Epithelial Barrier Theory

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Methodology

Advanced Human Models For Environmental Toxic Substances Replacing Mouse Research Summary

The advancement of human in vivo-like cellular systems utilizes induced pluripotent stem cell-derived organoids and organ-on-a-chip technology as substitutes for mouse models in studying the effects of environmental exposure to toxic substances.

More than 350,000 chemical substances have been introduced into our environment, coinciding with a noticeable increase in autoimmune and allergic diseases, reaching epidemic proportions since 1960s.

Exposure to chemicals disrupts cellular processes, initiating inflammatory responses and cellular demise, which can culminate in organ damage and potentially exacerbate the development of chronic diseases. Therefore, it is imperative to thoroughly assess the toxicity of these substances to safeguard public health and mitigate the risks associated with their presence in our environment.

Human research has been limited and remains impractical due to the known toxicity of certain substances. Consequently, there is a pressing need to shift focus towards methodologies aligned with the principles of Replacement, Reduction, and Refinement (the 3Rs) in animal research. This approach advocates for the replacement of animal models wherever feasible, prioritizing alternative methods to analyze both dosage effects and the molecular mechanisms of toxicity in these substances. Moreover, there is a critical imperative to advance the development of in vivo-like human models, which can more accurately simulate human physiology and responses to chemical exposure. By embracing these principles and advancing innovative research techniques, we can enhance our understanding of toxicity while minimizing reliance on animal testing and advancing human-relevant research methodologies.

We created experimental models that mimic human in vivo conditions by integrating induced pluripotent stem cell (iPSC)-derived intestine organoids with organ-on-a-chip technology. This approach enabled us to illustrate how epithelial cells respond to environmental toxins, demonstrating both their activation and regulatory mechanisms.

We elucidated the molecular mechanisms by which these substances impact intestinal epithelial cells, employing a combination of transcriptomic and proteomic analyses, alongside deletion studies utilizing CRISPR/Cas9 and siRNA technologies. Through these methods, we have gained insights that enable us to inform strategies aimed at mitigating associated diseases, regulating substance dosages, formulating less harmful products, and investigating novel therapeutic interventions.

Our newly established epithelial laboratory and innovative in vivo-relevant methodology are in accordance with the principles of the 3Rs, offering a significant decrease in reliance to animal research.