Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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    Defining in vivo dose-response curves for kidney DNA adduct formation of aristolochic acid I in rat, mouse and human by an in vitro and physiologically based kinetic modeling approach
    Abdullah, Rozaini ; Wesseling, Sebastiaan ; Spenkelink, Bert ; Louisse, Jochem ; Punt, Ans ; Rietjens, Ivonne M.C.M. - \ 2020
    Journal of Applied Toxicology (2020). - ISSN 0260-437X
    aristolochic acid I (AAI) - DNA adduct formation - in vitro-in vivo extrapolation - physiologically based kinetic (PBK) modeling - reverse dosimetry

    Aristolochic acid I (AAI) is a well-known genotoxic kidney carcinogen. Metabolic conversion of AAI into the DNA-reactive aristolactam-nitrenium ion is involved in the mode of action of tumor formation. This study aims to predict in vivo AAI-DNA adduct formation in the kidney of rat, mouse and human by translating the in vitro concentration-response curves for AAI-DNA adduct formation to the in vivo situation using physiologically based kinetic (PBK) modeling-based reverse dosimetry. DNA adduct formation in kidney proximal tubular LLC-PK1 cells exposed to AAI was quantified by liquid chromatography-electrospray ionization-tandem mass spectrometry. Subsequently, the in vitro concentration-response curves were converted to predicted in vivo dose-response curves in rat, mouse and human kidney using PBK models. Results obtained revealed a dose-dependent increase in AAI-DNA adduct formation in the rat, mouse and human kidney and the predicted DNA adduct levels were generally within an order of magnitude compared with values reported in the literature. It is concluded that the combined in vitro PBK modeling approach provides a novel way to define in vivo dose-response curves for kidney DNA adduct formation in rat, mouse and human and contributes to the reduction, refinement and replacement of animal testing.

    Monocrotaline-induced liver toxicity in rat predicted by a combined in vitro physiologically based kinetic modeling approach
    Suparmi, Suparmi ; Wesseling, Sebastiaan ; Rietjens, Ivonne M.C.M. - \ 2020
    Archives of Toxicology 94 (2020). - ISSN 0340-5761 - p. 3281 - 3295.
    Acute toxicity - Liver - Monocrotaline - PBK modeling - Reverse dosimetry

    The aim of the present study was to use an in vitro–in silico approach to predict the in vivo acute liver toxicity of monocrotaline and to characterize the influence of its metabolism on its relative toxic potency compared to lasiocarpine and riddelliine. In the absence of data on acute liver toxicity of monocrotaline upon oral exposure, the predicted dose–response curve for acute liver toxicity in rats and the resulting benchmark dose lower and upper confidence limits for 10% effect (BMDL10 and BMDU10) were compared to data obtained in studies with intraperitoneal or subcutaneous dosing regimens. This indicated the predicted BMDL10 value to be in line with the no-observed-adverse-effect levels (NOAELs) derived from availabe in vivo studies. The predicted BMDL10–BMDU10 of 1.1–4.9 mg/kg bw/day also matched the oral dose range of 1–3 mg PA/kg bw/day at which adverse effects in human are reported. A comparison to the oral toxicity of the related pyrrolizidine alkaloids (PAs) lasiocarpine and riddelliine revealed that, although in the rat hepatocytes monocrotaline was less toxic than lasiocarpine and riddelliine, due to its relatively inefficient clearance, its in vivo acute liver toxicity was predicted to be comparable. It is concluded that the combined in vitro-PBK modeling approach can provide insight in monocrotaline-induced acute liver toxicity in rats, thereby filling existing gaps in the database on PA toxicity. Furthermore, the results reveal that the kinetic and metabolic properties of PAs can vary substantially and should be taken into account when considering differences in relative potency between different PAs.

    Predicting the Acute Liver Toxicity of Aflatoxin B1 in Rats and Humans by an In Vitro–In Silico Testing Strategy
    Gilbert-Sandoval, Ixchel ; Wesseling, Sebastiaan ; Rietjens, Ivonne M.C.M. - \ 2020
    Molecular Nutrition & Food Research 64 (2020)13. - ISSN 1613-4125
    acute liver toxicity - aflatoxin B1 - physiologically based kinetic modeling - reverse dosimetry

    Scope: High-level exposure to aflatoxin B1 (AFB1) is known to cause acute liver damage and fatality in animals and humans. The intakes actually causing this acute toxicity have so far been estimated based on AFB1 levels in contaminated foods or biomarkers in serum. The aim of the present study is to predict the doses causing acute liver toxicity of AFB1 in rats and humans by an in vitro–in silico testing strategy. Methods and results: Physiologically based kinetic (PBK) models for AFB1 in rats and humans are developed. The models are used to translate in vitro concentration–response curves for cytotoxicity in primary rat and human hepatocytes to in vivo dose–response curves using reverse dosimetry. From these data, the dose levels at which toxicity would be expected are obtained and compared to toxic dose levels from available rat and human case studies on AFB1 toxicity. The results show that the in vitro–in silico testing strategy can predict dose levels causing acute toxicity of AFB1 in rats and human. Conclusions: Quantitative in vitro in vivo extrapolation (QIVIVE) using PBK modeling-based reverse dosimetry can predict AFB1 doses that cause acute liver toxicity in rats and human.

