Helena T. Hogberg
Johns Hopkins University
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Featured researches published by Helena T. Hogberg.
Stem Cells | 2009
Leonora Buzanska; Joanna Sypecka; Silvia Nerini-Molteni; Anna Compagnoni; Helena T. Hogberg; Riccardo del Torchio; Krystyna Domanska-Janik; Jens Zimmer; Sandra Coecke
The aim of our study was to investigate whether a human neural stem cell line derived from umbilical cord blood (HUCB‐NSC) can serve as a reliable test model for developmental neurotoxicity (DNT). We assessed the sensitivity of HUCB‐NSCs at different developmental stages to a panel of neurotoxic (sodium tellurite, methylmercury chloride, cadmium chloride, chlorpyrifos, and L‐glutamate) and non‐neurotoxic (acetaminophen, theophylline, and D‐glutamate) compounds. In addition, we investigated the effect of some compounds on key neurodevelopmental processes like cell proliferation, apoptotic cell death, and neuronal and glial differentiation. Less differentiated HUCB‐NSCs were generally more sensitive to neurotoxicants, with the notable exception of L‐glutamate, which showed a higher toxicity to later stages. The relative potencies of the compounds were: cadmium chloride > methylmercury chloride ≫ chlorpyrifos ≫ L‐glutamate. Fifty nanomolar methylmercury chloride (MeHgCl) inhibited proliferation and induced apoptosis in early‐stage cells. At the differentiated stage, 1 μM MeHgCl induced selective loss of S100β‐expressing astrocytic cells. One millimolar L‐glutamate did not influence the early stages of HUCB‐NSC development, but it affected late stages of neuronal differentiation. A valuable system for in vitro DNT assessment should be able to discriminate between neurotoxic and non‐neurotoxic compounds and show different susceptibilities to chemicals according to developmental stage and cell lineage. Although not exhaustive, this work shows that the HUCB‐NSC model fulfils these criteria and may serve as a human in vitro model for DNT priority setting. STEM CELLS 2009;27:2591–2601
ALTEX-Alternatives to Animal Experimentation | 2013
Tzutzuy Ramirez; Mardas Daneshian; Hennicke Kamp; Frédéric Y. Bois; Malcolm R. Clench; Muireann Coen; Beth Donley; Steven M. Fischer; Drew R. Ekman; Eric Fabian; Claude Guillou; Joachim Heuer; Helena T. Hogberg; Harald Jungnickel; Hector C. Keun; G. Krennrich; Eckart Krupp; Andreas Luch; Fozia Noor; E. Peter; Bjoern Riefke; Mark Seymour; Nigel Skinner; Lena Smirnova; Elwin Verheij; Silvia Wagner; Thomas Hartung; Bennard van Ravenzwaay; Marcel Leist
Metabolomics, the comprehensive analysis of metabolites in a biological system, provides detailed information about the biochemical/physiological status of a biological system, and about the changes caused by chemicals. Metabolomics analysis is used in many fields, ranging from the analysis of the physiological status of genetically modified organisms in safety science to the evaluation of human health conditions. In toxicology, metabolomics is the -omics discipline that is most closely related to classical knowledge of disturbed biochemical pathways. It allows rapid identification of the potential targets of a hazardous compound. It can give information on target organs and often can help to improve our understanding regarding the mode-of-action of a given compound. Such insights aid the discovery of biomarkers that either indicate pathophysiological conditions or help the monitoring of the efficacy of drug therapies. The first toxicological applications of metabolomics were for mechanistic research, but different ways to use the technology in a regulatory context are being explored. Ideally, further progress in that direction will position the metabolomics approach to address the challenges of toxicology of the 21st century. To address these issues, scientists from academia, industry, and regulatory bodies came together in a workshop to discuss the current status of applied metabolomics and its potential in the safety assessment of compounds. We report here on the conclusions of three working groups addressing questions regarding 1) metabolomics for in vitro studies 2) the appropriate use of metabolomics in systems toxicology, and 3) use of metabolomics in a regulatory context.
