A computational exploration of the SRC/PIK3CA/EGFR signaling axis linking PPCP exposure to preterm birth based on...

Pharmaceuticals and personal care products (PPCP) are ubiquitous environmental contaminants with potential endocrine-disrupting properties. Although maternal exposure to PPCP is widespread, the molecular mechanisms linking complex mixtures of PPCP to preterm birth (PTB) risk remain unclear. The present study aimed to explore potential molecular correlations between priority PPCP exposure and PTB, and to screen candidate hub genes and signaling axes rather than clarify definitive causal mechanisms.

Using an integrated computational network toxicology approach, we investigated the potential molecular associations between seven priority PPCP and PTB. Putative human targets were predicted via SwissTargetPrediction and Super-PRED, while PTB-associated genes were curated from GeneCards, NCBI, and OMIM. Overlapping targets underwent protein-protein interaction network construction, topological analysis, functional enrichment (DAVID, GeneMANIA), and molecular docking. Hub gene expression was validated using the GEO dataset GSE251663.

We identified 253 shared PPCP-PTB targets. Network analysis highlighted SRC, PIK3CA, and EGFR as the top hub genes involved in hormone signaling (e.g., prolactin pathway) and cellular metabolism. Expression analysis revealed significant downregulation of EGFR in PTB placental tissues, whereas SRC and PIK3CA showed no significant changes. Molecular docking indicated favorable theoretical binding energies between PPCP and the hub proteins, with ethinyl estradiol exhibiting the strongest interaction.

This exploratory study proposes a hypothetical framework wherein PPCP may disrupt PTB-associated placental biological processes via the SRC/PIK3CA/EGFR signaling axis. While placental transcriptional patterns support these genes as potential mediators of PPCP exposure, causality requires experimental validation. These findings provide testable molecular hypotheses for future wet-lab validation and population-based epidemiological studies incorporating real-world PPCP exposure assessments.