Hepatic toxicity of fluorene-9-bisphenol (BHPF) on CD-1 mice

Fluorene-9-bisphenol (BHPF), a substitute for bisphenol A (BPA), has been widely used in the synthesis of polyester polymers. Studies have reported multiple BHPF toxicities but its effect on the liver remains unknown. In this study, we performed short-term and subchronic toxicity tests, as well as primary hepatocyte experiments, to investigate the hepatic toxicity of BHPF using CD-1 mice. And microarray was used to analyze the changes of global gene expression in the liver of mice treated with BHPF. The results showed that the liver coefficient and the activities of serum aminotransferases were obviously elevated by BHPF at doses of 27.8 mg/kg body weight (bw)/day or higher in mice treated for 10 days. Histological analysis showed obvious changes, including narrowed hepatic sinuses, dilated central vein, leucocyte infiltration, and cytoplasmic vacuolation, in the livers of mice treated with BHPF at dosages of 2 mg/kg bw/3-day and higher for 36 days. Microarray analyses revealed 2623 differentially expressed genes (DEGs) in the livers of mice treated with 50 mg/kg bw/day of BHPF for 3 days, which could be enriched in GO terms of T cell activation, leukocyte migration, and leukocyte chemotaxis and KEGG pathways of natural killer cell-mediated cytotoxicity and autoimmune thyroid disease. The top 10 hub DEGs, including LTF and MMP8, were observed in the protein-protein interaction network obtained via STRING database analysis, and are proposed as potential biomarkers for liver injury studies. Primary hepatocyte experiments demonstrated the hepatotoxicity of BHPF at concentrations of 10^-6 M and higher. This study indicates that BHPF could cause liver injury at relatively low levels, suggesting that the risk of human BHPF exposure should be of concern.