Neurotoxicology | 2011
Helena T. Hogberg; Tomasz Sobanski; Antonio Novellino; Maurice Whelan; Dieter G. Weiss; Anna Bal-Price
Due to lack of knowledge only a few industrial chemicals have been identified as developmental neurotoxicants. Current developmental neurotoxicity (DNT) guidelines (OECD and EPA) are based entirely on in vivo studies that are both time consuming and costly. Consequently, there is a high demand to develop alternative in vitro methods for initial screening to prioritize chemicals for further DNT testing. One of the most promising tools for neurotoxicity assessment is the measurement of neuronal electrical activity using micro-electrode arrays (MEAs) that provides a functional and neuronal specific endpoint that until now has been used mainly to detect acute neurotoxicity. Here, electrical activity measurements were evaluated to be a suitable endpoint for the detection of potential developmental neurotoxicants. Initially, primary cortical neurons grown on MEA chips were characterized for different cell markers over time, using immunocytochemistry. Our results show that primary cortical neurons could be a promising in vitro model for DNT testing since some of the most critical neurodevelopment processes such as progenitor cell commitment, proliferation and differentiation of astrocytes and maturation of neurons are present. To evaluate if electrical activity could be a suitable endpoint to detect chemicals with DNT effects, our model was exposed to domoic acid (DomA), a potential developmental neurotoxicant for up to 4 weeks. Long-term exposure to a low concentration (50nM) of DomA increased the basal spontaneous electrical activity as measured by spike and burst rates. Moreover, the effect induced by the GABA(A) receptor antagonist bicuculline was significantly lower in the DomA treated cultures than in the untreated ones. The MEA measurements indicate that chronic exposure to DomA changed the spontaneous electrical activity leading to the possible neuronal mal functioning. The obtained results suggest that the MEAs could be a useful tool to identify compounds with DNT potential.
Journal of Applied Toxicology | 2013
Mounir Bouhifd; Thomas Hartung; Helena T. Hogberg; Andre Kleensang; Liang Zhao
Metabolomics use in toxicology is rapidly increasing, particularly owing to advances in mass spectroscopy, which is widely used in the life sciences for phenotyping disease states. Toxicology has the advantage of having the disease agent, the toxicant, available for experimental induction of metabolomics changes monitored over time and dose. This review summarizes the different technologies employed and gives examples of their use in various areas of toxicology. A prominent use of metabolomics is the identification of signatures of toxicity – patterns of metabolite changes predictive of a hazard manifestation. Increasingly, such signatures indicative of a certain hazard manifestation are identified, suggesting that certain modes of action result in specific derangements of the metabolism. This might enable the deduction of underlying pathways of toxicity, which, in their entirety, form the Human Toxome, a key concept for implementing the vision of Toxicity Testing for the 21st century. This review summarizes the current state of metabolomics technologies and principles, their uses in toxicology and gives a thorough overview on metabolomics bioinformatics, pathway identification and quality assurance. In addition, this review lays out the prospects for further metabolomics application also in a regulatory context. Copyright
Neurotoxicology | 2010
Anna Bal-Price; Helena T. Hogberg; Leonora Buzanska; Petros Lenas; Erwin van Vliet; Thomas Hartung
Environmental chemicals have a potential impact on childrens health as the developing brain is much more vulnerable to injury caused by different classes of chemicals than the adult brain. This vulnerability is partly due to the fact that very complex processes of cell development and maturation take place within a tightly controlled time frame. So different stages of brain development are susceptible to toxic effects at different time points. Additionally the adult brain is well protected against chemicals by the blood brain barrier (BBB) whereas the placenta only partially protects against harmful chemical exposure. Many metals easily cross the placenta and BBB barrier since even after the birth BBB is not entirely differentiated (until about 6 months after birth). Additionally, the susceptibility of infants and children is due to increased exposure, augmented absorption rates, and less efficient ability of defense mechanism in comparison to adults. The In Vitro Session during the 12th International Neurotoxicology Association meeting (Jerusalem, June, 2009) provided the opportunity to discuss the new challenges that have to be faced to create new type of safety assessments for regulatory requirements. The integration of various tests into testing strategies as well as combination of information-rich approaches with bioinformatics was discussed. Furthermore relevant models and endpoints for developmental neurotoxicity (DNT) evaluation using in vitro approach were presented. The primary neuronal cultures of cerebellar granule cells (CGCs) as well as 3D aggregate model and the possible application of human embryonic and adult stem cells was discussed pointing out the potential of these models to be used for DNT testing. The presented systems are relevant for DNT evaluation as the key processes of brain development such cell proliferation, migration and neuronal/glial differentiation are present. Furthermore, emerging technologies such as gene expression, electrical activity measurements and metabonomics have been identified as promising tools. In a combination with other assays the in vitro approach could be included into a DNT intelligent testing strategy to speed up the process of DNT evaluation mainly by initial prioritization of chemicals with DNT potential for further testing.
