Bisphenol mixture-induced DGKB downregulation promotes premature human neurogenesis through the activation of MAPK pathway

ABSTRACT:

The widespread industrial transition from bisphenol A (BPA) to structural analogs such as BPS, BPE, and BPAF has raised significant concerns regarding their potential health risks. However, their neurodevelopmental risks and underlying molecular mechanisms, particularly when present as complex mixtures, remain poorly defined in human-specific contexts. In this study, we employed human induced pluripotent stem cell (iPSC)-derived cortical organoids to investigate the developmental neurotoxicity of a bisphenol mixture (BPS, BPE, and BPAF at 1:1:1) at environmentally relevant concentrations (10–1000 nM). The mixture induced premature neuronal differentiation, characterized by a significant expansion of the CTIP2+ deep-layer neuronal population. Integrated analyses of network toxicology, transcriptomics, and lipidomics identified a novel diacylglycerol (DG)-mediated signaling hub. Specifically, we identified the transcriptional downregulation of diacylglycerol kinase beta (DGKB) as a critical molecular initiating event (MIE), that drives DG accumulation. This lipidomic disruption selectively activated the PKCα/JNK signaling axis, leading to the induction of the transcription factor FOS, which promoted transcription of neural differentiation genes (ASCL1, NEUROD1, TBR2, and CTIP2). Collectively, our findings reveal a DG-mediated PKCα/JNK/FOS axis underlying bisphenol mixture-induced premature neuronal differentiation, providing mechanistic insights into the developmental neurotoxicity of emerging bisphenol alternatives.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse-phase, Liquid Chromatography MS - positive - reverse-phase

PROVIDER: MTBLS15671 | MetaboLights | 2026-09-29

REPOSITORIES: MetaboLights