Joëlle Rüegg, PhD – Associate professor
The research focus of the Epigenetic Toxicology team is how endocrine disrupting chemicals affect epigenetic patterns, and how such effects link to common human diseases.
What is the problem?
We are exposed to a cocktail of thousands of chemicals on an everyday basis, some of which have the property to interfere with our endogenous hormonal system. Exposure to these so-called endocrine disrupting chemicals (EDCs) is associated with a number of diseases drastically increasing in the population, such as obesity, infertility, and neurodevelopmental disorders. Epigenetics represents the most likely mechanism underlying later life diseases resulting from early life exposures as epigenetic processes drive early development. Thus, epigenetic changes induced by EDCs could be highly valuable markers to predict disease susceptibility.
Why is our research needed?
Whilst there is growing evidence from both epidemiological and experimental studies to support an important role of epigenetics in the EDC field, there is still a lack of
a) Mechanistic insights how EDCs affect epigenetic regulation, and
b) Conclusive links between exposure, epigenetic changes and adversity.
What do we do?
Our team combines mechanistic studies in cellular models, analyses of exposed experimental animals, and insights from epidemiological data (see figure). Using this interdisciplinary approach, we hope to contribute to clarify the risks posed by EDC-exposure in early life and to develop methods assessing epigenetic endpoints that can be ultimately integrated into chemical risk assessment procedures.
Methods we use include:
- Cell culturing including stem cell differentiation
- Gene expression and epigenetic analyses (e.g. bisulfite Pyrosequencing) in cells, animal and human tissue
- Imaging (e.g. Fluorescence Cross Correlation Spectroscopy)
- Molecular cloning
Ali Alavian-Ghavanini, PhD
Elin Engdahl, PhD
Nina Johanesson, BSc
Interaction between EDC targets and epigenetic regulators
We have found that the EDC targets such as the estrogen receptor b (ERb) interacts with the epigenetic regulator thymine DNA glycosylase (TDG), thus regulating DNA methylation patterns at the estrogen receptor b (ERb) interacts with the epigenetic regulator thymine DNA glycosylase (TDG), thus regulating DNA methylation patterns at specific genomic regions. Disturbance of this interaction by EDCs could underlie epigenetic effects of these chemicals. We are in the process of developing cell-based methods to directly measure the interaction between TDG and ERb as well as other hormone receptors affected by EDCs. Subsequently we will measure if known EDCs can interfere with this interaction. This will lead to the identification of a molecular event underlying epigenetic changes induced by EDCs, which can subsequently be used to screen other chemicals for their potential to induce epigenetic changes via hormonal receptors. This project is carried out by Ali Alavian-Ghavanini .
Linking epigenetic patterns in exposed animals to human exposure and health outcomes
In several projects, we are linking epigenetic changes found in relevant tissues in developmentally exposed rats to human exposure and/or adverse health outcomes. For example, we have found that developmental exposure of rats to the EDC bisphenol A induces epigenetic changes in Grin2b, a gene coding for an NMDA-receptor subunit and associated with diseases such as ADHD and schizophrenia. We are now investigating if we can associate epigenetic changes at Grin2b with prenatal BPA exposure and neurodevelopmental outcomes in children.
Understanding the impact of EDCs on the blood-brain barrier (BBB)
In a new project, we will investigate the effects of EDCs on development and functioning of the blood-brain barrier (BBB). Dysfunction of the blood-brain barrier (BBB) is emerging as a common denominator for neurodevelopmental disorders. In a first step, we will identify EDCs that reach the human fetal brain and are associated with impaired neurodevelopment. This will be achieved by measuring 46 suspected EDCs in brain samples from stillbirths and associate the measurable ECDs with neurodevelopmental outcomes in a pregnancy cohort study. The identified chemicals will subsequently be tested in state-of-the-art human in vitro BBB systems, including organs-on-chips, for their effects on BBB function as well as on the differentiation of the cells that constitute the BBB.
