The Impact of the Exposome on Epithelial Barriers: New Approach Methodologies for Translational Research.

Environmental exposures experienced throughout life, collectively referred to as the exposome, play a fundamental role in shaping epithelial barrier integrity, repair capacity, and vulnerability to disease. These exposures encompass a broad spectrum of chemical, physical, biological, and lifestyle-related factors. Despite growing recognition of their importance, a key unresolved challenge is understanding how single exposures and, more importantly, complex real-world exposure mixtures jointly disrupt epithelial organization, stem and progenitor cell niches, and immune-epithelial communication across different organs. This review consolidates current evidence on environmentally relevant exposomes that directly affect epithelial barrier function and examines their consequences for tissue architecture, niche stability, and frontline defense mechanisms. We further discuss recent advances in new approach methodologies, including organ-specific epithelial barrier models, organoids, organ-on-a-chips, and interconnected multi-organ platforms. By synthesizing evidence across organ systems, we highlight convergent biological processes, such as oxidative stress, inflammatory signaling, disruption of intercellular junctions, and impaired epithelial survival or regeneration, as shared pathways linking environmental stressors to barrier failure. We hope that this review will help bridge exposure science, epithelial biology, and bioengineered human-based models to define critical knowledge gaps and key translational priorities for the field.