Project Summary In response to the Notice of Special Interest (NOSI) NOT-CA-24-030, our research addresses the urgent concern of escalating plastic pollution across the life course and across the cancer control continuum as an administrative supplement to University of New Mexico Cancer Center Support Grant (P30CA118100, Current Year 18). Despite numerous reports indicating the ubiquitous presence of plastics in the environment and growing global concern for ecosystems and human health, plastic production and use continue to grow unabatedly. Humans are exposed to plastic particles mainly through ingestion of contaminated food or water, through inhalation, or through skin contact. Humans consume up to 5g (weight of a credit card) microplastics weekly, and colonic epithelial cells will face the brunt of this contemporary modifiable exposure. Recent studies provide evidence for the accumulation of microplastics in multiple human organs including the colon. Toxic exposure to microplastics has been linked to the disruption of colonic epithelial cell structure and function. Moreover, studies in different preclinical models including mice indicate that microplastics exposure leads to various adverse intestinal effects including inflammation, barrier dysfunction, and microbial imbalance. Long- standing intestinal inflammation and oxidative stress increase the risk of colorectal cancer (CRC) development. However, to date, there have been no studies investigating the influence of microplastics on colon tumor growth and metastasis in vivo. Thus, investigation into the potential association between the environmental microplastics exposure and the risk of CRC is merited. Our objective is to investigate the impact of microplastics exposure across lifespan on human colons (n=64). We hypothesize that there's an increasing trend in the uptake of plastics into human colon tissues over time, potentially impacting CRC risk. Our hypothesis is based on our data showing that the most common microplastics in human colon tumors are polyethylene (PE), and there is a positive correlation between microplastics concentration and patient age. Moreover, PE and polystyrene (PS) are significantly increased in human colon tumors compared to normal colon tissues from cadavers. The proposal integrates human relevance through archived colon tissues from New Mexico's diverse and underprivileged population, as well as human colonoids (both normal and tumor). This project aims to enhance our comprehension of the fundamental mechanisms underlying microplastics' toxicity and identify actionable elements for community-level disease prevention and treatment.