decabromodiphenyl-ethane and Chemical-and-Drug-Induced-Liver-Injury

Topics: Benzene; Bromobenzenes; Chemical and Drug Induced Liver Injury; Dioxins; Flame Retardants; Halogenated Diphenyl Ethers; Humans

Decabromodiphenyl ethane (DBDPE) is one of the most commonly used novel brominated flame retardants (NBFRs), and its mass production and widespread application have caused health threats to the human being. Existing studies have shown that DBDPE has hepatotoxicity. And we have found that DBDPE could change cytochrome P450 3A (CYP3A) expression levels in rat livers, whereas the mechanism is unclear. In this study, we exposed human normal hepatocyte (L-02) to DBDPE to further study the effect and mechanism of DBDPE on hepatocellular injury and liver metabolic enzyme CYP3A changes in vitro. The results showed that DBDPE caused L-02 cell viability decrease, lactate dehydrogenase (LDH) and transaminase release, ultrastructural damage, and apoptosis. Moreover, DBDPE exposure induced oxidative stress (i.e., increased ROS generation and MDA levels and decreased GSH content, SOD activity, and mitochondrial membrane potential) and endoplasmic reticulum (ER) stress in L-02 cells as evidenced by the elevated PERK and IRE-1α expression levels. These results confirmed that DBDPE is toxic to hepatocytes. Besides, the CYP3A expression level was decreased in DBDPE exposed L-02 cells. However, pretreatment of L-02 cells with antioxidant N-Acetyl-l-cysteine (NAC) and endoplasmic reticulum stress inhibitor 4-PBA inhibited DBDPE-induced oxidative stress, endoplasmic reticulum stress, CYP3A expression decrease, and apoptosis. Therefore, we demonstrated that DBDPE could exert toxic effects and decrease CYP3A expression on L-02 cells by inducing ER stress and oxidative stress.

Topics: Animals; Apoptosis; Bromobenzenes; Chemical and Drug Induced Liver Injury; Endoplasmic Reticulum Stress; Oxidative Stress; Rats

Decabromodiphenyl ether (BDE-209) and its substitute decabromodiphenyl ethane (DBDPE) are heavily used in various industrial products as flame retardant. They have been found to be persistent in the environment and have adverse health effects in humans. Although some former studies have reported toxic effects of BDE-209, the study of DBDPE's toxic effects is still in its infancy, and the effects of DBDPE on hepatotoxicity are also unclear. This study aimed to evaluate and compare the hepatotoxicity induced by BDE-209 and DBDPE using a rat model. Sprague-Dawley rats were administered DBDPE or BDE-209 (5, 50, 500 mg/kg bodyweight) intragastrically once a day for 28 days. Twenty-four hours after the end of treatment, the rats were sacrificed, and body liver weight, blood biochemical parameters, liver pathology, oxidative stress, inflammation, pregnane X receptor (PXR), constitutive androstane receptor (CAR), and changes in cytochrome P450 (CYP3A) enzymes were measured. Our results showed that both BDE-209 and DBDPE could cause liver morphological changes, induce oxidative stress, increase γ-glutamyl transferase and glucose levels in serum, and down-regulate PXR, CAR, and CYP3A expression. In addition, BDE-209 was found to increase liver weight and the ratio of liver/body weight, lead to elevated total bilirubin and indirect bilirubin levels in serum, and induce inflammation. The present study indicated that BDE-209 and DBDPE may interfere with normal metabolism in rats through oxidative stress and inflammation, which inhibit PXR and CAR to induce the expression of CYP3A enzymes, and finally produce hepatotoxic effects and cause liver damage in rats. Comparatively, our results show that the damage caused by BDE-209 was more serious than that caused by DBDPE.

Topics: Animals; Bromobenzenes; Chemical and Drug Induced Liver Injury; Flame Retardants; Halogenated Diphenyl Ethers; Rats; Rats, Sprague-Dawley

Information regarding decabromodiphenyl ethane (DBDPE) effects on hepatotoxicity and metabolism is limited. In the present study, Wistar rats were given oral DBDPE at different doses. DBDPE induced oxidative stress, elevated blood glucose levels, increased CYP2B2 mRNA, CYP2B1/2 protein, 7-pentoxyresorufin O-depentylase (PROD) activity, and induced CYP3A2 mRNA, CYP3A2 protein, and luciferin benzylether debenzylase (LBD) activity. UDPGT activity increased with its increasing exposure levels, suggesting that oral DBDPE exposure induces drug-metabolizing enzymes in rats via the CAR/PXR signaling pathway. The induction of CYPs and co-regulated enzymes of phase II biotransformation may affect the homeostasis of endogenous substrates, including thyroid hormones, which may, in turn, alter glucose metabolism.

Topics: Animals; Bromobenzenes; Chemical and Drug Induced Liver Injury; Female; Flame Retardants; Liver; Male; Random Allocation; Rats; Rats, Wistar; Toxicity Tests