Chemical Exposome and Epithelial Barrier Dysfunction in Allergic Disease: Translational Pathways to Barrier-Targeted Therapeutics

The accumulation of synthetic chemicals in the human environment including airborne particulate matter, industrial pollutants, microplastics, endocrine-disrupting compounds, and household chemical agents has emerged as a primary upstream driver of epithelial barrier dysfunction across respiratory and cutaneous tissues. Unlike biological allergen exposures, these chemical and synthetic components of the exposome exert direct physicochemical effects on tight junction architecture, barrier lipid composition, and epithelial cell integrity, rendering the airway mucosa and skin susceptible to immune dysregulation. Growing evidence now positions chemically induced barrier failure, rather than sensitization to allergens alone, as a foundational mechanism in the onset and perpetuation of allergic disease.

A critical consequence of this chemically driven barrier failure is the dysregulated release of epithelial alarmins, including thymic stromal lymphopoietin (TSLP), IL-33, and IL-25. Crucially, in this context these signals function not as autonomous inflammatory mediators, but as the direct molecular readout of barrier breach induced by chemical exposome pressure. Understanding alarmin activation as a downstream, barrier-contingent event rather than a primary immune phenomenon reframes the mechanistic architecture of allergic disease and opens distinct avenues for intervention at the barrier level itself. This mechanistic continuum, from chemical exposure to barrier disruption to alarmin-mediated immune cascade, remains incompletely mapped and underrepresented in the therapeutic landscape.

This Research Topic aims to consolidate cutting-edge research that follows this causal chain from exposome to epithelium to immune activation, with a specific translational goal: identifying and validating interventions that act directly on the epithelial barrier axis. Rather than broad allergy precision medicine or endotype-based stratification, the therapeutic focus of this Topic is deliberately narrow, focusing on strategies that restore tight junction integrity, reinforce barrier lipid architecture, suppress chemically triggered alarmin release, or regenerate functional epithelium. These include barrier-restorative biologics (e.g., agents targeting the TSLP-barrier feedback loop), epithelial repair compounds, barrier-protective topical formulations, and emerging regenerative approaches validated in translational models of chemical exposure. Microbiome-modulating interventions are considered within this Topic only insofar as they demonstrably act on epithelial barrier competence as their primary mechanism, not as standalone probiotic or microbial ecology research.

A parallel aim is the development of epithelial barrier-specific biomarkers that reflect chemical exposome burden and predict disease trajectory; for example, circulating or tissue-level markers of tight junction disruption, alarmin stoichiometry relative to barrier integrity scores, or epidermal barrier lipid profiles as quantitative surrogates of exposome impact. These biomarkers serve a distinct function from general allergy diagnostic panels: they are designed to measure the barrier as an organ under chemical stress and to guide barrier-directed therapeutic decisions.

Key guiding questions include:
• Which classes of synthetic chemical exposures cause the most severe and persistent epithelial barrier impairment, and through which molecular mechanisms?
• How does the sequence from chemical barrier breach to alarmin release determine immune trajectory in skin versus airway epithelium?
• Which barrier-restorative or barrier-protective strategies (biological, chemical, or regenerative) have the strongest translational evidence for reversing chemically induced epithelial dysfunction?
• And which biomarkers of barrier failure most reliably predict clinical allergy severity and therapeutic response?

We welcome Original Research, Reviews, Mini Reviews, Clinical Trials, Perspectives, and Brief Research Reports addressing, but not limited to, the following themes:
o Direct effects of synthetic pollutants, microplastics, and endocrine-disrupting compounds on airway and skin epithelial barrier integrity
o Molecular mechanisms of chemical exposome-induced tight junction disruption, barrier lipid remodeling, and epithelial cell death
o Epithelial alarmin release (TSLP, IL-33, IL-25) as a downstream consequence of chemically induced barrier failure, mechanisms and immune sequelae
o Epithelial barrier-derived biomarkers of chemical exposome burden and allergic disease severity
o Barrier-restorative biologics, barrier-protective compounds, and regenerative epithelial therapies validated in translational exposome models
o Translational and pre-clinical models linking defined chemical exposures to measurable barrier dysfunction and downstream immune outcomes

Collectively, these contributions will map the mechanistic continuum from chemical exposome pressure to epithelial barrier failure to immune activation and advance the development of therapeutics that restore barrier competence as the primary clinical goal in allergy.

Article types and fees

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Classification
• Clinical Trial
• Community Case Study
• Data Report
• Editorial
• FAIR² Data
• General Commentary
• ... View all formats

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Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Classification
• Clinical Trial
• Community Case Study
• Data Report
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Policy and Practice Reviews
• Policy Brief
• Review
• Study Protocol
• Systematic Review
• Technology and Code

Keywords: Chemical exposome, Synthetic pollutants, Microplastics, Endocrine-disrupting compounds, Epithelial barrier dysfunction, Tight junction integrity, Airway epithelium, Skin barrier integrity, Barrier-induced alarmin signaling, TSLP, IL-33, IL-25, Epithelial immune crosstalk, Barrier-restorative biologics, Epithelial repair, Barrier-targeted therapeutics, Epithelial barrier biomarkers, Host-environment interactions, Translational allergy research, Epithelial remodeling

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.