Quantitative proteomic analysis reveals novel insights into hepatic toxicity in mice exposed chronically to okadaic acid

Okadaic acid (OA) is a principal shellfish toxin and a potent promoter of hepatic tumors. However, the molecular mechanisms of OA-induced susceptibility to carcinogenesis are largely unknown. Here, we applied a quantitative proteomic approach, two-dimensional differential gel electrophoresis, to characterize the differentially expressed proteins of hepatic tissue in adult male mice exposed chronically to OA (0.2, 2, and 10 μg/kg body weight) for 120 days via daily intraperitoneal injection. Our results showed that liver morphology was damaged by OA, and dilation of rough endoplasmic reticulum, swelling and ridge disappearance of mitochondria in hepatocytes were observed in all OA-treated mice. Serum malondialdehyde content increased significantly with increasing OA dose while hepatic protein phosphatase activity decreased. Furthermore, apoptotic cells in the liver showed a significant dose-response relationship. Quantitative proteomic analysis revealed that 46 proteins altered remarkably in abundance in OA-treated mice, and these proteins were involved in macromolecular metabolism, molecular chaperone/stress response, apoptosis, and cytoskeleton. Bioinformatic analysis indicated that OA might induce apoptosis by activating extracellular signal-regulated kinase-1/2, c-Jun N-terminal kinase, and nuclear factor-kappa B pathways, as well as causing endoplasmic reticulum stress, thereby leading to liver injury. OA-induced hepatocyte apoptosis might be a key mechanism responsible for hepatotoxicity. We showed, for the first time, the chronic toxic effects of OA on mice at the mechanistic level.