Nonalcoholic Fatty Liver Disease Development in Zebrafish upon Exposure to Bis(2-ethylhexyl)-2,3,4,5-tetrabromophthalate, a Novel Brominated Flame Retardant

Bis(2-ethylhexyl)-2,3,4,5-tetrabromophthalate (TBPH), a novel brominated flame retardant, can potentially cause lipid metabolism disorder; however, its biological effects on lipid homeostasis remain unknown. We investigated its ability to cause nonalcoholic fatty liver disease (NAFLD) in zebrafish. Female zebrafish were fed a high-fat diet (HFD, 24% crude fat) or normal diet (ND, 6% crude fat), and exposed to TBPH (0.02, 2.0 μM) for 2 weeks. Consequently, HFD-fed fish showed a higher measured concentration of TBPH than ND-fed fish. Further, TBPH-treated fish in the HFD group showed higher hepatic triglyceride levels and steatosis. In comparison to ND-fed fish, treating HFD-fed fish with TBPH led to an increase in the concentration of several proinflammatory markers (e.g., TNF-α, IL-6); TBPH exposure also caused oxidative stress. In addition, the mRNA levels of genes encoding peroxisome proliferator-activated receptors were increased, and the transcription of genes involved in lipid synthesis, transport, and oxidation was upregulated in both ND- and HFD-fed fish. Both the ND and HFD groups also showed demethylation of the peroxisome proliferator-activated receptor-γ coactivator 1-α gene promoter, accompanied by the upregulation of tet1 and tet2 transcription. To summarize, we found that TBPH amplified the disruption of lipid homeostasis in zebrafish, leading to the enhancement of diet-induced NAFLD progression.