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.