ABSTRACT We are pleased to submit this proposal in response to NOSI NOT-CA-24-030 - Administrative Supplements for Contemporary Modifiable Exposures and Cancer Across the Cancer Control Continuum. Microplastics (MPs), tiny plastic particles that enter the environment via the degradation of plastic waste and industrial pollution, have become a ubiquitous environmental contaminant. The presence of MPs in the oceans, drinking water, and food supply is increasingly well-documented. Accumulating evidence also demonstrates the presence of MP contamination in human tissues and biospecimens, raising significant questions as to the health implications of MP exposure and bioaccumulation. Given the ubiquity of MPs in different foods and in beverages, it is plausible that the effects of MP exposure would be especially pronounced for diseases of the colon and rectum, such as colorectal cancer (CRC). Several suggested pathways link MP exposure to CRC pathways. The presence of MPs has been implicated in triggering the production of reactive oxygen species, inducing DNA damage and an inflammatory response. Chemical additives that leach out of MPs (i.e., leachates) could also contribute to CRC pathways directly or indirectly via impacts on the gut microbiome. The objective of this proposal is to characterize the burden of MPs within the human gut, and to examine the potential implications of this burden with respect to CRC. Specifically, in Aim 1 we will quantify and contrast the burden of MPs in stool according to CRC history (1a) and in CRC tissue according to age at CRC diagnosis (1b). This latter comparison is timely given that CRC incidence rates among individuals aged <50 years have been steadily increasing over the past 30 years – consistent with the timeline of growing MP contamination. Our proposed Aim 2 allows a more mechanistic focus, where we will develop a system integrating anaerobic microbial metabolism with CRC-derived organoids to examine the host response to toxic polyvinylchloride MP leachates and to their microbial metabolites. Organoid cultures will be incubated with MP leachates and with microbial-derived metabolites of those MP leachates to assess proliferation and apoptosis, gene expression, and cancer-related pathways, yielding more detailed understanding as to the implications of MPs on the gut microbiome and CRC pathways. Production and use of plastics has increased >230-fold since 1950, meaning that each passing generation will experience greater potential for MP bioaccumulation and lifetime exposure. Given the pervasive and growing burden of MP contamination, it is critical we understand the implications of MP exposure in human populations. Through the proposed aims, this project will address a critical gap in knowledge as to the association of MP burden with CRC and will yield foundational knowledge as to the direct and indirect effects of MP exposures.