Emma Wincent

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.

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).

Additional areas of ongoing research and collaborations include studies on environmentally relevant mixtures found in the Baltic see, indoor environments, or drinking water, the role of gut microbiome in mediating chemical effects on metabolic health, as well as the use of zebrafish and OMICS data in regulatory risk assessment through adverse outcome pathway methodology. These projects, supported by national and international funding bodies such as FORMAS, Vetenskapsrådet, and the European Union, underscore my strive to improve the understanding of toxicological processes that impact both human and wildlife health and environmental sustainability.

The impact of indoor air exposure on human health is assessed in the HORIZON Europe project INQUIRE (2022-2027), aimed at improving indoor air quality through the identification of chemical and biological determinants, with potential applications in creating healthier living environments across Europe. NEMESIS (2024-2028) is another Horizon Europe funded project I am taking part in, focusing on the development of novel biomarkers to assess the impact of metabolic disruptors, aiming to bridge the gap between scientific knowledge and policy needs. In both these projects, I am responsible for assessing molecular and functional effects of chemicals and chemical mixtures using zebrafish and human cell culture models.

Selected publications
Kinetics and toxicity of an environmentally relevant mixture of halogenated organic compounds in zebrafish embryo [1]. Lindqvist D, Wincent E. Aquatic Toxicology. 2022 Nov.

AHR in the intestinal microenvironment: safeguarding barrier function. Stockinger B, Shah K, Wincent E. Nature Reviews Gastroenterol Hepatol. 2021 Mar 19.

Toxicokinetics of Perfluorinated Alkyl Acids Influences Their Toxic Potency in the Zebrafish Embryo (/Danio rerio/) [3]. Vogs C, Johansson G, Näslund M, Wulff S, Sjödin M, Hellstrandh M, Lindberg J, Wincent E. Environ Sci Technol. 2019 Apr 2;53(7):3898-3907.

Cytochrome P4501-inhibiting chemicals amplify aryl hydrocarbon receptor activation and IL-22 production in T helper 17 cells [4]. Schiering C, Vonk
A, Das S, Stockinger B, Wincent E. Biochem Pharmacol. 2018 May;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. [7]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 [8]. 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 [9]. 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 [13]. Luecke S, Wincent E, Backlund M. Rannug U, Rannug A. Chem. Biol. Interact. 2010 Mar 30;184(3):466-73.