    Cellular levels and molecular dynamics simulations of estragole DNA adducts point at inefficient repair resulting from limited distortion of the double-stranded DNA helix
    Yang, Shuo ; Diem, Matthias ; Liu, Jakob D.H. ; Wesseling, Sebastiaan ; Vervoort, Jacques ; Oostenbrink, Chris ; Rietjens, Ivonne M.C.M. - \ 2020
    Archives of Toxicology 94 (2020)4. - ISSN 0340-5761 - p. 1349 - 1365.
    DNA adduct - DNA repair efficiency - Estragole - Molecular modeling and simulation

    Estragole, naturally occurring in a variety of herbs and spices, can form DNA adducts after bioactivation. Estragole DNA adduct formation and repair was studied in in vitro liver cell models, and a molecular dynamics simulation was used to investigate the conformation dependent (in)efficiency of N2-(trans-isoestragol-3′-yl)-2′-deoxyguanosine (E-3′-N2-dG) DNA adduct repair. HepG2, HepaRG cells, primary rat hepatocytes and CHO cells (including CHO wild-type and three NER-deficient mutants) were exposed to 50 μM estragole or 1′-hydroxyestragole and DNA adduct formation was quantified by LC–MS immediately following exposure and after a period of repair. Results obtained from CHO cell lines indicated that NER plays a role in repair of E-3′-N2-dG adducts, however, with limited efficiency since in the CHO wt cells 80% DNA adducts remained upon 24 h repair. Inefficiency of DNA repair was also found in HepaRG cells and primary rat hepatocytes. Changes in DNA structure resulting from E-3′-N2-dG adduct formation were investigated by molecular dynamics simulations. Results from molecular dynamics simulations revealed that conformational changes in double-stranded DNA by E-3′-N2-dG adduct formation are small, providing a possible explanation for the restrained repair, which may require larger distortions in the DNA structure. NER-mediated enzymatic repair of E-3′-N2-dG DNA adducts upon exposure to estragole will be limited, providing opportunities for accumulation of damage upon repeated daily exposure. The inability of this enzymatic repair is likely due to a limited distortion of the DNA double-stranded helix resulting in inefficient activation of nucleotide excision repair.

    Meteorological aspects of heavy precipitation in relation to floods – An overview
    Breugem, A.J. ; Wesseling, J.G. ; Oostindie, K. ; Ritsema, C.J. - \ 2020
    Earth-Science Reviews 204 (2020). - ISSN 0012-8252
    Characteristics - Classification - Climate change - Heavy precipitation - Ingredients - Storm types

    Floods do have multiple aspects: they are integral phenomena by nature. In this paper we deal with the meteorological aspects, which need to be adequately understood in order to understand the occurrence and development of floods. This holds the more as different meteorological environments and accompanying mechanisms can result in different types of heavy precipitation and so in different flood responses. In this paper, the meteorological aspects of floods are described from the perspective of a precipitation event. The characteristics, the categorisations and the ingredients of the storm systems are presented. The influences of global warming on heavy precipitation events will be discussed as well. The sequence of these aspects reads as a logical succession of the distinct topics of the meteorological aspects of a heavy precipitation event. Since floods commonly have a profound impact on environment and society, the understanding of the meteorological aspects is a first and necessary step in a challenge of dealing with floods. The ultimate goal of this step is to diminish the harmful consequences of floods as adequately as possible.

    Risk benefit analysis of botanical varieties growing in the Mediterranean region
    Papadi, Georgia - \ 2020
    Wageningen University. Promotor(en): I.M.C.M. Rietjens, co-promotor(en): A. Troganis; S. Wesseling. - Wageningen : Wageningen University - ISBN 9789463953191 - 217

    Despite the long history of use of medicinal plants for the treatment and prevention of diseases, the safety of botanicals and botanical preparations is not certain, since some of the contained bioactive phytochemicals can induce undesired effects. Thus, there is need to assure that the risks of the use of botanicals and botanical preparations do not outweigh the benefits. The aim of the present thesis was to reveal potential health benefits and hazards of 18 botanical varieties grown in the Mediterranean region, that are used traditionally for the treatment and prevention of several health conditions, using a series of in vitro bioassays.

