Multiomics: TBPH Enhances Thyroid Hormone Synthesis via PIS-LPI-ERK-EGR1 Pathway

Abstract Bis(2-ethylhexyl)-tetrabromophthalate (TBPH), a high-production-volume novel brominated flame retardant (NBFR), has been shown to perturb thyroid hormone synthesis, yet the underlying molecular mechanism remains poorly understood. Using transcriptomics, phosphoproteomics, and metabolomics as discovery tools, combined with validation in Sprague–Dawley (SD) rats and human thyroid follicular epithelial cells (Nthy-ori 3–1), we investigated this mechanism. TBPH increased thyroglobulin (TG) and thyroid peroxidase (TPO) in rat thyroid and elevated circulating triiodothyronine (T3) and thyroxine (T4) levels. In Nthy-ori 3–1 cells, TBPH remodeled glycerophospholipid metabolism, leading to phosphatidylinositol synthase (PIS)-dependent accumulation of the signaling lipid lysophosphatidylinositol 18:1 (LPI_18:1). LPI 18:1 selectively activated the ERK-EGR1 signaling axis and drove TG/TPO upregulation. Knockdown of PIS or EGR1, or pharmacological inhibition of ERK, abolished TBPH-induced TG/TPO expression. These findings reveal a previously unrecognized PIS-LPI-ERK-EGR1 pathway through which TBPH enhances thyroid hormone synthesis, highlighting a lipid metabolism-driven mechanism of endocrine disruption and providing a mechanistic basis for reassessing the health risks of NBFRs.