for 31,815 products (small molecules and bio-logics) with their approval history, 2505 active ingredients, together with as many ADMET properties, 1629 molecular structures, 2.5 million adverse effects and 36,963 experimental drug-target bioactivity data. Conclusion: IDAAPM is a unique resource that, in a single relational database, provides detailed information on FDA approved drugs including their ADMET properties and adverse effects, the corresponding targets with bioactivity data, coupled with a data analytics platform. It can be used to perform basic to complex drug-target ADMET or adverse effects analysis and predictive modeling. IDAAPM is freely accessible at and can be exploited through a KNIME workflow connected to the database.
  • Belz, Regina G.; Sinkkonen, Aki (2021)
    BACKGROUND Low toxin doses that do not affect mean responses in plant populations can still change the growth of subpopulations. Studies covering vegetative stages ascribed fast-growing plants higher thresholds for growth stimulation and inhibition, compared with the rest of the population. We hypothesized that such selective effects also play a role after reproduction; that is, the offspring of glyphosate-treated tolerant, fast-growing phenotypes is more tolerant than the offspring of untreated plants. An experimental, high-density barley population was exposed to a range of glyphosate concentrations in the greenhouse, and reproduction and final growth were analyzed for selective effects. Therefore, F0, F1 treated and F1 non-treated offspring were re-exposed to glyphosate. RESULTS Low doses of glyphosate inhibited the growth and reproduction of slow-growing plants at concentrations that did not change the population mean. Concentrations that inhibited average-sized plants hormetically increased the biomass and seed yield of fast-growing plants. Compared with F0 and F1 non-treated offspring, F1-treated offspring from hormetically stimulated fast-growing plants were more glyphosate tolerant. Hence, a pesticide can shape the reproductive pattern of a plant population and alter offspring tolerance at concentrations that have no effect on average yield. CONCLUSIONS Toxin levels that do not change the population mean still alter the reproductive output of individuals. Sensitive phenotypes suffer, whereas the reproduction of tolerant phenotypes is boosted compared with toxin-free conditions. Because glyphosate is one of the leading herbicides in the world, tolerant phenotypes may benefit from current agricultural practices. If these results apply to other toxicants, low toxin doses may increase the fitness of tolerant phenotypes in a way not previously anticipated.