Research overview
The overall aim of the research in my group is to increase the understanding of how chemical factors may cause toxicity by altering critical biological pathways, and in contrast, how biological factors, such as inflammation, tissue damage or dysbiosis, may influence the outcome of chemical exposure. We are specifically focusing on biotransformation systems and how interactions between chemical/biological factors affecting these may impact immune function, metabolic signaling and cell differentiation. To study these pathways and functions we use a wide range of experimental models, including recombinant enzymes, tissue fractions, cell/organoid cultures and zebrafish, and methods such as toxicity assays, enzyme kinetics, transcriptomics, metabolomics and chromatography (HPLC, LC-MS, GC-MS). The major ongoing projects are briefly described below.
Project 1: The role of AHR/CYP1-feedback signalling in epithelial barrier 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, and how these are regulated. We previously reported on a critical role of the CYP1 enzyme family in regulating AHR signalling during zebrafish embryo development, intestinal immunity in mice and immune cell differentiation (Schiering C, Wincent E et al Nature 542, 2017).
The aim of this project is to investigate how the dichotomy of detrimental vs. beneficial functions of the AHR in might be resolved, focusing on AHR functions in epithelial stem cell differentiation by analysing related endpoints in cells, tissues, or serum from mice models with genetic alterations in the AHR or CYP1 pathways. In addition to stem cell differentiation, we are also investigating effects on metabolic and endocrine signalling. The project is funded by the Swedish Research Council (VR) and performed in collaboration with the research group led by Brigitta Stockinger at the Francis Crick Institute.
Project 2: Chemical impact on tissue repair and regeneration
The purpose of this project is to investigate the impact of xenobiotic chemicals on the ability to repair tissue damage, focusing on the role of the aryl hydrocarbon receptor (AHR) as mediator of key events of tissue repair. While the AHR is a transcription factor originally discovered for mediating the toxicity of xenobiotics, the discovery of natural ligands formed endogenously, present in the diet or formed by commensal microbiota has pinpointed important functions of the AHR in e.g. barrier organs such as the skin, lung, and gut. Successful tissue repair depends on synchronized and tightly controlled action of the immune system and proliferation/differentiation of tissue-specific stem cells at the site of injury, processes in which physiological AHR signalling has proven to be critical.
The aim of this project is to determine if and how xenobiotic chemicals may interfere with tissue repair processes by subverting AHR from its physiological functions, and to determine the consequences of such interference. This is achieved using zebrafish models for tissue repair and regeneration, and by combining OMICS-based effect screening with targeted analysis of markers for tissue integrity and inflammatory signalling. The project is financed by the Swedish Research Council Sustainable Development (FORMAS).