Microphysiological systems as a pillar of the Human Exposome Project.

The Human Exposome Project (HEP) aims to decode how lifelong environmental exposures shape health and disease, complementing genomic insights with a systems-level understanding of external influences. Achieving this vision requires experimental platforms that move beyond the limitations of animal models, which often lack human relevance and mechanistic resolution. Microphysiological systems (MPSs)-including organoids and organs-on-chips derived from human stem cells-offer such an opportunity. These engineered models recapitulate human tissue architecture and function under controlled conditions, enabling direct study of exposure-response relationships at the cellular and organ levels. In this review, we outline how MPS can serve as a foundation for exposome research by bridging epidemiological observations with mechanistic biology. We describe applications ranging from air pollutant toxicity to food contaminants, endocrine disruptors, and nanomaterials, highlighting how MPS integrated with omics technologies and artificial intelligence can reveal pathways of injury, identify biomarkers, and support the development of digital twins to simulate exposure-disease trajectories. We also discuss frameworks for validation, quality assurance, and transparent reporting, which are essential for reproducibility and regulatory acceptance. Finally, we consider ethical issues, such as donor rights, data sovereignty, and equitable access, underscoring the importance of anticipatory governance. Together, MPS represent more than alternatives to animal testing-they are strategic enablers of a human-relevant, artificial intelligence-empowered exposome science. By anchoring statistical associations in mechanistic data, MPS can accelerate translation into public health policies that are predictive, preventive, and personalized.