    Chapter 1 provides background information about the use of botanicals for medicinal purposes, the traditional use and pharmacological properties of the 18 selected botanical varieties, as well as the beneficial and toxicological endpoints selected for a qualitative risk-benefit evaluation. In Chapter 2, an overview of the available in vitro bioassays, suitable for the detection of beneficial and adverse effects of botanicals, botanical preparations and their active constituents and the characteristics that make these assays valuable tools for a qualitative risk-benefit assessment, is presented. The pitfalls of bioassay use are also highlighted, discussing among others the factors that may generate false-positive or false-negative results and the limitations in the extrapolation of in vitro data to the in vivo situation.

    Several in vitro bioassays were applied to reveal the potential benefits and hazards of the 18 selected botanical varieties. Methanol extracts compatible with in vitro bioassays were prepared and tested in the EpRE-LUX (Chapter 3) and the PPARγ CALUX® (Chapter 4) reporter gene assays. Results obtained revealed that half of the tested extracts, are able to exert a potential chemopreventive action via activation of EpRE mediated gene expression,  while most of the tested extracts (16 out of 18) may contribute to potential health benefits via the activation of PPARγ mediated gene expression. LC-MS analysis combined with MAGMa (MS Annotation based on in silico Generated Metabolites) software was applied in order to facilitate tentative identification of the active constituents within selected active extracts. Many active ingredients of the methanol extracts from Juglans regia, Rhamnus frangula and Urtica dioica were revealed, albeit in low concentrations, in the respective extracts. The presence of many compounds exerting the same activity and/or synergistic effects between the different constituents, could explain the full potential detected for the extract as a whole.

    The possibility that the benefits of these botanical preparations would be contraindicated by potential hazards, was also investigated. In Chapter 5, the potential estrogenic activity of the extracts was assessed in the ERα CALUX® assay resulting 13 extracts that tested positive. The zebrafish embryotoxicity test (ZET), used to reveal potential developmental toxicity, resulted in a concentration dependent drop in the GMS (general morphology score) when zebrafish embryos were exposed to Rhamnus frangula, Ruta graveolens and Achillea millefolium extracts. For the extracts from Rhamnus frangula and Achillea millefilium this drop in the GMS might be ascribed to toxicity, in contrast to the extract from Ruta graveolents that shows specific in vitro developmental toxicity.

    In Chapter 6, the potential genotoxicity of the extracts was tested using the AMES test. The extracts from Ruta graveolens, Fumaria officinalis and Juglans regia tested positive for mutagenicity. These results were combined with the all data obtained in Chapters 3, 4 and 5, and with information derived from the EFSA compendium of botanicals containing substances that may raise a concern, enabling an initial qualitative risk-benefit assessment for the 18 Mediterranean botanicals. For some of the botanicals, the risks clearly outweigh the potential benefits, as in the case of the extracts that tested positive for developmental toxicity and mutagenicity, for others it is not possible to come to a conclusion based on the obtained data and for others, especially for Urtica dioica L. and potentially also Equisetum arvense L., Taraxacum officinale and Veronica officinalis L., further development into functional food ingredients would be indicated, focussing in future studies on their further safety assessment and their potential to activate PPARy which could be of interest for therapeutic effects in type II diabetes mellitus.

    Chapter 7 summarizes the results obtained in the present thesis and provides the overall discussion and future perspectives, concluding on the value of the results obtained from in vitro bioassays in potential (pre)clinical testing strategies to support the selection of promising candidate botanicals and/or their extracts for the development of functional food ingredients.

    In vitro metabolism of naphthalene and its alkylated congeners by human and rat liver microsomes via alkyl side chain or aromatic oxidation
    Wang, Danlei ; Bruyneel, Ben ; Kamelia, Lenny ; Wesseling, Sebastiaan ; Rietjens, Ivonne M.C.M. ; Boogaard, Peter J. - \ 2020
    Chemico-Biological Interactions 315 (2020). - ISSN 0009-2797
    Alkylated naphthalene - Human - Michaelis-menten kinetics - Microsomes - Rat

    Mineral oils are wide applied in food production and processing and may contain polycyclic aromatic hydrocarbons (PAHs). The PAHs that may be present in mineral oils are typically alkylated, and have been barely studied. Metabolic oxidation of the aromatic ring is a key step to form DNA-reactive PAH metabolites, but may be less prominent for alkylated PAHs since alkyl substituents would facilitate side chain oxidation as an alternative. The current study investigates this hypothesis of preferential side chain oxidation at the cost of aromatic oxidation using naphthalene and a series of its alkyl substituted analogues as model compounds. The metabolism was assessed by measuring metabolite formation in rat and human liver microsomal incubations using UPLC and GC-MS/MS. The presence of an alkyl side chain markedly reduced aromatic oxidation for all alkyl-substituted naphthalenes that were converted. 1-n-Dodecyl-naphthalene was not metabolized under the experimental conditions applied. With rat liver microsomes for 1-methyl-, 2-methyl-, 1-ethyl-, and 2-ethyl- naphthalene, alkyl side chain oxidation was preferred over aromatic oxidation. With human liver microsomes this was the case for 2-methyl-, and 2-ethyl-naphthalene. It is concluded that addition of an alkyl substituent in naphthalene shifts metabolism in favor of alkyl side chain oxidation at the cost of aromatic ring oxidation. Furthermore, alkyl side chains of 6 or more carbon atoms appeared to seriously hamper and reduce overall metabolism, metabolic conversion being no longer observed with the C12 alkyl side chain. In summary, alkylation of PAHs likely reduces their chances of aromatic oxidation and bioactivation.

