Subchronic exposure to tri-ortho-cresyl phosphate induces nephrotoxicity through induction of oxidative stress with neuropathy target esterase inhibition

Tri-ortho-cresyl phosphate (TOCP), an organophosphate compound widely used in industry as a lubricant, plasticizer, and hydraulic fluid, could cause organophosphate-induced delayed neuropathy (OPIDN) which is a phospholipase and involved in phospholipid metabolism. However, whether TOCP could induce nephrotoxicity is not clear. In this study, we used a mouse model with subchronic exposure to TOCP, and a human renal proximal tubular epithelial cell line HK-2 cells as the in vitro model to study the TOCP-induced nephrotoxicity. We found that TOCP-exposed mice developed severe renal dysfunctions, increased serum creatinine (p < 0.01), serum urea nitrogen (p < 0.01), and urinary protein (p < 0.05) levels. Histological analyses demonstrated severe tubular degeneration, glomerular atrophy. TOCP induced oxidative stress, increased malondialdehyde (MDA) (p < 0.01) and reduced glutathione (GSH) (p < 0.01) levels in kidney and serum. The antioxidant L-ascorbic acid (Vc) cotreatment significantly decreased TOCP-induced oxidative stress, increased GSH levels (p < 0.01), and partially alleviated renal dysfunction and histological damage in vivo. In vitro, the TOCP metabolite cresyl saligenin phosphate (CBDP) caused cytotoxicity to HK-2 cells through reactive oxygen species (ROS) production, which was decreased by Vc (p < 0.05). The direct toxicity target of TOCP is neuropathy target esterase (NTE), which is highly expressed in kidney and plays a key role in kidney functions such as maintaining osmotic pressure. We found that TOCP significantly decreased the activity of NTE in kidney (p < 0.01), but TOCP treatment induced NTE gene expression (p < 0.05), possibly through negative feedback. Therefore, these findings indicate that the TOCP-induced nephrotoxicity is largely mediated by the induction of oxidative stress possibly by the inhibition of NTE. This study contributes to the understanding of the mechanisms of TOCP toxicity in kidney and provides the scientific basis for the risk assessment of TOCP exposure.