期刊
CHEMICO-BIOLOGICAL INTERACTIONS
卷 387, 期 -, 页码 -出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.cbi.2023.110812
关键词
1-Nitropyrene; Ferroptosis; Placenta; ERK
Fetal growth restriction (FGR) is a common complication in obstetrics, and its exact cause is unknown. In this study, we constructed 1-NP exposed pregnant mice models and found that 1-NP induced FGR. Additionally, we observed significant ferroptosis in placental trophoblasts from 1-NP exposed mice and human FGR patients. Using in vitro cell models, we demonstrated that 1-NP impaired trophoblast biological function and induced cellular ferroptosis. We also identified the ERK signaling pathway and CYP1B1 as key regulators of 1-NP-induced ferroptosis. This study provides new insights into the aetiology of FGR and the reproductive toxicity of environmental pollutants.
Fetal growth restriction (FGR) is a prevalent complication in obstetrics, yet its exact aetiology remains unknown. Numerous studies suggest that the degradation of the living environment is a significant risk factor for FGR. 1Nitropyrene (1-NP) is a widespread environmental pollutant as a representative substance of nitro-polycyclic aromatic hydrocarbons. In this study, we revealed that 1-NP induced FGR in fetal mice by constructing 1-NP exposed pregnant mice models. Intriguingly, we found that placental trophoblasts of 1-NP exposed mice exhibited significant ferroptosis, which was similarly detected in placental trophoblasts from human FGR patients. In this regard, we established a 1-NP exposed cell model in vitro using two human trophoblast cell lines, HTR8/SVneo and JEG-3. We found that 1-NP not only impaired the proliferation, migration, invasion and angiogenesis of trophoblasts, but also induced severe cellular ferroptosis. Meanwhile, the ferroptosis inhibitor ferrostatin-1 (Fer-1) effectively rescued 1-NP-induced trophoblast biological function impairment. Mechanistically, we revealed that 1-NP regulated ferroptosis by activating the ERK signaling pathway. Moreover, we innovatively revealed that CYP1B1 was essential for the activation of ERK signaling pathway induced by 1-NP. Overall, our study innovatively identified ferroptosis as a significant contributor to 1-NP induced trophoblastic functional impairment leading to FGR and clarified the specific mechanism by which 1-NP induced ferroptosis via the CYP1B1/ERK signaling pathway. Our study provided novel insights into the aetiology of FGR and revealed new mechanisms of reproductive toxicity of environmental pollutants.
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