Benzo(α)pyren-7,8-dihydrodiol-9,10-epoxide induces human trophoblast Swan 71 cell dysfunctions due to cell apoptosis through disorder of mitochondrial fission/fusion

摘要

AbstractBenzo(a)pyren-7,8-dihydrodiol-9,10-epoxide (BPDE) is an endocrine disrupter and ultimate carcinogenic product of benzo(a)pyrene (BaP). Numerous studies have shown that BPDE causes trophoblast-related diseases, such as preeclampsia, growth restriction or miscarriages. However, the underlying mechanism, especially the mitochondria-related BPDE-induced trophoblast dysfunction remains unknown. In this study, we examined mitochondrial functions in BPDE-induced human trophoblast cell line Swan 71. BPDE decreased cell ability, attenuated cell invasion and HCG secretion, induced cell apoptosis, decreased mitochondrial membrane potential, increased reactive oxygen species (ROS) and MDA, and decreased SOD activity in a dose-dependent manner. In the mechanism, BPDE significantly increased pro-apoptosis protein (P53 and Bak1) and decreased anti-apoptosis protein (Bcl-2). Furthermore, the protein expression levels of mitochondrial fusion genes (Mfn1, Mfn2, and OPA1) were decreased and those of fission genes (Fis1 and Drp1) were increased with increasing concentrations of BPDE and incubation time, resulting in the release of Cyt c and activation of Caspase 3, which irreversibly induced trophoblast cell apoptosis. This study reveals the mechanism of dysfunction of trophoblast cells through cell apoptosis due to the disorder of mitochondrial fission/fusion after exposure to BPDE, providing a further experimental understanding the adverse effects of BaP on trophoblast cells in early pregnancy.Graphical abstractSchematic diagram of BPDE-induced human trophoblast Swan 71 cells dysfunctions due to cell apoptosis through the disorder of mitochondrial fission/fusion. BPDE exposure leads to increase in ROS, MDA, and inflammation, decrease in SOD. The increased oxidative stress increases mitochondrial membrane permeability and damages mitochondrial structures. The change in mitochondrial structures is due to decrease in fusion and increase in fission, leading to mitochondrial fragmentation and dysfunctions. Subsequently, Cyt c is released from mitochondria to the cytoplasm, leading to increasing in Activated-caspase 3, which further induces cell apoptosis. Finally, the apoptosis of Swan 71 cells decreases the invasion and HCG secretion abilities.Display OmittedHighlights•BPDE decreases cell ability, attenuates cell invasion and HCG secretion, and induces cell apoptosis.•BPDE decreases mitochondrial membrane potential, destroys mitochondrial structures, increases oxidative damage.•BPDE increases the expression of pro-apoptosis genes and decreases that of anti-apoptosis gene (Bcl-2).•BPDE decreases the expression of mitochondrial fusion genes and increases those of fission genes (Fis1 and Drp1).•BPDE results in the release of Cyt c and activation of Caspase 3, inducing trophoblast cell apoptosis.