Exploring Nanoplastics Neurological Effects by Tackling Lipid Mechanisms and Glial Inflammation

About This Grant

Project Summary The exponential increase in plastic production and extensive usage has led to millions of metric tons of plastic waste accumulating in the environment. Micro(nano)plastics (MNPs) are common environmental pollutants that bioaccumulate in the human brain. Our early findings show that MNPs tend to accumulate more in the human brain than in the liver and kidneys, with their levels rising over time. Initial data from our laboratory also reveal the presence of MNPs as solid particles in human cerebrospinal fluid (CSF) samples. The question remains about the physicochemical forms and molecular interactions of these circulatory particulates within the CSF matrix and central nervous system (CNS), and ultimately the corresponding physiological and pathological events. CSF reflects the essential biochemical aspects of the extracellular brain milieu. A tight concentration of cholesterol can be exchanged between CSF and blood in the form of the oxysterol metabolites, such as 27-hydroxycholesterol (27-OHC) and 24S-hydroxycholesterol (24S-OHC). Dysregulation in CNS cholesterol homeostasis is linked to neurodegenerative disorders and cerebrovascular diseases. Nanoplastics are polymer particles that may interact with lipids and proteins. Lipid coating on therapeutic nanoparticles enhances biocompatibility, but cholesterol-containing lipid corona is linked to increased cholesterol hydroxylases, ROS, lysosomal damage, and NLRP3 inflammasome activation, causing glial changes like foam cells. Whether this same process occurs for polymeric plastic to which humans are exposed remains unknown. Our project will address glial inflammation and cholesterol metabolism dysregulation in response to plastic-lipid particles composed of endogenous lipids in simulated human CSF. Aim 1 will assess the molecular interactions of lipid-nanoplastic mixtures in simulated human CSF using state-of-the-art spectroscopy. We will evaluate the size, shape, composition, and surface functional chemistry of the circulatory plastic-lipid nanoparticles that develop through interactions involving real-world nanoplastics and endogenous primary lipid classes (phospholipids, cholesterol, and sphingomyelin) in simulated human CSF. In the second aim of our study, we will evaluate in vitro the inflammatory and lipidomic dysregulation in glial cells in response to plastic-lipid nanoparticles in simulated human CSF. We will assess the astrocyte response to plastic-lipid nanoparticles compared to original non-lipidic nanoplastics by examining cholesterol and lipid metabolism and the NLRP3 inflammasome using transcriptome, lipidome, and proteome analyses. This research offers insight into the molecular and physicochemical characteristics of real-world circulatory nanoplastics. CSF biochemical matrix is more diluted than plasma, offering a simplified view of the molecular interactions that might occur between endogenous lipids and circulatory nanoplastics. Knowledge of astrocyte-secreted proteins and oxidized cholesterol will serve as biomarkers in human CSF cohort studies.