Fritsche research group: modern risk assessment and sphere biology

Head of research group:
Univ.-Prof. Dr. med. Ellen Fritsche
Phone: +49 (0)211-3389-217

Postdocs:
Dr. rer. nat. Janette Goniwiecha
Dr. rer. nat. Julia Tigges (together with Krutmann lab)

PhD students:
Mohamed Elgamal, MD, MSc
Jördis Klose, MSc
Stefan Masjosthusmann, MSc
Laura Nimtz, Diplom Biologin

Master students:
Nils Förster
Anna Wellenberg
Saskia Wuttke

Technical assistance:
Farina Bendt, biology laboratory assistant
Gaby Brockerhoff, biologic-technical assistent 
Ulrike Hübenthal, biology laboratory assistant

Research profile

A major issue in developmental neurotoxicity (DNT) risk assessment is the lack of toxicological hazard information for most compounds. Therefore, new approaches are needed to provide adequate experimental data that allow regulatory decisions. The Fritsche lab has developed a 3D method for DNT hazard assessment based on human, rat and mouse neurospheres that mimic early neurodevelopmental processes like neural progenitor cell (NPC) proliferation, migration, differentiation into neurons and glial cells as well as apoptosis in vitro. This system is thus suited to perform pathway-to-function analyses in a species-specific context. Such data is also valuable to translate rodent in vivo data to humans on a mechanistic basis within the Adverse Outcome Pathway (AOP) concept. The Fritsche lab focuses currently on the assay’s scientific validation in order to define its biological application domain. Furthermore, algorithms are developed for the analysis of neurospheres in medium-throughput Hight Content Imaging Analyses (HCA).

The Fritsche lab contributes to the ‘Neurotoxicology’ subject of the IUF by integrating life-stage specificity, the developmental period, into neurotoxicity assessment. Mechanisms of DNT are very different compared to adult neurotoxicity and thus need special attention and specific testing methods. The Neurosphere Assay is complementary to the animal work with transgenic animals performed by the AGs Heuer and Schins. Collaborations with these groups allow studying molecular mechanisms in developing brain cells of these animals. Human relevance can then be added by gene manipulation of human neurospheres. In addition, the group operates the Cellomics Array Scan for HCA and helps with individual application needs of other groups at the IUF, the Heinrich Heine University and external laboratories like VITO (Belgium).

Projects

VIP

funded by the Federal Ministry of Research and Education (BMBF)

Currently, the biological application domain of the ‘Neurosphere Assay’ within a putative integrated testing strategy for DNT as well as the human-specificity of cell signaling during NPC development are evaluated by performing -omics analyses. Moreover, the Neurosphere Assay is challenged by specific pathway inhibitors and environmental chemicals to generate pathway-related fingerprints for DNT.

Major cooperation partners are Prof. Dr. Karl Köhrer (BMFZ, University Clinic Düsseldorf), Dr. Cornelia Prehn (Helmholtz Zentrum München) and Maria Teresa Colomina (University Rovira i Virgili, Tarragona/Spain).


Thyroid Hormone

funded by US Environmental Protection Agency (US-EPA, Star Grant) and until 2014 by the German Research Foundation (DFG).

Thyroid Hormone (TH) is the longest known neurotrophic factor for brain development. However, there is a profound data gap on understanding of TH transport and specific TH action within individual brain cell types. We are evaluating species- and cell-type specific TH transporter expression as well as TH-dependence of individual neurodevelopmental processes in a species-specific context. This information will form the basis for a better understanding of cellular TH disruption by environmental chemicals, contribute to building of TH-dependent AOPs and help establishing specific assays that aim to identify TH disruptors in a fast and reliable way.

Major cooperation partners are Prof. Dr. Pamela J. Lein (University of California, Davis, USA), Prof. Dr. Thomas Scanlan (Oregon Health & Science University, Portland, USA), Tom Knudsen, Kevin Crofton (both US EPA), PD Dr. Heike Heuer, PD Dr. Joachim Altschmiedt (both IUF).


Omnisphero

For a more efficient chemical testing the usage of HCA is encouraged. As evaluation software is generally designed for low density pure neuronal cell cultures, one cannot reliably study high density mixed 3D cultures, with these programs. Therefore, we have developed the novel software Omnisphero, to assess relevant endpoints of the ’Neurosphere Assay’ with high accuracy and precision. Omnisphero was developed as a user-friendly software by utilizing intuitive, supervised learning assisted, algorithms for a faster adaptation to the daily laboratory routine (www.omnisphero.com). In the future, this program will facilitate data evaluation of the Neurosphere Assay and enable analyses of mechanisms of highly complex endpoints like neuronal migration on a glia scaffold in vitro.

Major cooperation partner is Prof. Dr. Axel Mosig (Ruhr University Bochum).


Molecular aspects of skin aging

As we age, our skin ages intrinsically (pure chronological aging) and extrinsically (influenced by environmental factors like UV-irradiation). During extrinsic skin aging an increased degradation of collagen fibers is caused by the collagen-degrading enzyme matrix metalloproteinase-1 (MMP-1). MMP-1 is up-regulated by UV-irradiation, tobacco smoke as well as traffic related particulate matter, the latter two both containing polycyclic aromatic hydrocarbons e.g. benzo(a)pyrene (B(a)P). As UV-irradiation and B(a)P treatment leads to an activation of the aryl hydrocarbon receptor, we investigate the role of this molecule in extrinsic aging.