The EDC-MixRisk project
EDC-MixRisk is a Horizon 2020 research and innovation programme including 12 partners . Its aim is to determine risks for adverse health outcomes after early life exposure to EDC mixtures, based on the identification of involved molecular mechanisms. It has the following work-flow:
- Identifying EDC mixtures that are associated with multiple adverse health outcomes in three health domains in an epidemiological study;
- Identifying molecular mechanisms and pathways underlying the associations between exposure and adverse health outcomes by testing these mixtures in experimental models and
- Developing a transparent and systematic framework in risk assessment for integrating epidemiological and experimental research.
Our activities within EDC-MixRisk focus on two main tasks:
- Investigating the effects of the growth and metabolism-related EDC mixtures on adipogenesis and osteogenesis in vitro, and
- Measuring and comparing DNA methylation patterns in all experimental systems included in EDC-MixRisk, and in samples of children involved in the epidemiological study.
This project is carried out by Elin Engdahl.
- Swedish Research Council Formas
- European commission’s Horizon 2020 program
- Swedish Research Council (Vetenskapsrådet)
At Karolinska Institutet
- Prof. Tomas Ekström, Department of Clinical Neuroscience
- Dr. Catharina Lavebratt, Department of Molecular Medicine and Surgery
- Dr. Ivan Nalvarte, Department of Biosciences and Nutrition
- Prof. Sandra Ceccatelli, Department of Neuroscience
- Dr. Pia Steensland, Department of Clinical Neuroscience
- Prof. Olle Söder, Department of Women’s and Children’s health
At other Swedish Universities
- Prof. Joachim Sturve, Göteborg University
- Prof. Carl-Gustaf Bornehag, Karlstad University
- Prof. Helen Karlsson, Linköping University
- Prof. Christina Rudén, Stockholm University
- Anna Herland, KTH
- Dr. Ylva Sjunnesson, Swedish University of Agricultural Sciences (SLU)
- Dr. Maria Jönsson, Uppsala University
- Drs Monica Lind and Margareta Halin Lejonklou, Uppsala University
- Steffen Keiter, Örebro University
At international Institutions (not including the 38 partners of the EC-funded EUToxRisk project)
- Dr. Efthymia Kitraki, School of Health Sciences, University of Athens, Greece
- Dr. Giuseppe Testa, European Institute of Oncology (IEO) Milan, Italy
- Prof. Barbara Demeneix, Muséum National d’Histoire Naturelle, Paris, France
- Prof. Chris Gennings, Mount Sinai School of Medicine New York, USA
- Dr. Hannu Kiviranta, National Institute for Health and Welfare, Finland
- Prof. Wieland Kiess, University of Leipzig, Germany
- Dr. Yun Liu, Fudan University, Shanghai, China
- Drs Miriam Jacobs and Emma Marczylo, Public Health England
- Dr. Theo Rein, Max Planck Institute of Psychiatry, Munich, Germany
- Prof. Gunter Schumann, King’s College, London, UK
- Dr. Christian Unger, Department of Biomedical Sciences, University of Sheffield
Feltmann K, Borroto-Escuela DO, Rüegg J, Pinton L, de Oliveira Sergio T, Narváez M, Jimenez-Beristain A, Ekström TJ, Fuxe K, Steensland P. Effects of Long-Term Alcohol Drinking on the Dopamine D2 Receptor: Gene Expression and Heteroreceptor Complexes in the Striatum in Rats. Alcohol Clin Exp Res. 2018 Feb;42(2):338-351. doi: 10.1111/acer.13568. Epub 2018 Jan 24. PMID: 29205397
Lupu D, Sjödin MOD, Varshney M, Lindberg J, Loghin F, Rüegg J. Fluoxetine modulates sex steroid levels in vitro. Clujul Med. 2017;90(4):420-424. doi: 10.15386/cjmed-868. Epub 2017 Oct 20.
Varshney MK, Inzunza J, Lupu D, Ganapathy V, Antonson P, Rüegg J, Nalvarte I, Gustafsson JÅ. Role of estrogen receptor beta in neural differentiation of mouse embryonic stem cells. Proc Natl Acad Sci U S A. 2017 Nov 28;114(48):E10428-E10437. doi: 10.1073/pnas.1714094114. Epub 2017 Nov 13.
