High-fat diet exacerbated decabromodiphenyl ether-induced hepatocyte apoptosis via intensifying the transfer of Ca2+ from endoplasmic reticulum to mitochondria

Polybrominated diphenyl ether (PBDE) as the flame retardant is heavily used in daily necessities, causing adverse health effects on humans. This study aimed to evaluate the hepatotoxicity of decabromodiphenyl ether (BDE-209), the most widely used PBDE, in lean and high-fat diet (HFD)-treated obese mice and elucidate the underlying mechanism. Firstly, the increasing levels of TG and proinflammatory factors in the liver and ALT and AST in serum demonstrated the hepatic damage caused by BDE-209 and further exacerbated by HFD. Tunel image revealed that BDE-209 induced more severe hepatocyte apoptosis with the assistant of HFD. Next, the mechanism analysis showed that the pro-apoptotic action of BDE-209 was in an endoplasmic reticulum (ER)/Ca2+ flux/mitochondria-dependent manner, concluded from the impairment of mitochondrial membrane potential, the enhancive protein expression of p-PERK/PERK, p-IRE1/IRE1, ATF6, CHOP, Bax/Bcl-2, cleaved caspase-3/caspase-3, IP3R1 and Sig-1R, and the over-transfer of Ca2+ from ER to mitochondria. Such proposed mechanism was further confirmed by the IP3R1 siRNA transfection cell experiment, where apoptotic rate was reduced in parallel with the reduced mitochondrial Ca2+ level. Finally, the higher expression of PACS-2 protein and the expanded ER contributed to the enriched ER-mitochondria interaction, reflected by the closer distance between ER and mitochondria visually displayed in the TEM image in HFD groups. This change was conducive to the rapid delivery of apoptosis signals via Ca2+, as proven, mechanically explaining the strengthening effect of HFD on BDE-209 hepatotoxicity. These findings detailedly explained the mechanism of BDE-209 hepatotoxicity and clarified the auxiliary effect of HFD, providing a theoretical basis for further studying other analogs. [Display omitted] •The hepatotoxicity of BDE-209 was enhanced by high fat diet (HFD).•BDE-209 induced hepatocytes apoptosis via ER/Ca2+/mitochondria pathway.•The enhanced ER-mitochondria interaction by HFD promoted Ca2+ transfer.