Sex-specific intestinal transcriptional responses to oral polyvinyl chloride microplastic exposure in Wistar rats, with an in-vitro validation in a human gut model.

The widespread presence of microplastics in the environment has raised concerns about potential health effects following oral exposure in humans, particularly in individuals with impaired intestinal barrier function. This study investigated the effects of dietary polyvinyl chloride (PVC) microplastics fragments (< 25 μm) in healthy and dextran sodium sulfate (DSS)-induced colitis Wistar rats, with a complementary assessment in a human 3D intestinal microtissue model. Rats received control feed or feed supplemented with 0.1% (w/w) PVC for three weeks, with or without 3 % DSS administration during the first week to induce mild colitis. Intestinal permeability was evaluated using a FITC-dextran assay, tight junctions' proteins were investigated by Western blot, histopathology was assessed in colon sections, and transcriptomic changes were analysed in jejunum and colon tissue by RNA sequencing followed by pathway enrichment analysis. In parallel, human EpiIntestinal FT microtissues were exposed to PVC and/or DSS to assess viability, barrier integrity, and tissue morphology. PVC exposure was well tolerated and did not affect weight gain or overall well-being of the animals. Intestinal permeability increased in female rats exposed to PVC or DSS alone, whereas no significant changes were observed in males. Histological alterations were subtle and mainly focal. Transcriptomic analyses revealed pronounced sex- and tissue-specific responses, with stronger effects in females, particularly in the colon and under inflammatory conditions. Altered genes and enriched pathways were primarily related to apoptosis, lipid metabolism, immune and inflammatory signalling, energy homeostasis, and hormone signalling, including PPAR-associated pathways. Male rats showed fewer and less consistent transcriptional changes. No adverse effects were observed in the human intestinal model, suggesting limited acute toxicity. Overall, short-term oral PVC exposure induced modest but distinct sex-dependent molecular responses, highlighting the importance of considering sex and pre-existing inflammatory status when assessing microplastic toxicity.