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BaP/BPDE exposure up-regulated free Fe2+ level and accelerated lipid peroxidation. Meanwhile, BaP/BPDE exposure also up-regulated MARCHF1 protein level, promoted its mediated ubiquitination degradation of GPX4, and hence decreased GPX4 protein level. Both pathways led to ferroptosis and further suppressed angiogenesis, which possibly induced miscarriage. Supplement with Gpx4 could efficiently suppress ferroptosis and recover angiogenesis in BPDE-exposed HUVECs and also alleviate miscarriage in BaP-exposed mouse miscarriage model. This study discovered novel toxicological effects and their underlying mechanisms that BaP/BPDE exposure induced ferroptosis, suppressed angiogenesis, and eventually induced miscarriage, as well as provided a promising approach to predict and treat against miscarriage. [Display omitted] • BPDE promoted HUVEC ferroptosis and suppressed angiogenesis by down-regulating GPX4 level. • BPDE promoted MARCHF1-mediated ubiquitination degradation of GPX4. • High level of BPDE-DNA adduct, ferroptosis, and defective angiogenesis in decidual tissues were associated with miscarriage. • Supplement with GPX4 suppressed ferroptosis, recovered angiogenesis, and alleviated miscarriage in BaP-exposed mouse model. • The levels of free Fe2+ and VEGFA in serum might reflect the risk of miscarriage. 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 Fe2+ 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 Fe2+ 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. [ABSTRACT FROM AUTHOR]

Environmental Benzo(a)pyrene (BaP) and its ultimate metabolite BPDE (benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide) are typical persistent organic pollutants and endocrine disrupting chemicals. BaP/BPDE exposure might cause human trophoblast cell dysfunctions and induce miscarriage. However, the underlying mechanisms remain largely elusive. In this study, we found that BPDE exposure induced human trophoblast cell pyroptosis by up-regulating NLRP3/Caspase1/GSDMD pathway. We also identified that lnc-HZ14 was highly expressed in BPDE-exposed trophoblast cells and in recurrent miscarriage (RM) vs healthy control (HC) villous tissues. Lnc-HZ14 promoted trophoblast cell pyroptosis by promoting IRF1-mediated ZBP1 transcription, increasing METTL3-mediated m6A methylation on NLRP3 mRNA and its stability, and also enhancing ZBP1/NLRP3 protein interactions. Knockdown of lnc-HZ14/ZBP1/NLRP3 axis could efficiently alleviate BPDE-induced trophoblast cell pyroptosis. Higher level of pyroptosis, as indicated by the up-regulation of lnc-HZ14/ZBP1/NLRP3 axis, was found in RM vs HC villous tissues. In BaP-exposed mouse model, BaP exposure induced placental tissue pyroptosis and miscarriage by up-regulating murine Zbp1/Nlrp3 axis, and knockdown of Nlrp3 could efficiently reduce placenta pyroptosis and alleviate BaP-induced mouse miscarriage. Serum IL-1β protein level might act as a promising indicator to predict the risk of miscarriage. These findings provided new insights into BaP/BPDE-induced trophoblast cell pyroptosis and miscarriage and might be helpful for further assessment of the toxicological effects of BaP/BPDE on the female reproduction. [Display omitted] • BPDE induced trophoblast pyroptosis by up-regulating lnc-HZ14/ZBP1/NLRP3 axis. • Lnc-HZ14 promoted ZBP1 transcription, increased NLRP3 mRNA stability, and enhanced ZBP1/NLRP3 interactions. • Higher level of pyroptosis was found in RM vs HC villous tissues. • BaP induced murine placenta pyroptosis and mouse miscarriage via Zbp1/Nlrp3 axis. • IL-1β protein level in serum might predict the risk of miscarriage [ABSTRACT FROM AUTHOR]