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Chronic Polystyrene Nanoplastics Exposure Reprograms Gene Expression, Alternative Splicing, and Disrupts Host–Microbiome–Metabolic Networks to Promote Atherosclerosis in LDLr⁻/⁻ Mice
Original title: Chronic Polystyrene Nanoplastics Exposure Reprograms Gene Expression, Alternative Splicing, and Disrupts Host–Microbiome–Metabolic Networks to Promote Atherosclerosis in LDLr⁻/⁻ Mice
Summary
Tiny plastic particles (nanoplastics), similar in size to what's already been found in human arteries, made clogged-artery disease significantly worse in mice by disrupting liver function, altering gut bacteria, and throwing off protective body chemicals—all at the same time. This matters because these mice were genetically similar to how many people process cholesterol, and the same disease patterns showed up when researchers compared their data to human artery disease samples, suggesting everyday plastic exposure could be a hidden contributor to heart disease risk in people, too.
Abstract Although micro- and nanoplastics have been detected in human atherosclerotic plaques, their mechanistic contribution to disease pathogenesis remains poorly defined. Most experimental studies have used microplastics (particles > 1 μm) in non-atherosclerotic animal models or the ApoE⁻/⁻ mouse, relying on short-term exposure or single-pathway analyses, whereas the chronic cardiovascular effects of nanoplastics (< 100 nm) remain exceedingly scarce—despite their higher biological reactivity and greater tissue penetrance. To address this gap, this study employs a multi-omics approach to investigate the chronic (12-week) oral exposure to 80 nm polystyrene nanoplastics in LDLr⁻/⁻ mice. We uniquely integrate aortic plaque quantification, hepatic transcriptomics with global alternative splicing profiling, gut microbiome 16S sequencing, and liver untargeted metabolomics to construct a unified host–microbiome–metabolite network. Nanoplastic exposure significantly exacerbates aortic lipid deposition, suppresses hepatic detoxification and anti-atherogenic lipid pathways primarily through transcriptional and post-transcriptional level changes driven by alternative splicing events (e.g., intron retention and isoform switching), and induces gut dysbiosis marked by a reduction in SCFA-producing commensals and enrichment of pro-atherogenic pathobionts—perturbations that correlate with specific hepatic functional modules. Metabolomic changes, including decreased levels of the glutathione precursor γ-glutamylcysteine and the choline-derived metabolite neurine, implicate oxidative stress and TMAO-related pathways. Cross-species validation using human atherosclerotic transcriptomic and metagenomic datasets supports the clinical translatability. By integrating multi-level biological responses, this work establishes nanoplastics as an environmental cardiovascular risk factor and uncovers novel regulatory mechanisms involving splicing-associated transcriptional reprogramming and gut–liver crosstalk, offering potential early-warning biomarkers and therapeutic targets for nanoplastic-associated cardiovascular disease. Highlights Exposure to polystyrene nanoplastics (80 nm) increases aortic lipid burden in LDLr⁻/⁻ mice. Alternative splicing and isoform switching were identified as novel hepatic responses. SCFA-producing gut commensals are depleted, and pathobionts are enriched in response to nanoplastics. A gut–liver network links suppressed detoxification to gut microbial dysbiosis. Mouse transcriptomics and metagenomics overlap with human atherosclerosis omics datasets. Graphical Abstract