Transcriptomic Meta-Analysis Unveils Shared Neurodevelopmental Toxicity Pathways and Sex-Specific Transcriptional Signatures of Established Neurotoxicants and Polystyrene Nanoplastics as an Emerging Contaminant

Environmental contaminants exhibit heterogeneous neurotoxicity profiles, yet systematic comparisons between legacy neurotoxicants and emerging pollutants remain scarce. To address this gap, we implemented an integrative transcriptome meta-analysis framework that harmonized eight transcriptomic datasets spanning in vivo and in vitro neural models exposed to two legacy neurotoxicants (bisphenol A [BPA], 2, 2′, 4, 4′-tetrabromodiphenyl ether [BDE-47]) and polystyrene nanoplastics (PSNPs) as an emerging contaminant. Our analysis revealed a substantial overlap (68% consistency) in differentially expressed genes (DEGs) between BPA and PSNPs, with shared enrichment in extracellular matrix disruption pathways (e.g., “fibronectin binding” and “collagen binding”, p < 0.05). Network-based toxicogenomic mapping linked all three contaminants to six neurological disorders, with BPA showing the strongest associations with Hepatolenticular Degeneration. Crucially, a sex-stratified analysis uncovered male-specific transcriptional responses to BPA (e.g., lipid metabolism and immune response dysregulation), whereas female models showed no equivalent enrichment. This highlights the sex-specific transcriptional characteristics of BPA exposure. This study establishes a novel computational toxicology workflow that bridges legacy and emerging contaminant research, providing mechanistic insights for chemical prioritization and gender-specific risk assessment.