Apoptosis And Autophagy Are Participated In 2,2',4,4'-tetrabromodiphenylether-Induced Rat Ovarian Injury:Roles Of Endoplasmic Reticulum Stress

Objective:Polybrominated diphenyl ethers (PBDEs) are one class of flame retardants in consumer products such as electronic products, building materials, which have become global environmental pollutants. In recent years, the toxicity of endocrine disruptors have attracted more and more attention, but the specific mechanism of ovarian toxicity is still not very clear. We aim to study the roles of endoplasmic reticulum stress (ERS), autophagy and apoptosis in PBDE-47-induced Sprague Dawley rat ovarian injury.Methods:New-born female Sprague-Dawley rats were randomly divided into 6 groups:control (corn oil),1 mg/kg.bw PBDE-47,5 mg/kg.bw PBDE-47,10 mg/kg.bw PBDE-47, ERS inhibitor 4-phenylbutyric acid (4-PBA) alone (150 mg/kg.bw), and 4-PBA (150 mg/kg.bw)+10 mg/kg.bw PBDE-47. On postnatal day (PND) 10, PBDE-47 was administered by oral gavage with different concentrations. From PND 8,4-PBA was daily administered by intraperitoneal injection of two times at a total dose of 150 mg/kg body weight for three weeks. After two months treatment, all animals were sacrificed, body weight and ovarian weight were recorded, and ovares were collected. Histopathological changes were observed in ovaries, ERS-related proteins (GRP78, IRE1, Caspase-12), apoptosis-related proteins (PARP, Caspase-3) and autophagy-related proteins (P62, Beclinl, LC3) expression levels were detected by Western blot.Results:Ovarian coefficients of all PBDE-47 treated groups were lower than in the control group (P<0.05), but ovarian coefficients of PBA groups restored to the normal (P>0.05). Moreover, with increasing concentrations of PBDE-47, GRP78, IRE1, Caspase-12, Beclinl, LC3 and P62 were persistently increased (P<0.05) indicative of ERS and autophagy. In the 10 mg/kg.bw PBDE-47 treated group, PARP and Caspase-3 expression were markedly activated (P<0.05), indicative of apoptosis. These were accompanied by significantly typical histopathological damage. Intriguingly,4-PB A treatment attenuated all these changes (P<0.05)Conclusion:ERS played a significant role in PBDE-47-induced autophagy and apoptosis, with increasing concentrations of PBDE-47, the expression levels of autophagy-related proteins and apopto sis-related proteins were increased continuously, eventually led to ovarian structural damage. PBA-treatment can effectively relieve the endoplasmic reticulum stress-mediated autophagy and apoptosis, and thus played a protective effect in ovarian tissue, this will also provide a new clue for the PBDE-47 prevention in the future.