Research Center for Environment and Female Reproductive Health, the Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen 518033, China; Key Laboratory of Environment and Female Reproductive Health, West China School of Public Health & West China Fourth Hospital, Sichuan University, Chengdu 610041, China.
Research Center for Environment and Female Reproductive Health, the Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen 518033, China.
Environ Int. 2023 Oct;180:108237. doi: 10.1016/j.envint.2023.108237. Epub 2023 Sep 28.
Environmental benzo(a)pyrene (BaP) and its ultimate metabolite BPDE (benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide) are universal and inevitable persistent organic pollutants and endocrine disrupting chemicals. Angiogenesis in placental decidua plays a pivotal role in healthy pregnancy. Ferroptosis is a newly identified and iron-dependent cell death mode. However, till now, BaP/BPDE exposure, ferroptosis, defective angiogenesis, and miscarriage have never been correlated; and their regulatory mechanisms have been rarely explored. In this study, we used assays with BPDE-exposed HUVECs (human umbilical vein endothelial cells), decidual tissues and serum samples collected from unexplained recurrent miscarriage and their matched healthy control groups, and placental tissues of BaP-exposed mouse miscarriage model. We found that BaP/BPDE exposure caused ferroptosis and then directly suppressed angiogenesis and eventually induced miscarriage. In mechanism, BaP/BPDE exposure up-regulated free Fe level and promoted lipid peroxidation and also up-regulated MARCHF1 (a novel E3 ligase of GPX4) level to promote the ubiquitination degradation of GPX4, both of which resulted in HUVEC ferroptosis. Furthermore, we also found that GPX4 protein down-regulated the protein levels of VEGFA and ANG-1, two key proteins function for angiogenesis, and thus suppressed HUVEC angiogenesis. In turn, supplement with GPX4 could suppress ferroptosis, recover angiogenesis, and alleviate miscarriage. Moreover, the levels of free Fe and VEGFA in serum might predict the risk of miscarriage. Overall, this study uncovered the crosstalk among BaP/BPDE exposure, ferroptosis, angiogenesis, and miscarriage, discovering novel toxicological effects of BaP/BPDE on human reproductive health. This study also warned the public to avoid exposure to polycyclic aromatic hydrocarbons during pregnancy to effectively prevent adverse pregnancy outcomes.
环境中的苯并(a)芘（BaP）及其最终代谢物 BPDE（苯并(a)芘-7,8-二氢二醇-9,10-环氧化物）是普遍存在且不可避免的持久性有机污染物和内分泌干扰化学物质。胎盘蜕膜中的血管生成在健康妊娠中起着关键作用。铁死亡是一种新发现的、依赖铁的细胞死亡方式。然而，到目前为止，BaP/BPDE 暴露、铁死亡、血管生成缺陷和流产从未被关联过；其调控机制也很少被探索过。在这项研究中，我们使用了 BPDE 暴露的 HUVEC（人脐静脉内皮细胞）、不明原因复发性流产及其匹配的健康对照组的蜕膜组织和血清样本，以及 BaP 暴露的小鼠流产模型的胎盘组织进行了实验。我们发现，BaP/BPDE 暴露会导致铁死亡，进而直接抑制血管生成，最终导致流产。在机制上，BaP/BPDE 暴露会增加游离铁水平，促进脂质过氧化，还会上调 MARCHF1（GPX4 的新型 E3 连接酶）水平，促进 GPX4 的泛素化降解，这两者都会导致 HUVEC 铁死亡。此外，我们还发现 GPX4 蛋白下调了血管生成关键蛋白 VEGFA 和 ANG-1 的蛋白水平，从而抑制了 HUVEC 的血管生成。相反，补充 GPX4 可以抑制铁死亡，恢复血管生成，缓解流产。此外，血清中游离铁和 VEGFA 的水平可能可以预测流产的风险。总的来说，这项研究揭示了 BaP/BPDE 暴露、铁死亡、血管生成和流产之间的相互作用，发现了 BaP/BPDE 对人类生殖健康的新的毒理学作用。这项研究还警告公众在怀孕期间避免接触多环芳烃，以有效预防不良妊娠结局。
