Diphenyl phosphate triggers renal injury through integrated dysregulation of phosphatidylcholine metabolism, inflammation and apoptosis.

Abstract

Diphenyl phosphate (DPHP), a widely used plasticizer, has been ubiquitously detected in human urine with potential health risks. However, its nephrotoxicity mechanisms remain poorly understood. In this study, we investigated DPHP-induced renal injury using human renal tubular epithelial (HK-2) cells and C57BL/6J mice. In vitro, DPHP caused concentration-dependent cytotoxicity in HK-2 cells. DPHP significantly induced oxidative stress, upregulated renal injury markers (KIM-1, TIMP-3, NGAL) and pro-inflammatory cytokines (TNF-α, IL-6, MCP-1 and IL-1β). DPHP triggered p53-mediated mitochondrial apoptosis, as evidenced by Cytochrome c release, the increase in p53 and PUMA expression, BAX/ BCL-2 ratio and caspase-3 activity. In vivo, mice exposed to 0.5 or 5mg/L DPHP exhibited renal pathological injury. DPHP induced renal dysfunction, with significantly upregulated renal injury markers (Kim-1, Timp-1, Timp-3, Clu, Opn), alongside oxidative stress, inflammation, and apoptosis. Notably, non-targeted metabolomics revealed glycerophospholipid metabolism disorder as a core feature with elevated renal total cholesterol, triglycerides, and phosphatidylcholine (PC). PC metabolism-related enzymes (Chka, Pcyt1a, Pcyt2, Cept1) were dysregulated, and inhibition of PC biosynthesis significantly attenuated DPHP-induced inflammation and apoptosis. Collectively, these findings demonstrate that DPHP exposure induces renal injury by PC biosynthesis dysregulation to trigger inflammation and apoptosis, providing a mechanistic basis for its health risk assessment.

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