Environmental benzo(a)pyrene (BaP) and itsmetabolite benzo(a)pyrene-7, 8-dihydrodiol-9, 10-epoxide (BPDE), classic endocrine disrupting chemical and persistent organic pollutant, could cause miscarriage. However, the detailed mechanisms are still largely unclear and should be further explored. In this study, we discovered that exposure of trophoblast cells with BPDE could suppressed cell invasion/migration by inhibiting MEST/VIM (Vimentin) pathway. Moreover, BPDE exposure also increased lnc-HZ01 expression level, which further inhibited MEST/VIM pathway and then suppressed invasion/migration. Knockdown of lnc-HZ01 or overexpression of MEST could efficiently rescue invasion/migration of BPDE-exposed Swan 71 cells. Furthermore, lnc-HZ01 was highly expressed and MEST/VIM were lowly expressed in recurrent miscarriage (RM) villous tissues compared with healthy control (HC) group. Finally, we also found that BaP exposure inhibited murine Mest/Vim pathway in placental tissues and induced miscarriage in BaP-exposed mice. Therefore, the regulatory mechanisms were similar in BPDE-exposed human trophoblast cells, RM villous tissues, and placental tissues of BaP-exposed mice with miscarriage, building a bridge to connect BaP/BPDE exposure, invasion/migration, and miscarriage. This study provided novel insights in the toxicological effects and molecular mechanisms of BaP/BPDE-induced miscarriage, which is helpful for better elucidating the toxicological risks of BaP/BPDE on female reproduction.

中文翻译：

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环境 BaP/BPDE 通过下调 lnc-HZ01/MEST/VIM 轴抑制滋养层细胞侵袭/迁移并诱导流产


环境中的苯并(a)芘(BaP)及其代谢物苯并(a)芘-7,8-二氢二醇-9,10-环氧化物(BPDE)是典型的内分泌干扰化学物质和持久性有机污染物，可能导致流产。然而，具体机制仍不清楚，应进一步探讨。在这项研究中，我们发现滋养层细胞暴露于 BPDE 可以通过抑制 MEST/VIM (Vimentin) 途径来抑制细胞侵袭/迁移。此外，BPDE暴露还增加了lnc-HZ01的表达水平，从而进一步抑制MEST/VIM通路，进而抑制侵袭/迁移。 lnc-HZ01的敲低或MEST的过表达可以有效地挽救BPDE暴露的Swan 71细胞的侵袭/迁移。此外，与健康对照组（HC）相比，复发性流产（RM）绒毛组织中lnc-HZ01高表达，MEST/VIM低表达。最后，我们还发现 BaP 暴露抑制小鼠胎盘组织中的 Mest/Vim 通路并诱导 BaP 暴露小鼠流产。因此，BPDE暴露的人滋养层细胞、RM绒毛组织和BaP暴露的流产小鼠的胎盘组织中的调节机制是相似的，搭建了连接BaP/BPDE暴露、侵袭/迁移和流产的桥梁。该研究为BaP/BPDE引起流产的毒理学效应和分子机制提供了新的见解，有助于更好地阐明BaP/BPDE对女性生殖的毒理学风险。