The biosocial genome? Interdisciplinary perspectives on environmental epigenetics, health and society. Müller R, Hanson C, Hanson M, Penkler M, Samaras G, Chiapperino L, Dupré J, Kenney M, Kuzawa C, Latimer J, Lloyd S, Lunkes A, Macdonald M, Meloni M, Nerlich B, Panese F, Pickersgill M, Richardson S, Rüegg J, Schmitz S, Stelmach A, Villa PI. EMBO Rep. 2017 Oct;18(10):1677-1682. doi: 10.15252/embr.201744953. Epub 2017 Sep 20.
Birgersson L, Borbely G, Caporale N, Germain P-L, Leemans M, Rendel F, D’Agostino G, Bardini Bressan R, Cavallo F, Even Chorev N, Munic Kos V, Lazzarin M, Pollard S, Sundstrom B, Lopez Tobon A, Trattaro S, Zanella M, Bergman A, Damdimopoulou P, Jonsson M, Kiess W, Kitraki E, Kiviranta H, Oberg M,. Rantakkoko P, Ruden C, Soder O, Bornehag CG, Demeneix B, Fini J-B, Gennings C, Nanberg E, Rüegg J*, Sturve J and Testa G. From Cohorts to Molecules: Adverse Impacts of Endocrine Disrupting Mixtures. Deposited as preprint on BioRxiv (https://doi.org/10.1101/206664) *shared senior and corresponding author
Jacobs MN, Marczylo EL, Guerrero-Bosagna C, Rüegg J. Marked for Life: Epigenetic Effects of Endocrine Disrupting Chemicals. Annual Review of Environment and Resources 2017 42:1, 105-160.
Understanding Epigenetic Effects of Endocrine Disrupting Chemicals: From Mechanisms to Novel Test Methods. Alavian-Ghavanini A, Rüegg J. Basic Clin Pharmacol Toxicol. 2018 Jan;122(1):38-45. doi: 10.1111/bcpt.12878. Epub 2017 Sep 14. Review.
Barde S, Rüegg J, Prud’homme J, Ekström TJ, Palkovits M, Turecki G, Bagdy G, Ihnatko R, Theodorsson E, Juhasz G, Diaz-Heijtz R, Mechawar N, Hökfelt TG. Alterations in the neuropeptide galanin system in major depressive disorder involve levels of transcripts, methylation, and peptide. Proc Natl Acad Sci U S A. 2016 Dec 27;113(52):E8472-E8481. doi: 10.1073/pnas.1617824113. PubMed PMID: 27940914; PubMed Central PMCID: PMC5206567.
Liu Y, Duong W, Krawczyk C, Bretschneider N, Borbély G, Varshney M, Zinser C, Schär P, Rüegg J. Oestrogen receptor β regulates epigenetic patterns at specific genomic loci through interaction with thymine DNA glycosylase. Epigenetics Chromatin. 2016 Feb 16;9:7. doi: 10.1186/s13072-016-0055-7. PubMed PMID:26889208; PubMed Central PMCID: PMC4756533.
Gassen NC, Fries GR, Zannas AS, Hartmann J, Zschocke J, Hafner K, Carrillo-Roa T, Steinbacher J, Preißinger SN, Hoeijmakers L, Knop M, Weber F, Kloiber S, Lucae S, Chrousos GP, Carell T, Ising M, Binder EB, Schmidt MV, Rüegg J, Rein T. Chaperoning epigenetics: FKBP51 decreases the activity of DNMT1 and mediates epigenetic effects of the antidepressant paroxetine. Sci Signal. 2015 Nov 24;8(404):ra119. doi: 10.1126/scisignal.aac7695. PubMed PMID: 26602018.