Main cooperation partners are Dr. Thomas Haarmann-Stemmann, Dr. Susanne Grether-Beck, Prof. Dr. Jean Krutmann, Prof. Dr. Petra Boukamp (all IUF), Prof. Dr. Karl Köhrer, Prof. Dr. Kai Stühler (both BMFZ, University Clinic Düsseldorf), Prof. Dr. Monika Schäfer-Korting (FU Berlin), Prof. Dr. Jens Fischer (Heinrich-Heine-University Düsseldorf), Prof. Dr. Fritz Boege (University Clinic Düsseldorf).


Molecular investigations of neurological defects observed in patients with nucleotide-excision-repair (NER)-deficiency by employment of iPS cells

funded by iBrain, the interdisciplinary graduate school for brain research and translational neuroscience at Heinrich Heine University Düsseldorf

Patients with genetically-determined defects in nucleotide-excision-repair (NER) exert a high photosensitivity. At the same time, such individuals display neurological symptoms although the central nervous system is protected against UV-induced DNA defects due to its anatomical location. Cockayne Syndrome (CS) is one of these diseases caused by a mutation either in the CSA or CSB gene with a higher prevalence in CSB. In this project, human induced pluripotent stem cells (hiPSCs) derived from CSB patients are differentiated into neurospheres to determine neurodevelopmental differences in CSB-hiPSC derived neurospheres compared to healthy controls.

Major cooperation partners are Prof. Dr. Jean Krutmann (IUF), Prof. Dieter Willbold (FZ Jülich), Prof.  Dr. James Adjaye (University Clinic Düsseldorf) and Prof. Dr. Jean-Marc Egly (Institut Génétique Biologie Moléculaire Cellulaire, Strasbourg).

Consultation for political organizations

Mrs. Fritsche is working group member of the panel ‚Plant Protection Products and their Residues’ (PPR): ‘Scientific Opinion of the PPR Panel investigating experimental toxicology data of pesticides and their potential link to Parkinson's disease and childhood leukaemia’ (European Food Safety Authority, EFSA). She is also member of the EU expert group: Horizon 2020 Advisory Group for health, demographic change and wellbeing (E02942).

Cooperations

IUF internal:
Haarmann-Stemmann junior research group
Haendeler research group
Heuer research group
Krutmann research group
Schins research group

National:
Prof. Dr. Adjaye, University Hospital Düsseldorf
Dr. Cornelia Prehn, Helmholtz Zentrum München (German Research Center for Environmental Health, Munich)
Prof. Dr. Orhan Aktas, University Hospital Düsseldorf
Prof. Dr. Karl Köhrer, BMFZ, University Hospital Düsseldorf
Prof. Dr. Kai Stühler, BMFZ, University Hospital Düsseldorf
Prof. Dr. Mosig, Ruhr University Bochum
Prof. Dr. Monika Schäfer-Korting, Freie Universität Berlin (one of the universities in Berlin)
Prof. Dr. Jens Fischer, Heinrich Heine University, Düsseldorf
Prof. Dr. Fritz Boege, University Hospital Düsseldorf

International:
Prof. Dr. Egly, IGBMC Strasbourg, France
Prof. Pamela J. Lein, UC Davis, California, USA
Dr. Anna Bal-Price, JRC Joint Research Center European Commission, Brussels, Belgium (Cooperation partner for AOPs, EFSA)
Tom Knudsen, Environmental Protection Agency, USA
Kevin Crofton, Environmental Protection Agency, USA
Hilda Witters, VITO, Belgium
Maria Teresa Colomina, Universität Rovira i Virgili, Tarragona, Spain
Prof. Dr. Thomas Scanlan, Oregon Health & Science University, USA

Selected publications

Bal-Price A, Crofton KM, Sachana M, Shafer TJ, Behl M, Forsby A, Hargreaves A, Landesmann B, Lein PJ, Louisse J, Monnet-Tschudi F, Paini A, Rolaki A, Schrattenholz A, Suñol C, van Thriel C, Whelan M, Fritsche E: Putative adverse outcome pathways relevant to neurotoxicity. Crit Rev Toxicol 45(1): 83-91, 2015. [pubmed]

Gassmann K, Schreiber T, Dingemans MM, Krause G, Roderigo C, Giersiefer S, Schuwald J, Moors M, Unfried K, Bergman Å, Westerink RH, Rose CR, Fritsche E: BDE-47 and 6-OH-BDE-47 modulate calcium homeostasis in primary fetal human neural progenitor cells via ryanodine receptor-independent mechanisms. Arch Toxicol 88(8): 1537-1548, 2014. [pubmed]

Tigges J, Weighardt H, Wolff S, Götz C, Förster I, Kohne Z, Huebenthal U, Merk HF, Abel J, Haarmann-Stemmann T, Krutmann J, Fritsche E: Aryl hydrocarbon receptor repressor (AhRR) function revisited: repression of CYP1 activity in human skin fibroblasts is not related to AhRR expression. J Invest Dermatol 133(1): 87-96, 2013. [pubmed]

Schreiber T, Gassmann K, Götz C, Hübenthal U, Moors M, Krause G, Merk HF, Nguyen NH, Scanlan TS, Abel J, Rose C, Fritsche E: Polybrominated Diphenyl Ethers Induce Developmental Neurotoxicity in a Human in Vitro Model: Evidence for Endoctrine Disruption. Environ Health Perspect 118(4): 572-578, 2010. [pubmed] (open access)

Gassmann K, Abel J, Bothe H, Haarmann-Stemmann T, Merk HF, Quasthoff KN, Rockel TD, Schreiber T, Fritsche E: Species-specific differential AhR-expression protects human neural progenitor cells against developmental neurotoxicity of PAHs. Environ Health Perspect 118: 1571–1577, 2010. [pubmed] (open access)