    The impact of sensitivity and uncertainty of soil physical parameters on the terms of the water balance: Some case studies with default R packages. Part I: Theory, methods and case descriptions
    Wesseling, Jan ; Kroes, Joop ; Campos Oliveira, Thalita ; Damiano, Francisco - \ 2020
    Computers and Electronics in Agriculture 170 (2020). - ISSN 0168-1699
    HPC - IRS - LHS - Numerical model - R - Sensitivity - Sobol - SWAP - Uncertainty

    These papers (part I and part II) emphasize the need for sensitivity and uncertainty analyses. A number of techniques are applied, e.g. latin hypercube sampling, impact response surfaces and Sobol-analyses. Five examples are presented, four of them concerning the numerical model SWAP. The data generation and analysis is performed with standard R packages. Although the computations can be made on any computer, the most time-consuming examples in this paper have been run on a High Performance Computer Cluster. With the relatively simple Impact Response Surface technique it is shown that variation of the saturated hydraulic conductivity has far less impact than changing the moisture content at saturation. Analyses according to the Sobol-Jansen method show that when the soil physical relationships are described according to Damiano, then the parameter b has a very large influence on the results. If the well-known Mualem - Van Genuchten equations are applied, most variation can be explained by the parameter n.

    The impact of sensitivity and uncertainty of soil physical parameters on the terms of the water balance: Some case studies with default R packages. Part II: Results and discussion
    Wesseling, Jan ; Kroes, Joop ; Campos Oliveira, Thalita ; Damiano, Francisco - \ 2020
    Computers and Electronics in Agriculture 170 (2020). - ISSN 0168-1699
    HPC - IRS - LHS - Numerical model - R - Sensitivity - Sobol - Swap - Uncertainty

    These papers (part I and part II) emphasize the need for sensitivity and uncertainty analyses. A number of techniques are applied, e.g. latin hypercube sampling, impact response surfaces and Sobol-analyses. Five examples are presented, four of them concerning the numerical model Swap. The data generation and analysis is performed with standard R packages. Although the computations can be made on any computer, the most time-consuming examples in this paper have been run on a High Performance Computer Cluster. With the relatively simple Impact Response Surface technique it is shown that variation of the saturated hydraulic conductivity has far less impact than changing the moisture content at saturation. Analyses according to the Sobol-Jansen method show that when the soil physical relationships are described according to Damiano, then the parameter b has a very large influence on the results. If the well-known Mualem - Van Genuchten equations are applied, most variation can be explained by the parameter n.

    Physiologically Based Kinetic Modeling-Facilitated Reverse Dosimetry to Predict in Vivo Red Blood Cell Acetylcholinesterase Inhibition following Exposure to Chlorpyrifos in the Caucasian and Chinese Population
    Zhao, Shensheng ; Kamelia, Lenny ; Boonpawa, Rungnapa ; Wesseling, Sebastiaan ; Spenkelink, Bert ; Rietjens, Ivonne M.C.M. - \ 2019
    Toxicological sciences 171 (2019)1. - ISSN 1096-6080 - p. 69 - 83.
    acetylcholinesterase inhibition - chlorpyrifos - interethnic variation - organophosphate pesticide - physiologically based kinetic modeling - reverse dosimetry

    Organophosphates have a long history of use as insecticides over the world. The aim of the present study was to investigate the interethnic differences in kinetics, biomarker formation, and in vivo red blood cell acetylcholinesterase inhibition of chlorpyrifos (CPF) in the Chinese and the Caucasian population. To this purpose, physiologically based kinetic models for CPF in both the Chinese and Caucasian population were developed, and used to study time-and dose-dependent interethnic variation in urinary biomarkers and to convert concentration-response curves for red blood cell acetylcholinesterase inhibition to in vivo dose-response curves in these 2 populations by reverse dosimetry. The results obtained revealed a marked interethnic difference in toxicokinetics of CPF, with lower urinary biomarker levels at similar dose levels and slower CPF bioactivation and faster chlorpyrifos-oxon detoxification in the Chinese compared with the Caucasian population, resulting in 5-to 6-fold higher CPF sensitivity of the Caucasian than the Chinese population. These differences might be related to variation in the frequency of single-nucleotide polymorphisms for the major biotransformation enzymes involved. To conclude, the interethnic variation in kinetics of CPF may affect both its biomarker-based exposure assessment and its toxicity and risk assessment and physiologically based kinetic modeling facilitates the characterization and quantification of these interethnic variations.

