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

Abstract

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.

3-tert-Butyl-4-hydroxyanisole Impairs Hepatic Lipid Metabolism in Male Mice Fed with a High-Fat Diet

“…Conversely, the mRNA level of PPAR α was significantly decreased due to HFD ( p < 0.05), and the other test genes remained unaffected. Similar alterations in the transcriptional profile induced by HFD were also reported previously …”

“…The data from this study also showed that the transcriptional patterns of the test genes involved in the hepatic lipid metabolism responded differently to 3-BHA stimulation under the ND and HFD conditions, which was also occasionally reported in previous studies, , showing the crucial regulation of the diet factor in chemical-disturbed biological processes. The lipid homeostasis under HFD conditions was more vulnerable to 3-BHA exposure than that under ND conditions.…”

“…Recent evidence has indicated that continuous exposure to endocrine-disrupting chemicals (EDCs) may increase the incidence of NAFLD. , For instance, bisphenol A exposure could result in abnormal lipid accumulation in hepatocytes, along with hepatocellular inflammation and oxidative stress, mainly through the modulation of nuclear hormone receptors and alteration in the epigenome . EDCs may exacerbate the NAFLD phenotype in experimental animals when interacting with other established risk factors, such as a HFD. − Considering the application of 3-BHA in lipid-rich foods, its potential in disturbing liver lipid homeostasis could be plausible, especially when in combination with a HFD.…”

Hepatic Gene Expression Profiling of American Kestrels (Falco sparverius) Exposed In Ovo to Three Alternative Brominated Flame Retardants

“…Upregulation of PPARG in chicken liver is correlated with body fat deposition [ 50 ], and, although the effects of hepatic downregulation in birds have not been fully explored, decreased expression of PPARG may prevent lipid accumulation in the liver [ 48 ]. Our results contrasted with those reported by Guo et al [ 51 ] in adult zebrafish; after 2 weeks of TBPH exposure, expression of PPAR genes increased. Further research is needed to determine whether the transcriptional changes observed in the present study correspond to functional changes in cholesterol, bile acid, and/or fatty acid metabolism that can lead to liver pathology or whether these low-level changes are compensatory in nature.…”

Using Zebrafish as a Disease Model to Study Fibrotic Disease

“…It is well known that NAFLD is associated with type 2 diabetes [83], obesity, metabolic syndrome [84], and some cardiovascular diseases [85]. Although many of these diseases have been modelled in mice, and a few zebrafish models of NAFLD were generated [69,86,87], only one zebrafish obesity-associated fibrotic liver model is described so far [69]. Investigating whether menopause is associated with the severity of liver fibrosis, Turola et al [69] overfed male and female adults for 24 weeks with a high-calorie diet.…”