Abstract

Background: Pollution from plastics is an increasing health threat. Microplastics are small plastic pieces, which are formed by direct synthesis for industrial or consumer applications as well as by environmental plastic degradation. As plastic degradation is increased by UV light and “weathering”, global warming has increased environmental microplastics. Polystyrene (PS) microplastics are ingested endocrine and metabolism disrupting chemicals, which have previously been associated with diabetes, obesity, NAFLD, gut dysbiosis, and increased intestinal permeability. PS in combination with polyethylene and polypropylene, makes up over 50% of environmental microplastics. Here, in order to better understand the hepatic effects of PS exposures, we performed mRNA-Seq in livers from a mouse PS exposure model.

Methods: Chow diet-fed male C57Bl/6j were exposed to either 0.5 μm or 5 μm PS beads in water at 1μg/ml and controls were given water without PS beads for 12 weeks. Lipid analysis and mRNA-Seq was performed in whole liver abstracts and pathway enrichment analyses were performed using Ingenuity pathway analysis software (IPA).

Results: Hepatic cholesterol was significantly increased by PS. Transcriptomics analysis revealed a size-dependent effect of PS bead exposures. The 0.5 μm exposures were associated with 278 unique differentially expressed genes (DEGs) in liver. Of these, Steap4, Tnfaip3, and Ccl2 were the most up-regulated, while Tpm2 and Trib3 were the most down-regulated. 5 μm PS was associated with 44 unique DEGs. Firre was the most up-regulated gene, while Slpi and Ctgf were the most down-regulated. 5 DEGs (e.g., Rev1, Brpf1, Ccnt2, Cavin2, and Pea15a) were common to both exposure groups. 60 processes were enriched by 0.5 μm PS, and 6 were enriched by 5 μm PS. These processes included FXR/RXR Activation, Aryl Hydrocarbon Receptor Signaling, and LPS/IL-1 mediated inhibition of RXR.

Conclusion: PS disrupted hepatic cholesterol metabolism. It was associated with hepatic transcriptional reprogramming in a PS bead size-dependent manner. Pathway enrichment analyses demonstrated a potential role for gut-derived signaling molecules (e.g., bile acids impacting FXR, indoles impacting AhR, and endotoxin impacting TLR4) in the metabolic toxicities associated with PS exposures. A confirmatory fecal/liver metabolomics analysis is currently ongoing.