    Waterafstotendheid: een veel voorkomend verschijnsel in de natuur : Voortschrijdend inzicht in het fenomeen waterafstotendheid
    Dekker, L.W. ; Ritsema, C.J. ; Oostindie, K. ; Wesseling, J.G. - \ 2019
    Stromingen : vakblad voor hydrologen 25 (2019)3. - ISSN 1382-6069 - p. 57 - 67.
    Before 1988 soil investigators generally assumed that the dry topsoil from "nollen" (small dunes) in sandy grasslands was only a consequence of a too deep groundwater table. The bad grass performance should be due to the minor capillary rise of the groundwater towards the topsoil. An explanation for the relatively low water contents in the topsoil after several rain events or sprinkler irrigation applications could not be given at that time. However, in 1988 a second important factor for this phenomenon was determined, namely the extreme water repellency of the topsoil during dry periods. This explained that water infiltrates slowly into the dry topsoil and therefore could flow from the higher nollen to the lower environment. Although not interrogated the occurrence of water repellency, Dr. G.P. Wind showed, in the middle of the seventies of the past century, how application of the detergent Lodaline accelerated the infiltration of rainwater in the soil of his sandy garden. During the last twenty-five years, we performed several studies concerning the prevention of water repellency and the effect of the treatments with surfactants on the wetting and grass performance of sandy soils. Between 1910 and 1970, publications concerning soil water repellency appeared occasionally. After this period, the number of publications increased and resulted in around 100 publications each year during the period between 2000 and now. Although the hydrological importance of water repellency in soils attracted much interest, relatively few studies spent attention to the significance of water repellency of plants. Twenty years ago it was shown that the leaves of the Lotus flower were superhydrofobic and self-cleaning. But also, several animals have superhydrofobic properties that enable them to collect water for drinking.
    Aflatoxin B1 in nixtamalized maize in Mexico; occurrence and accompanying risk assessment
    Gilbert Sandoval, Ixchel ; Wesseling, Sebastiaan ; Rietjens, Ivonne M.C.M. - \ 2019
    Toxicology Reports 6 (2019). - ISSN 2214-7500 - p. 1135 - 1142.
    Aflatoxin B1 - Liver cancer - Maize - Margin of exposure (MOE) - Mexico - Risk assessment

    Maize is a staple food in Mexico that might contain Aflatoxin B1 (AFB1). Nonetheless, data on the exposure and risk assessment of AFB1 from maize for the Mexican population are limited. The aim of the present study was to analyse the occurrence of AFB1 in Mexican nixtamalized maize samples, and to assess the accompanying exposure and risk. Four out of 88 samples contained AFB1 at levels above the limit of detection (1 ng/g). AFB1 occurrence values obtained in this study and additional occurrence values from literature were combined with available literature data for mean and P95 consumption of maize based products. For a 70 kg body weight person, lower bound and upper bound exposure assessments resulted in estimated daily intakes (EDI) of 0.7–8.5 ng/kg bw/day, based on a mean maize consumption. Based on the P95 maize consumption these EDI values amounted to 3.3–11.7 ng/kg bw/day. The corresponding Margin of Exposure (MOE) values amounted to 257-20 for the mean and 50-15 for the P95 consumers. The estimated increased cancer risks were 9-320 and 43-439 cases/106 individuals/lifetime of 75 years for the mean and P95 consumers, respectively. Altogether, the assessment reveals the need for continued risk management of AFB1 in Mexico.

    Investigation of possible hazards and benefits of use of 'Ashkulebya' (Maerua subcordata (Gilg) DeWolf) as famine and/or potential functional food
    Hiben, Mebrahtom Gebrelibanos - \ 2019
    Wageningen University. Promotor(en): I.M.C.M. Rietjens, co-promotor(en): J.J.M. Vervoort; S. Wesseling. - Wageningen : Wageningen University - ISBN 9789463951265 - 208