Toxicological Sciences | 2010
Helena T. Hogberg; Agnieszka Kinsner-Ovaskainen; Sandra Coecke; Thomas Hartung; Anna Bal-Price
So far, only a few industrial chemicals have been identified as developmental neurotoxicants. Because the current developmental neurotoxicity (DNT) guideline (Organisation for Economic Co-operation and Development TG 426) is based entirely on in vivo studies that are both time consuming and costly, there is a need to develop alternative in vitro methods for initial screening to prioritize chemicals for further DNT testing. In this study, gene expression at the mRNA level was evaluated to determine whether this could be a suitable endpoint to detect potential developmental neurotoxicants. Primary cultures of rat cerebellar granule cells (CGCs) were exposed to well known (developmental) neurotoxicants (methyl mercury chloride, lead chloride, valproic acid, and tri-methyl tin chloride) for different time periods. A significant downregulation of the mRNA level for the neuronal markers (NF-68, NF-200, N-methyl D-aspartate glutamate receptor, and gamma-amino butyric acid receptor) was observed after exposure to methyl mercury chloride, valproic acid, and tri-methyl tin chloride. Moreover, a significant increase of the neural precursor marker nestin mRNA was also observed. The mRNA expression of the astrocytic markers (glial fibrillary acidic protein [GFAP] and S100beta) was unchanged. In contrast, exposure to lead chloride significantly decreased the mRNA level of the astrocytic marker GFAP, whereas the neuronal markers were less affected. These results suggest that gene expression could be used as a sensitive tool for the initial identification of DNT effects induced by different mechanisms of toxicity in both cell types (neuronal and glial) and at various stages of cell development and maturation.
Neurotoxicology and Teratology | 2010
Anna Bal-Price; Helena T. Hogberg; Leonora Buzanska; Sandra Coecke
The current testing requirements for both adult and developmental neurotoxicity evaluation are based on in vivo animal models and the neurotoxic potency of compounds is mainly determined by neurobehavioural and neuropathological effects. In vitro studies are considered complementary to animal tests because they provide an understanding of the molecular/cellular mechanisms involved in neurotoxicity. However, the selection of relevant in vitro neuronal/glial specific endpoints applied to various neuronal cellular models should be done in a careful way to build reliable and feasible testing strategies since usually these endpoints have to be tested in various complementary in vitro systems. The requirements for applying a more complex test strategy where toxicokinetic aspects are included together with different tools to compensate for the lack of in vitro metabolic competence are discussed. Taking into consideration the recent European Commission chemical legislation concerning registration, evaluation and authorisation of chemicals (REACH) it has become a priority to develop new intelligent testing strategies integrating computational models and in vitro assays based on cell culture models and endpoints that are amenable for adaptation to high throughput screening to be able to test a large number of chemicals.
