Role of endocrine disruptors in atopic dermatits

Wider research context: Atopic dermatitis (AD) is the most common inflammatory skin disease worldwide and the initial step of the so-called atopic march. The prevalence of this disease can reach up to 18% of the adult population and is constantly increasing. The limited impact of genetic predisposition and the increasing incidence of AD in past decades emphasize the contribution of environmental factors in disease etiology. Endocrine disruptors (EDs) have been recurrently associated with AD in several cross-sectional studies. However, the involvement of these molecules in AD pathogenesis and their mechanism of action remain uninvestigated. Hypotheses and objectives: Our preliminary data strongly indicate a role of EDs in AD pathogenesis via perturbations of epidermal homeostasis and alterations of the epidermal immunological profile. Thus, we hypothesize that repeated skin exposure to EDs present in a myriad of products used in everyday life promotes the transition from healthy or genetically predisposed skin to AD. This project will focus on 4 objectives: (1) uncover and decipher the molecular pathways through which EDs promote AD, (2) identify genetic variants which lower epidermal resilience to EDs (gene-environment interactions), (3) demonstrate in vivo the role of EDs in AD pathogenesis and the atopic march (4) identify entry routes of EDs in AD patients. Methods: We will utilize 3D organotypic human epidermal equivalents (HEEs) made with healthy donor keratinocytes topically treated with EDs that we will compare with HEEs made with keratinocytes from AD patients. Metabolism, ED-receptor signaling, inflammation, and oxidative stress will be studied in details by using state-of-the-art techniques. We will also topically apply low doses of EDs to HEEs made with keratinocytes from donors with specific single nucleotide polymorphisms (SNPs) to uncover genetic variants that lower epidermal resilience to EDs. Then, mice will be topically treated with EDs, and local and systemic AD-like features will be assessed to demonstrate the role of these noxious molecules in AD pathogenesis and in the atopic march as well as in gene-environment interactions. Moreover, EDs will be assessed in various AD patient matrices (blood, hair, urine and skin D-squames) to identify entry routes in AD patients. Level of originality: Although EDs are believed to increase AD incidence, their primary role in AD pathogenesis or as potentializers in predisposed populations has never been studied. Moreover, we will challenge the hypothesis, that impairment of the epidermal barrier favors the penetration of pollutants in the skin. Primary researchers involved: Sandrine Dubrac is Associate Professor at the Department of Dermatology of Innsbruck (Austria) and hold/held grants from the FWF (FWF P21449, FWF P28039, FWF31662).