    Currently, wild edible plants are getting into the research focus of both food and pharmaceutical domains as they are considered valuable resources for improving food and nutritional security as well as for bioactive ingredients that can be used for functional foods or managing chronic diseases. Wild edible plants, in addition to their potential nutritional contribution, may provide important health benefits as the health-promoting components of plant based foods, so called nutraceuticals or functional food ingredients, are usually higher in wild plants. However, at the same time, these plants may contain toxic ingredients that may lead to adverse effects. At the current state of the art novel foods have to comply with novel food regulation while safety of the use of botanicals and botanical preparation as food is the responsibility of the provider and not subject to premarket safety evaluation. This implies that a concern requiring adequate consideration of both risks and benefits has to be addressed when introducing wild edible plants as novel components in a regular diet or as herbal medicine or food supplement. The present PhD thesis aims at investigating the possible hazards and potential health benefits of Maerua subcordata (Gilg) DeWolf, a wild plant locally called ‘ashkulebya’ by the Kunama ethnics of Northern Ethiopia, as a novel nutritional resource and/or as a health food/functional food. To meet this aim, the thesis tested the activity of different extracts of M. subcordata in a wide range of in vitro assays for both adverse and beneficial endpoints, along with, phytochemical studies to identify active constituents. Consideration of ethnobotanical data was also part of the study. The phytochemical studies identified glucosinolates and biogenic amines such as quaternary ammonium compounds and guanidine derivatives in the different M. subcordata extracts. The potential health benefits of M. subcordata extracts via their effects on the expression of electrophile-responsive element (EpRE), peroxisome proliferator-activated receptor gamma (PPARg), and nuclear factor kappa B (NF-κB) regulated genes was evaluated. The induction of EpRE-mediated genes have implications of maintaining redox homeostasis. The fruit, leaf, and seed extracts induced the expression of EpRE-mediated genes while induction by the root extract was minimal. Candidate glucosinolates (or their matching isothiocyanates) exhibited strong induction while some biogenic amines exhibited either no significant induction or slight inhibition. Inhibition of NF-κB regulated genes have implications for anti-inflammatory effects while induction of PPARg regulated genes have implications for control of diseases of the metabolic syndrome. The fruit, root, and seed extracts induced PPARγ-mediated gene expression while induction by the leaf extract was minimal. Instead, all extracts inhibited bacterial lipopolysaccharide (LPS) induced nitric oxide production, with the root showing the lowest potency. Selected candidates such as isothiocyanates and some biogenic amines also inhibited the LPS induced nitric oxide production. Equally, a battery of in vitro tests was applied to identify selected endpoints that could be used to assess the potential hazards associated with the use of botanical preparations or parts of M. subcordata. The Ames test and in silico (Derek Nexus) predictions were applied for initial genotoxicity screening whereas the aryl hydrocarbon receptor and the estrogen receptor alpha reporter gene assays as well as the embryonic stem cell test and the zebrafish embryotoxicity test were applied to investigate alerts for developmental toxicity. The overall hazard assessment results indicated that all extracts of M. subcordata do not point to a genotoxicity hazard; fruit, root, and seed extracts do not raise a concern with respect to developmental toxicity; but the data on the leaf extract may point towards a developmental toxicity hazard. In conclusion, the overall results obtained argue in favour of the use of the root, fruit, and seed parts of M. subcordata as (famine) food and/or functional food whereas the leaf part may be used as a herbal medicine. The outcomes of the study may also contribute scientific data to design further in vivo studies on safety and proper utilization of the plant while the methodology applied can be extrapolated to serve as an approach to the risk-benefit assessment of other plant based products.

    Zand moet bedreigde Roggenplaat redden
    Ysebaert, T. - \ 2019
    Hazard assessment of Maerua subcordata (Gilg) DeWolf. for selected endpoints using a battery of in vitro tests
    Gebrelibanos Hiben, Mebrahtom ; Kamelia, Lenny ; Haan, Laura de; Spenkelink, Bert ; Wesseling, Sebastiaan ; Vervoort, Jacques ; Rietjens, Ivonne M.C.M. - \ 2019
    Journal of Ethnopharmacology 241 (2019). - ISSN 0378-8741
    CALUX assays - Embryonic stem cell test - Hazard - In vitro - Maerua subcordata - Zebrafish embryotoxicity test

    Ethnopharmacological relevance: Maerua subcordata (Gilg) DeWolf is a medicinal and wild food plant growing mainly in east Africa. Especially its root tuber is widely used in traditional medicine to treat several infectious and chronic diseases but also in some toxicity implications like use as abortifacient. Aim of the study: the present study applied in silico and in vitro tests to identify possible hazards of M. subcordata (fruit, leaf, root, seed) methanol extracts focussing on developmental toxicity. Materials and methods: Ames test, estrogen receptor alpha (ERα) assay, aryl hydrocarbon receptor (AhR) assay, embryonic stem cell test (EST), and zebrafish embryotoxicity test (ZET) were employed. Besides, a Derek Nexus toxicity prediction was performed on candidate structures obtained from metabolomics profiling of the extracts using liquid chromatography coupled to multistage mass spectroscopy (LC/MSn) and a MAGMa software based structural annotation. Results: Glucosinolates, which degrade to isothiocyanates, and biogenic amines were among the candidate molecules identified in the extracts by LC/MSn - MAGMa software structural annotation. Isothiocyanates and some other candidate molecules suggested a positive mutagenicity alert in Derek toxicity predictions. All the extracts showed negative mutagenicity in the Ames test. However, the Derek predictions also identified endocrine and developmental toxicity as possible endpoints of concern. This was further assessed using in vitro tests. Results obtained reveal that leaf extract shows AhR and ERα agonist activities, inhibited differentiation of ES-D3 stem cells into contracting cardiomyocytes in the EST (p < 0.001) as well as inhibited hatching (p < 0.01) and showed acute toxicity (p < 0.01) in the ZET. Also, the fruit extract showed toxicity (p < 0.05) towards zebrafish embryos and both fruit and seed extracts showed AhR agonist activities while root extract was devoid of activity in all in vitro assays. Conclusion: The leaf extract tests positive in in vitro tests that may point towards a developmental toxicity hazard. The current evaluations did not raise concerns of genotoxicity or developmental toxicity for the fruit, seed and root extracts. This is important given the use of especially these parts of M. subcordata, in traditional medicine and/or as (famine) food.

