Environmental Pollutant PCB 153 Is Associated with Candidate Alternative Splicing Alterations in Intellectual...

Background/Objectives: Polychlorinated biphenyls (PCBs) are persistent environmental contaminants associated with chronic toxicity and neurological dysfunction. PCB 153 is among the most prevalent congeners detected in environmental and dietary matrices. Although transcriptional responses to PCB 153 have been described, its potential association with post-transcriptional regulation remains poorly defined. Here, we performed an exploratory computational RNA-seq splicing analysis of previously generated transcriptomic data from retinoic acid-differentiated SH-SY5Y cells exposed to a sub-cytotoxic concentration of PCB 153. Methods: RNA-seq data were analyzed to identify candidate differentially alternative splicing events (DASEs). Candidate events were further examined for retained intron (RI)-related premature termination codons (PTCs), and potential regulatory interactions, including DASE-RNA-binding protein (RBP) motif enrichment. Results: PCB 153 exposure was associated with differential expression of 32 RNA-binding protein (RBP) encoding genes and with 90 candidate DASEs. Disease enrichment analysis indicates that genes affected by candidate splicing alterations overlapped with gene sets annotated to intellectual disability and related neurodevelopmental phenotypes. Among retained intron events, several were predicted to introduce PTCs, suggesting potential effects on transcript stability or coding potential. Motif enrichment analysis identified positional enrichment of motifs corresponding to CELF2, NUMA1, PRPF8, and RBM22 within DASE-associated regions, nominating these RBPs as putative regulators associated with the observed splicing alterations. Conclusions: This computational study identifies candidate PCB 153-associated splicing alterations and RBP-related regulatory hypotheses in a neuron-like in vitro model, suggesting a potential mechanistic link between PCB 153 and neurodevelopmental dysfunction.