Environmentally relevant concentrations of carbamazepine induce liver histopathological changes and a gender-specific response in hepatic proteome of Chinese rare minnows (Gobiocypris rarus)

Abstract

To assess hepatotoxicity and to determine the underlying mechanisms of carbamazepine (CBZ) toxicity in fish, histopathology and the liver proteome were examined after Chinese rare minnow (Gobiocypris rarus) were exposed to 1, 10, and 100 μg/L CBZ for 28 days. Histopathological changes included disruption of spatial structure, pyknotic nuclei, cellular vacuolization and deformation of cell nuclei, in addition to marked swelling of hepatocytes in all treatment groups. Protein analysis revealed that there were gender-specific responses in rare minnow following exposure, and there were 47 proteins in females and 22 proteins in males identified as differentially abundant following CBZ treatments. Pathway analysis revealed that cellular processes affected by CBZ included apoptosis, cell differentiation, cell proliferation, and the respiratory chain, indicating impaired energy homeostasis. Noteworthy was that 15 proteins identified as different in abundance were associated with carcinogenicity. Relative mRNA levels for select transcripts were consistent with the changes of proteins N-myc downstream regulated gene (NDRG), Tropomyosin 2-Beta (TPM2) and annexin A4 (ANXA4). Protein pyruvate kinase, liver and RBC (PKLR) were increased at 1 and 100 μg/L CBZ without significant difference in transcript levels. These findings characterize molecular responses and histological changes in the liver that generate new insights into CBZ hepatotoxicity in Chinese rare minnow.

Keywords: Cancer; Carbamazepine (CBZ); Chinese rare minnow (Gobiocypris rarus); Pharmaceuticals and personal care products (PPCPs); Proteomics.