    Induction of EpRE-mediated gene expression by a series of mediterranean botanicals and their constituents
    Papadi, Georgia ; Wesseling, Sebastiaan ; Troganis, Anastassios N. ; Vervoort, Jacques ; Rietjens, Ivonne M.C.M. - \ 2019
    Journal of Ethnopharmacology 240 (2019). - ISSN 0378-8741 - 13 p.
    Aloe-emodin - Botanical extracts - Chrysophanol - EpRE/Nrf2 - MAGMa - Rhamnus frangula

    Ethnopharmacological relevance: A variety of Mediterranean plant species, traditionally used for the prevention and treatment of several health conditions, contain ingredients with potential biological activity of which many remain unexplored. Among the beneficial health effects of bioactive phytochemicals is the activation of cellular defense mechanisms involving the activation of EpRE (electrophile responsive element) - mediated changes in gene expression. Aim of the study: The present study aimed to identify botanicals and their active constituents able to activate the EpRE mediated gene expression within a series of Mediterranean plant species known for their hepatoprotective and/or cardioprotective properties. Materials and methods: Methanolic extracts of 18 botanicals were prepared and tested for their ability to induce gene expression in EpRE-LUX reporter cells. Subsequently, LC-MS (Liquid Chromatography Mass Spectrometry) analysis combined with MAGMa (MS Annotation based on in silico Generated Metabolites) software for automated compound annotation was used to facilitate tentative identification of the active constituents within two of the active extracts. Selected annotated compounds were tested in the EpRE-LUX reporter gene assay followed by definite identification of the most active ones. Results: It appeared that 9 of the 18 extracts were able to activate EpRE-mediated gene expression. Many active ingredients of the methanolic extracts from Juglans regia and Rhamnus frangula were revealed. Among them, chrysophanol and aloe-emodin were confirmed to be active EpRE inducing ingredients and were definitely identified in the Rhamnus Frangula extract. Conclusions: The protective effect of half of the tested botanical varieties via the activation of EpRE-mediated gene expression was confirmed. The study also provided an example of how in vitro bioassays can be combined with LC-MS and the automated chemical annotation software MAGMa, to identify biologically active constituents in complex botanical extracts.

    Selecting the dose metric in reverse dosimetry based QIVIVE : Reply to: ‘Comment on ‘Use of an in vitro–in silico testing strategy to predict inter-species and inter-ethnic human differences in liver toxicity of the pyrrolizidine alkaloids lasiocarpine and riddelliine’ by Ning et al.
    Rietjens, Ivonne M.C.M. ; Ning, Jia ; Chen, Lu ; Wesseling, Sebastiaan ; Strikwold, Marije ; Louisse, Jochem - \ 2019
    Archives of Toxicology 93 (2019)5. - ISSN 0340-5761 - p. 1467 - 1469.
    Assessing the impact of climate change on rainwater harvesting in the Oum Zessar watershed in Southeastern Tunisia
    Adham, Ammar ; Wesseling, Jan G. ; Abed, Rasha ; Riksen, Michel ; Ouessar, Mohamed ; Ritsema, Coen J. - \ 2019
    Agricultural Water Management 221 (2019). - ISSN 0378-3774 - p. 131 - 140.
    Climate change - GCMs - SDSM - Tunisia - Water harvesting model

    Climate change is believed to have a large impact on water resources system both globally and regionally. It has become a major global issue, especially in developing countries because these are most affected by its impacts. Rainwater harvesting techniques offer an alternative source of water and represent specific adaptive strategies to cope with water scarcity within future climate change. Studying the impact of climate change on rainwater harvesting techniques, however, is difficult, because the general circulation models (GCMs) which are widely used to simulate scenarios of future climate change operate on a coarse scale. We estimated the impact of climate change on water availability at the watershed level by downscaling precipitation and temperature from the GCMs using a statistical downscaling model. A water harvesting model then assessed the performance of the rainwater harvesting techniques for the Oum Zessar watershed in southeastern Tunisia under current climatic conditions and scenarios of future climate change. Annual temperature tended to increase and precipitation tended to decrease. These changes of climatic variables were used in the water harvesting model to simulate future water availability. Changing the directions of water flow between sub-catchments in combination with changing the spillway heights strongly affected the performance of rainwater harvesting under the scenarios of future climate, resulting in a sufficient water supply for 92% of all sub-catchments, compared to 72% without these changes.