Nalvarte I, Damdimopoulos AE, Rüegg J, Spyrou G. The expression and activity of thioredoxin reductase 1 splice variants v1 and v2 regulate the expression of genes associated with differentiation and adhesion. Biosci Rep. 2015 Oct 13;35(6). pii: e00269. doi: 10.1042/BSR20150236. PubMed PMID: 26464515; PubMed Central PMCID: PMC4660583.
Kitraki E, Nalvarte I, Alavian-Ghavanini A, Rüegg J. Developmental exposure to bisphenol A alters expression and DNA methylation of Fkbp5, an important regulator of the stress response. Mol Cell Endocrinol. 2015 Dec 5;417:191-9. doi: 10.1016/j.mce.2015.09.028. PubMed PMID: 26427651.
Fries GR, Vasconcelos-Moreno MP, Gubert C, dos Santos BT, Sartori J, Eisele B, Ferrari P, Fijtman A, Rüegg J, Gassen NC, Kapczinski F, Rein T, Kauer-Sant’Anna M. Hypothalamic-pituitary-adrenal axis dysfunction and illness progression in bipolar disorder. Int J Neuropsychopharmacol. 2014 Oct 31;18(1). pii: pyu043. doi: 10.1093/ijnp/pyu043. PubMed PMID: 25522387; PubMed Central PMCID: PMC4368875.
Karpyak VM, Biernacka JM, Geske JR, Jenkins GD, Cunningham JM, Rüegg J, Kononenko O, Leontovich AA, Abulseoud OA, Hall-Flavin DK, Loukianova LL, Schneekloth TD, Skime MK, Frank J, Nöthen MM, Rietschel M, Kiefer F, Mann KF, Weinshilboum RM, Frye MA, Choi DS. Genetic markers associated with abstinence length in alcohol-dependent subjects treated with acamprosate. Transl Psychiatry. 2014 Oct 7;4:e462. doi: 10.1038/tp.2014.103. PubMed PMID: 25290263; PubMed Central PMCID: PMC4350512.
Swedenborg E, Kotka M, Seifert M, Kanno J, Pongratz I, Rüegg J. The aryl hydrocarbon receptor ligands 2,3,7,8-tetrachlorodibenzo-p-dioxin and 3-methylcholanthrene regulate distinct genetic networks. Mol Cell Endocrinol. 2012 Oct 15;362(1-2):39-47. doi: 10.1016/j.mce.2012.05.006. PubMed PMID: 22634562.
Tammimies K, Tapia-Páez I, Rüegg J, Rosin G, Kere J, Gustafsson JÅ, Nalvarte I. The rs3743205 SNP is important for the regulation of the dyslexia candidate gene DYX1C1 by estrogen receptor β and DNA methylation. Mol Endocrinol. 2012 Apr;26(4):619-29. doi: 10.1210/me.2011-1376. PubMed PMID: 22383464.
10: Rüegg J, Cai W, Karimi M, Kiss NB, Swedenborg E, Larsson C, Ekström TJ, Pongratz I. Epigenetic regulation of glucose transporter 4 by estrogen receptor β. Mol Endocrinol. 2011 Dec;25(12):2017-28. doi: 10.1210/me.2011-1054. PubMed PMID: 22016564; PubMed Central PMCID: PMC3231832.
Swedenborg E, Power KA, Cai W, Pongratz I, Rüegg J. Regulation of estrogen receptor beta activity and implications in health and disease. Cell Mol Life Sci. 2009 Dec;66(24):3873-94. doi: 10.1007/s00018-009-0118-z. Review. PubMed PMID: 19669093.
Schuchardt JP, Wahlström D, Rüegg J, Giese N, Stefan M, Hopf H, Pongratz I, Håkansson H, Eichele G, Pettersson K, Nau H. The endogenous retinoid metabolite S-4-oxo-9-cis-13,14-dihydro-retinoic acid activates retinoic acid receptor signalling both in vitro and in vivo. FEBS J. 2009 Jun;276(11):3043-59. doi: 10.1111/j.1742-4658.2009.07023.x. PubMed PMID: 19490107.
