Surface-water estradiol-benzo[a]pyrene mixtures: Transcriptomics in a PC12 neuronal differentiation model nominate an E2F1-PTPRO axis as a candidate mechanistic biomarker.

BACKGROUND

Mixtures of estradiol (E2) and benzo[a]pyrene (BaP) occur in surface waters. Seasonal sampling at Longxing Village (Jilin, China) showed total PAHs 1.07-3.14 mg L⁻¹ (BaP 3.0 ×10⁻²-1.3 ×10⁻¹ mg L⁻¹) and estrogenic compounds 42.4-81.8 ng L⁻¹ .We investigated mechanistic indicators and testable hypotheses capturing their joint neurotoxic effects.

METHODS

A PC12 neuronal-differentiation model was exposed to BaP, E2 and NGF. Phenotypic assays (proliferation/viability, ROS, neurite outgrowth) were integrated with time-series transcriptomics (GO/KEGG), qPCR, and molecular docking of E2/BaP to protein tyrosine phosphatase receptor type O (PTPRO).

SIGNIFICANT FINDINGS: BaP accelerated proliferation and increased ROS, accompanied by transcriptomic enrichment of chemokine/GPCR-PI3K-Akt survival and anti-apoptotic signaling. Under BaP background, NGF-containing conditions were associated with a shift toward TrkA-MAPK-linked programs and up-regulation of neuronal differentiation/axonogenesis genes, consistent with the observed neurite outgrowth. Docking suggested plausible binding poses of E2 and BaP within a ligandable pocket on PTPRO and associated residue-level interaction features. Consistently, NGF up-regulated PTPRO, BaP attenuated this induction, and E2 + NGF partially restored expression, consistent with an E2F1-PTPRO-linked module. Overall, NGF partially offset BaP-associated toxicity, and PTPRO was nominated as a mechanistic candidate node associated with exposure to axonal growth. Together, these results provide mechanistic plausibility and prioritize E2F1/PTPRO- and ROS-linked pathways as mixture-associated indicators for follow-up validation in water-quality-relevant contexts.