Project 1: The role of AHR/CYP1-feedback signalling in endocrine signalling and energy homeostasis
The aryl hydrocarbon receptor (AHR), also known as the dioxin receptor, is renowned in toxicology for mediating the adverse effects of environmental pollutants such as dioxins and dioxin-like PCBs. These adverse effects include for example immunotoxicity, reproductive toxicity, endocrine disruption and carcinogenesis.
While the toxicity of AHR signalling has been the focus for the last 40 years within the AHR-field, the focus is more and more shifting to understanding the physiological functions of this receptor pathway. What is known today is that the AHR appears to have critical functions in immune system function, haematopoiesis, cell differentiation processes, hormone secretion and much more. However, how these physiological functions of the AHR are regulated is still unknown.
We previously reported on a critical role of the CYP1 enzyme family in regulating AHR signalling during zebrafish embryo development and intestinal immunity in mice. The aim of this study is to investigate the role of AHR signalling and CYP1 function in endocrine signalling and energy homeostasis by analysing related endpoints in tissues or serum samples obtained from mice models with genetic alterations in the AHR or CYP1 pathways.
Project 2: Impact of inflammatory factors on chemical toxicity
This project aims to understand the effect of intestinal inflammation on the internal dose and metabolism of environmental chemicals, their distribution to target organs and ability of the chemicals and their metabolites to interact with biological targets.
The biological effects of chemical exposure largely depend on the toxicokinetic properties referred to as ADME, i.e. how a chemical is Absorbed, Distributed, Metabolized, and Excreted. Thus, alterations in any of these properties may significantly impact chemical toxicity. In humans, the gastro-intestinal (GI) tract is a major route of exposure to environmental chemicals. What is overlooked is how intestinal inflammation influences ADME and toxicity of environmental chemicals and thereby if individuals with intestinal inflammation may be at higher risk of chemically induced toxicity.
Around 0.5% of the general population in industrialized countries is diagnosed with chronic intestinal inflammation such as ulcerative colitis and crohn´s disease, with numbers increasing exponentially. Moreover, bacterial pathogens, viral infections, exposure to drugs and autoimmunity may also induce different degrees of inflammation in the gut.
The aim of this project is to identify and describe the impact of intestinal inflammation on local and systemic toxicity of chemical exposure by combining analysis of human samples from patients with intestinal inflammation with in vivo and in silico models.
Project 3: Toxicokinetic modelling of internal dose in zebrafish (Danio rerio) embryo
The zebrafish embryo is increasingly used as a vertebrate animal model to assess adverse effects of chemicals. The acceptance of such tests from a health risk assessment perspective relies on the possibility to extrapolate toxicity data from zebrafish embryo tests to humans, similar to the extrapolations from laboratory animals such as mice and rats carried out today.
Until now, little attention has been paid to the relation between external and internal dose in fish embryos. Detailed knowledge of the toxicokinetic processes including adsorption, distribution and the resulting target dose, and physiologically based toxicokinetic (PBTK) models are frequently used to characterize the internal dose and to extrapolate animal toxicity data to humans.
The aim of this study is to develop a better understanding of the toxicokinetics and target dose of chemical substances in the zebrafish embryo by a combination of experimental toxicokinetic studies and mathematical modelling.
- Assoc. Prof. Maria Jönsson, Unit of Environmental Toxicology, Uppsala University
- Prof. Gunnar Johansson, Institute of Environmental Medicine, Karolinska Institutet
- Assoc. Prof. Kristian Dreij, Institute of Environmental Medicine, Karolinska Institutet
- Assoc. Prof. Eduardo Villablanca, Department of Medicine, Karolinska Institutet
- Prof. Margareta Törnqvist, Department of Environmental Science and Analytical Chemistry, Stockholm University
- Assoc. Prof. Åsa Keita, Department of Clinical and Experimental Medicine, Linköping University
- PhD, MD. Pär Myrelid, Department of Clinical and Experimental Medicine, Linköping University
- Prof. Brigitta Stockinger, the AHR Immunity lab, The Francis Crick Institute, London, UK
- Assoc. Prof. Chris Schiering, the Inflammation and Obesity Lab, Imperial College, London, UK
- Prof. Mark Hahn, Woods Hole Oceanographic Institution, Woods Hole, US
- Prof. John Stegeman, Woods Hole Oceanographic Institution, Woods Hole, US
- Prof. Oliver Poetz, Natural and Medical Sciences Institute, University of Tuebingen, Reutlingen. Germany
Cytochrome P4501-inhibiting chemicals amplify aryl hydrocarbon receptor activation and IL-22 production in T helper 17 cells.
Biochem. Pharmacol. 2018 05;151():47-58
Feedback control of AHR signalling regulates intestinal immunity. Schiering C, Wincent E, Metidji A, Iseppon A, Li Y, Potocnik AJ, Omenetti S, Henderson CJ, Wolf CR, Nebert DW, Stockinger B. Nature. 2017 Feb 9;542(7640):242-245.
Biological effects of 6-formylindolo[3,2-b]carbazole (FICZ) in vivo are enhanced by loss of CYP1A function in an Ahr2-dependent manner. Wincent E, Kubota A, Timme-Laragy A, Jönsson ME, Hahn ME, Stegeman JJ. Biochem Pharmacol. 2016 Jun 15;110-111:117-29
Induction and inhibition of human cytochrome P4501 by oxygenated polycyclic aromatic hydrocarbons. Wincent E, Le Bihanic F, Dreij K. Toxicol. Res. 2016 Mar 5:788-99
Evidence for new light-independent pathways for generation of the endogenous aryl hydrocarbon receptor agonist FICZ. Smirnova A, Wincent E, Vikström Bergander L, Alsberg T, Bergman J, Rannug A, Rannug U. Chem Res Toxicol. 2016 Jan 19;29(1):75-86.
Combination effects of AHR agonists and Wnt/β-catenin modulators in zebrafish embryos: Implications for physiological and toxicological AHR functions. Wincent E, Stegeman JJ, Jönsson ME. Toxicol Appl Pharmacol. 2015 Apr 15;284(2):163-79
Quercetin, resveratrol, and curcumin are indirect activators of the aryl hydrocarbon receptor (AHR). Mohammadi Bardbori A, Bengtsson J, Rannug U, Rannug A, Wincent E. Chem Res Toxicol. 2012 Sep 17;25(9):1878-84.
Inhibition of cytochrome P4501 as a novel mechanism of Ah receptor activation. Wincent E, Bengtsson J, Mohammadi Bardbori A, Alsberg T, Luecke S, Rannug U, Rannug A. Proc Natl Acad Sci U S A. 2012 Mar 20;109(12):4479-84.
Cytochrome P450 1A1 gene regulation by UVB involves crosstalk between the aryl hydrocarbon receptor and nuclear factor kappa B. Luecke S, Wincent E, Backlund M. Rannug U, Rannug A. Chem. Biol. Interact. 2010 Mar 30;184(3):466-73.