Laenger A, Lang-Rollin I, Kozany C, Zschocke J, Zimmermann N, Rüegg J, Holsboer F, Hausch F, Rein T. XAP2 inhibits glucocorticoid receptor activity in mammalian cells. FEBS Lett. 2009 May 6;583(9):1493-8. doi: 10.1016/j.febslet.2009.03.072. PubMed PMID: 19375531.
Swedenborg E, Rüegg J, Mäkelä S, Pongratz I. Endocrine disruptive chemicals: mechanisms of action and involvement in metabolic disorders. J Mol Endocrinol. 2009 Jul;43(1):1-10. doi: 10.1677/JME-08-0132. Review. PubMed PMID: 19211731.
Rüegg J, Penttinen-Damdimopoulou P, Mäkelä S, Pongratz I, Gustafsson JA. Receptors mediating toxicity and their involvement in endocrine disruption. EXS. 2009;99:289-323. Review. PubMed PMID: 19157066.
16: Swedenborg E, Rüegg J, Hillenweck A, Rehnmark S, Faulds MH, Zalko D, Pongratz I, Pettersson K. 3-Methylcholanthrene displays dual effects on estrogen receptor (ER) alpha and ER beta signaling in a cell-type specific fashion. Mol Pharmacol. 2008 Feb;73(2):575-86. PubMed PMID: 18003862.
Rüegg J, Swedenborg E, Wahlström D, Escande A, Balaguer P, Pettersson K, Pongratz I. The transcription factor aryl hydrocarbon receptor nuclear translocator functions as an estrogen receptor beta-selective coactivator, and its recruitment to alternative pathways mediates antiestrogenic effects of dioxin. Mol Endocrinol. 2008 Feb;22(2):304-16. PubMed PMID: 17991765.
18: Wochnik GM, Rüegg J, Abel GA, Schmidt U, Holsboer F, Rein T. FK506-binding proteins 51 and 52 differentially regulate dynein interaction and nuclear translocation of the glucocorticoid receptor in mammalian cells. J Biol Chem. 2005 Feb 11;280(6):4609-16. PubMed PMID: 15591061.
Rüegg J, Holsboer F, Turck C, Rein T. Cofilin 1 is revealed as an inhibitor of glucocorticoid receptor by analysis of hormone-resistant cells. Mol Cell Biol. 2004 Nov;24(21):9371-82. PubMed PMID: 15485906; PubMed Central PMCID: PMC522229.
Abel GA, Wochnik GM, Rüegg J, Rouyer A, Holsboer F, Rein T. Activity of the GR in G2 and mitosis. Mol Endocrinol. 2002 Jun;16(6):1352-66 12040020.
Marked for Life: How Environmental Factors affect the Epigenome.
Damdimopoulou P, Weis S, Nalvarte I, Rüegg J. In: I. Pongratz, L. V. Bergander (eds): Hormone-disruptive Chemical Contaminants in Food (2011), RSC Publishing, 44-69.
Coregulators in Toxicology.
Rüegg, J, Hedengran-Faulds M, Hase M, Pongratz I and Gustafsson J-Å. In: R. Kumar, B. W. O’Malley (eds): Nuclear Receptor Coregulators and Human Diseases (2008), World Scientific Publishing, 519-538.
Receptors mediating toxicity and their involvement in endocrine disruption.
Rüegg J, Penttinen-Damdimopoulou P, Mäkelä S, Pongratz I and Gustafsson J-Å. In A. Luch (ed): Molecular, Clinical, and Environmental Toxicology, Volume 1: Molecular Toxicology (2008), Birkhäuser Verlag, 289-324.
Popular science articles
Cocktail-effekten – farligare än man trott.
Bornehag CG, Bergman Å, Rudén C, Rüegg J. VVS Forum, October 2015
Bisfenol A ökar känsligheten för stress.
Joëlle Rüegg, Identification of cofilin as a novel inhibitor of the glucocorticoid receptor using a functional genetic screen , 2004.
Please contact Joëlle Rüegg if you would like to do a Master/Bachelor project or internship with us.