Alteration of endoplasmic reticulum stress, inflammation and anti-oxidative status in cyclophosphamide-damaged liver of Nile tilapia (Oreochromis niloticus)

Abstract

Cyclophosphamide (CTX) is a common immunosuppressant, and it can also results in liver injury in human and animals. In this study, the CTX-induced liver injury mechanism in tilapia (Oreochromis niloticus) was investigated by studying alteration of endoplasmic reticulum stress (ERS), inflammation and anti-oxidative status. Tilapia was intraperitoneally injected CTX at the doses of 10, 25, 50, 75 and 100 mg·kg−1, and the blood and liver tissues were collected. The results showed that CTX administration had a significant cytotoxicity on hepatocytes, and increased the liver index. The extensive vacuolar degeneration, unclear cell outline and other histological lesions were also observed. CTX administration markedly decreased the antioxidant ability and enhanced lipid peroxidation in liver. Furthermore, qPCR data showed that CTX administration at 50–100 mg·kg−1 up-regulated gene expressions of cyp1a, cyp2k1 and cyp3a, and inflammatory response-related genes including rel, relb, nfκb1, il-6, il-8, il-10 and tnf-α. CTX significantly promoted the mRNA levels of ERS-related genes (eif2α, crt, parp1, grp78, ire1, xbp1s and chop) in a dose dependent manner. Additionally, CTX injection at 75–100 mg·kg−1 could down-regulate gene expressions of anti-oxidative status including nrf2, ucp2, ho-1, gpx3, gstα and cat. Overall results suggested CTX injection induced liver damage which was related to the cytotoxic effect on hepatocytes, decrease of antioxidant capacity, inflammatory response and ERS.