Mechanisms of Micro-Nanoplastics Uptake, Translocation, and Toxicity in In Vitro Human Intestinal Models: Implications for Health and Inflammation - PROJECT SUMMARY Micro-nano-plastics (MNPs) are small plastic particles resulting from the environmental breakdown of plastic waste over time. These particles have accumulated in ecosystems and entered the food web through contaminated water and food, trophic transfer, and exposure during food processing and packaging. Recent studies have detected MNPs in nearly every human organ and tissue, underscoring their widespread presence. While it is known that MNPs can cross biological barriers like the intestine, the health effects of MNP exposure are still poorly understood, and the mechanisms that allow MNPs to bypass these barriers remain unclear. Additionally, most toxicological studies have relied on simplified MNP models, such as polystyrene beads, which do not accurately reflect the complex physicochemical properties of real-world MNPs. This project aims to bridge these knowledge gaps by exploring the intestinal uptake mechanisms, biodistribution, and impacts on intestinal health of environmentally relevant MNPs. The focus will be on the effects of MNP polymer type, size, surface chemistry (including weathering), and prolonged exposure on MNP toxicity and inflammatory responses. Our central hypotheses are: (I) MNP properties such as size, polymer type, and environmental weathering influence their uptake, translocation, toxicity, and inflammatory effects; (II) MNPs are taken up through both passive diffusion and energy-dependent endocytosis pathways; (III) prolonged exposure enhances MNP uptake by altering gene expression related to cell junctions, endocytosis, and inflammation; and (IV) intestinal inflammation, such as in inflammatory bowel disease (IBD), increases MNP translocation by enhancing intestinal permeability, which further promotes biodistribution. To achieve these objectives, the study is organized into two specific aims: Aim 1: Synthesize and characterize environmentally relevant “tracer” MNPs (Au Core-Plastic Shell) for use in toxicological studies. These physicochemically characterized MNPs will be subjected to weathering/aging processes to simulate environmental conditions, and will enable MNP quantification using ICP-MS. The characterization will focus on the physicochemical properties of MNPs, including size, polymer type, and surface chemistry. Aim 2: Investigate MNP translocation mechanisms and toxicity using advanced in vitro models. This will include a triculture model of the small intestinal epithelium and human Intestine-on-Chip (IOC) models derived from both healthy and IBD donor organoids. Simulated digestion will replicate real-world exposure conditions, and the effects of MNPs on intestinal toxicity, gene expression, and inflammatory response will be examined. In addition to providing state of the art, transdisciplinary training to a doctoral student, the findings from this research will provide critical data for assessing the risks of MNP ingestion, inform regulatory actions, and open new research avenues in toxicology and epidemiology for this emerging environmental pollutant.