Archives of Toxicology | 2015
Anna Bal-Price; Kevin M. Crofton; Marcel Leist; Sandra Allen; Michael Arand; Timo Buetler; Nathalie Delrue; Rex E. FitzGerald; Thomas Hartung; Tuula Heinonen; Helena T. Hogberg; Susanne Hougaard Bennekou; Walter Lichtensteiger; Daniela Maria Oggier; Martin Paparella; Marta Axelstad; Aldert H. Piersma; Eva Rached; Benoît Schilter; Gabriele Schmuck; Luc Stoppini; Enrico Tongiorgi; Manuela Tiramani; Florianne Monnet-Tschudi; Martin F. Wilks; Timo Ylikomi; Ellen Fritsche
Abstract A major problem in developmental neurotoxicity (DNT) risk assessment is the lack of toxicological hazard information for most compounds. Therefore, new approaches are being considered to provide adequate experimental data that allow regulatory decisions. This process requires a matching of regulatory needs on the one hand and the opportunities provided by new test systems and methods on the other hand. Alignment of academically and industrially driven assay development with regulatory needs in the field of DNT is a core mission of the International STakeholder NETwork (ISTNET) in DNT testing. The first meeting of ISTNET was held in Zurich on 23–24 January 2014 in order to explore the concept of adverse outcome pathway (AOP) to practical DNT testing. AOPs were considered promising tools to promote test systems development according to regulatory needs. Moreover, the AOP concept was identified as an important guiding principle to assemble predictive integrated testing strategies (ITSs) for DNT. The recommendations on a road map towards AOP-based DNT testing is considered a stepwise approach, operating initially with incomplete AOPs for compound grouping, and focussing on key events of neurodevelopment. Next steps to be considered in follow-up activities are the use of case studies to further apply the AOP concept in regulatory DNT testing, making use of AOP intersections (common key events) for economic development of screening assays, and addressing the transition from qualitative descriptions to quantitative network modelling.
Toxicology and Applied Pharmacology | 2009
Helena T. Hogberg; Agnieszka Kinsner-Ovaskainen; Thomas Hartung; Sandra Coecke; Anna Bal-Price
The major advantage of primary neuronal cultures for developmental neurotoxicity (DNT) testing is their ability to replicate the crucial stages of neurodevelopment. In our studies using primary culture of cerebellar granule cells (CGCs) we have evaluated whether the gene expression relevant to the most critical developmental processes such as neuronal differentiation (NF-68 and NF-200) and functional maturation (NMDA and GABA(A) receptors), proliferation and differentiation of astrocytes (GFAP and S100beta) as well as the presence of neural precursor cells (nestin and Sox10) could be used as an endpoint for in vitro DNT. The expression of these genes was assessed after exposure to various pesticides (paraquat parathion, dichlorvos, pentachlorophenol and cycloheximide) that could induce developmental neurotoxicity through different mechanisms. All studied pesticides significantly modified the expression of selected genes, related to the different stages of neuronal and/or glial cell development and maturation. The most significant changes were observed after exposure to paraquat and parathion (i.e. down-regulation of mRNA expression of NF-68 and NF-200, NMDA and GABA(A) receptors). Similarly, dichlorvos affected mainly neurons (decreased mRNA expression of NF-68 and GABA(A) receptors) whereas cycloheximide had an effect on neurons and astrocytes, as significant decreases in the mRNA expression of both neurofilaments (NF-68 and NF-200) and the astrocyte marker (S100beta) were observed. Our results suggest that toxicity induced by pesticides that target multiple pathways of neurodevelopment can be identified by studying expression of genes that are involved in different stages of cell development and maturation, and that gene expression could be used as a sensitive endpoint for initial screening to identify the compounds with the potential to cause developmental neurotoxicity.
ALTEX-Alternatives to Animal Experimentation | 2014
Lena Smirnova; Helena T. Hogberg; Marcel Leist; Thomas Hartung
In recent years neurodevelopmental problems in children have increased at a rate that suggests lifestyle factors and chemical exposures as likely contributors. When environmental chemicals contribute to neurodevelopmental disorders developmental neurotoxicity (DNT) becomes an enormous concern. But how can it be tackled? Current animal test- based guidelines are prohibitively expensive, at