B(a)P induces ovarian granulosa cell apoptosis via TRAF2-NFicB-Caspase1 axis during early pregnancy

作者全名：Xu, Hanting; Chen, Fangyuan; Liu, Zhihao; Gao, Rufei; He, Junlin; Li, Fangfang; Li, Nanyan; Mu, Xinyi; Liu, Taihang; Wang, Yingxiong; Chen, Xuemei

作者地址：[Chen, Fangyuan; Liu, Zhihao; Gao, Rufei; He, Junlin; Li, Fangfang; Chen, Xuemei] Chongqing Med Univ, Sch Publ Hlth, Dept Hlth Toxicol, Joint Int Res Lab Reprod & Dev, Chongqing 400016, Peoples R China; [Xu, Hanting; Mu, Xinyi; Liu, Taihang; Wang, Yingxiong] Chongqing Med Univ, Coll Basic Med, Joint Int Res Lab Reprod & Dev, Chongqing 400016, Peoples R China; [Li, Nanyan] Chongqing Med Univ, Jiulongpo Dist Ctr Dis Control & Prevent, Joint Int Res Lab Reprod & Dev, Chongqing 400039, Peoples R China

通信作者：Chen, XM (通讯作者)，Chongqing Med Univ, Sch Publ Hlth, Dept Hlth Toxicol, Joint Int Res Lab Reprod & Dev, Chongqing 400016, Peoples R China.; Wang, YX (通讯作者)，Chongqing Med Univ, Coll Basic Med, Joint Int Res Lab Reprod & Dev, Chongqing 400016, Peoples R China.

来源：ENVIRONMENTAL RESEARCH

ESI学科分类：ENVIRONMENT/ECOLOGY

WOS号：WOS:001225340600001

JCR分区：Q1

影响因子：7.7

年份：2024

卷号：252

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Benzo(a)pyrene; BPDE; Ovarian granulosa cell; Apoptosis; TRAF2

摘要：Benzo(a)pyrene [B(a)P] is an environmental endocrine disruptor with reproductive toxicity. The corpus luteum (CL) of the ovary plays an important role in embryo implantation and pregnancy maintenance. Our previous studies have shown that B(a)P exposure affects embryo implantation and endometrial decidualization in mouse, but its effects and mechanisms on CL function remain unclear. In this study, we explore the mechanism of ovarian toxicity of B(a)P using a pregnant mouse model and an in vitro model of human ovarian granulosa cells (GCs) KGN. Pregnant mice were gavaged with corn oil or 0.2 mg/kg.bw B(a)P from pregnant day 1 (D1) to D7, while KGN cells were treated with DMSO, 1.0IU/mL hCG, or 1.0IU/mL hCG plus benzo(a)pyrene-7,8dihydrodiol-9,10-epoxide (BPDE), a B(a)P metabolite. Our findings revealed that B(a)P exposure damaged embryo implantation and reduced estrogen and progesterone levels in early pregnant mice. Additionally, in vitro, BPDE impaired luteinization in KGN cells. We observed that B(a)P/BPDE promoted oxidative stress (OS) and inflammation, leading to apoptosis rather than pyroptosis in ovaries and luteinized KGN cells. This apoptotic response was mediated by the activation of inflammatory Caspase1 through the cleavage of BID. Furthermore, B (a)P/BPDE inhibited TRAF2 expression and suppressed NFicB signaling pathway activation. The administration of VX-765 to inhibit the Caspase1 activation, over-expression of TRAF2 using TRAF2-pcDNA3.1 (+) plasmid, and BetA-induced activation of NFicB signaling pathway successfully alleviated BPDE-induced apoptosis and cellular dysfunction in luteinized KGN cells. These findings were further confirmed in the KGN cell treated with H2O2 and NAC. In conclusion, this study elucidated that B(a)P/BPDE induces apoptosis rather than pyroptosis in GCs via TRAF2-NFicB-Caspase1 during early pregnancy, and highlighting OS as the primary contributor to B(a)P/BPDEinduced ovarian toxicity. Our results unveil a novel role of TRAF2-NFicB-Caspase1 in B(a)P-induced apoptosis and broaden the understanding of mechanisms underlying unexplained luteal phase deficiency.

基金机构：Basic and Frontier Research Program of Chongqing [cstc2018jcyjAX0315]; Postdoctoral ScienceFoundation of Chongqing [CSTB2022NSCQ-BHX0716]; Program for Youth Innovation in Future Medicine, Chongqing Medical University [W0092]

基金资助正文：This work was supported by grants from the Basic and Frontier Research Program of Chongqing (Grant No. cstc2018jcyjAX0315) , the Postdoctoral ScienceFoundation of Chongqing (Grant No. CSTB2022NSCQ-BHX0716) , and Program for Youth Innovation in Future Medicine, Chongqing Medical University (Grant number W0092) .