    Effects of Maerua subcordata (Gilg) DeWolf on electrophile-responsive element (EpRE)mediated gene expression in vitro
    Hiben, Mebrahtom Gebrelibanos ; Haan, Laura De; Spenkelink, Bert ; Wesseling, Sebas ; Louisse, Jochem ; Vervoort, Jacques ; Rietjens, Ivonne M.C.M. - \ 2019
    PLoS ONE 14 (2019)4. - ISSN 1932-6203

    Plant extracts and phytochemicals may prevent chronic diseases via activation of adaptive cellular stress response pathways including induction of antioxidant and phase II detoxifying enzymes. The regulatory regions of these inducible genes encode the electrophile-response element (EpRE). This study tested the EpRE induction ability of Maerua subcordata (fruit, leaf, root, seed) methanol extracts and selected candidate constituents thereof, identified by liquid chromatography coupled with multistage mass spectroscopy, employing an EpRE luciferase reporter gene assay using hepa-1c1c7 mouse hepatoma cells. A parallel Cytotox CALUX assay using human osteosarcoma U2OS cells was used to monitor any non-specific changes in luciferase activity or cytotoxicity. Results showed that fruit, root, and seed extracts were non-cytotoxic up to a concentration of 30 gram dry weight per litre but the leaf extract exhibited some cytotoxicity and that the leaf (despite some cytotoxicity), fruit, and seed extracts showed strong induction of EpRE mediated gene expression while induction by the root extract was minimal. Selected candidates included glucosinolates, isothiocyanates, and some biogenic amines. Subsequent studies showed that methyl-, ethyl-, isopro-pyl-, isobutyl- isothiocyanates, and sec-butyl thiocyanate as well as glucobrassicin induced concentration (1–100 μM) dependent EpRE-mediated gene expression while the biogenic amines stachydrine and trigonelline acted as inhibitors of EpRE-mediated gene expression at 100 μM. The identification of glucolepidiin, glucobrassicin, glucocapparin, stachydrine, and trigonelline in all extracts was confirmed using standards and based on multiple reaction monitoring; yet, glucobrassicin level in the root extract was negligible. In conclusion, this study provided a first report on EpRE mediated gene expression effects of M. subcordata; and despite detection of different glucosinolates in all extracts, those containing glucobrassicin particularly displayed high EpRE induction. Because EpRE inducers are cytoprotective and potential chemopreventive agents while inhibitors are suggested adjuvants of chemotherapy, results of this study imply that process manipulation of this plant may result in herbal preparations that may be used as chemopreventive agents or adjuvants of chemotherapies.

    Levels of methyleugenol and eugenol in instant herbal beverages available on the Indonesian market and related risk assessment
    Suparmi, Suparmi ; Ginting, Alex Junico ; Mariyam, Siti ; Wesseling, Sebastiaan ; Rietjens, Ivonne M.C.M. - \ 2019
    Food and Chemical Toxicology 125 (2019). - ISSN 0278-6915 - p. 467 - 478.
    BMDL - Estimated daily intake (EDI) - Instant herbal beverages - Margin of exposure (MOE) - Methyleugenol - Model averaging

    The presence and accompanying risks of methyleugenol and eugenol in herbal beverages available on the Indonesian market were evaluated. Methyleugenol was detected in 49 out of 114 samples, at levels amounting to 2.6–443.7 μg/g, while 4 samples contained eugenol at 21.4–101.2 μg/g. The EDI resulting from drinking these preparations amounted to 0.1–51.2 μg/kg bw/day and 1.1–3.3 μg/kg bw/day, respectively for samples targeted at adults and children. A BMDL10 value of 22.2 mg/kg bw/day for methyleugenol was defined using literature data and model averaging. MOE values were below 10,000 for 46 samples (40.4%), indicating a priority for risk management when assuming daily lifelong consumption, while the EDI for 4 samples containing eugenol did not exceed the ADI of 2.5 mg/kg bw thus did not raise a concern for human health. Using Haber's rule to correct for less than lifetime exposure, consumption of methyleugenol via these beverages would be of low concern when consumed for less than 2 weeks/year during a lifetime. This conclusion holds for herbal beverages collected by targeted sampling, not for all herbal beverages on the Indonesian market. The study provides data that can support establishment of a maximum permitted level (MPL) for methyleugenol in herbal beverages in Indonesia.

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