1-nitropyrene (1-NP) is a key component of diesel exhaust-sourced fine particulate matter (PM2.5). Our recent study demonstrated that gestational 1-NP exposure caused placental proliferation inhibition and fetal intrauterine growth restriction (IUGR). This study aimed to investigate the role of genotoxic stress on 1-NP-induced placental proliferation inhibition and fetal IUGR. Human trophoblasts were exposed to 1-NP (10 μM). Growth index was reduced and PCNA was downregulated in 1-NP-exposed placental trophoblasts. More than 90% of 1-NP-exposed trophoblasts were arrested in either G0/G1 or G2/M phases. CDK1 and cyclin B, two G2/M cycle-related proteins, and CDK2, a G0/G1 cycle-related protein, were reduced in 1-NP-exposed trophoblasts. Phosphorylated Rb, a downstream molecule of CDK2, was inhibited in 1-NP-exposed trophoblasts. Moreover, DNA double-strand break was observed and γ-H2AX, another indicator of DNA double-strand break, was upregulated in 1-NP-exposed trophoblasts. Phosphorylated ATM, a key molecule of genotoxic stress, and its downstream molecule Chk2 were elevated. By contrast, Cdc25A, a downstream target of Chk2, was reduced in 1-NP-exposed trophoblasts. Phenyl-N-t-butylnitrone (PBN), a free radical scavenger, inhibited 1-NP-induced genotoxic stress and trophoblast cycle arrest. Animal experiment showed that N-acetylcysteine (NAC), an antioxidant, rescued 1-NP-induced placental proliferation inhibition and fetal IUGR in mice. These results provide evidence that reactive oxygen species (ROS)-mediated cellular genotoxic stress partially contributes to 1-NP-induced placental proliferation inhibition and fetal IUGR.

1-硝基py（1-NP）是柴油机废气来源的细颗粒物（PM2.5）的关键成分。我们最近的研究表明，妊娠1-N​​P暴露会导致胎盘增殖抑制和胎儿宫内生长受限（IUGR）。这项研究旨在调查遗传毒性应激对1-NP诱导的胎盘增殖抑制和胎儿IUGR的作用。将人类滋养细胞暴露于1-NP（10μM）。暴露于1-NP的胎盘滋养细胞中生长指数降低，PCNA被下调。超过90％的1-NP暴露的滋养层细胞被阻滞在G0 / G1或G2 / M期。在暴露于1-NP的滋养细胞中，两种与G2 / M周期相关的蛋白CDK1和细胞周期蛋白B和与G0 / G1周期相关的蛋白CDK2减少。磷酸化的Rb，CDK2的下游分子，在1-NP暴露的滋养细胞中被抑制。此外，观察到DNA双链断裂，并且在暴露于1-NP的滋养细胞中，DNA双链断裂的另一种指标γ-H2AX被上调。遗传毒性应激的关键分子磷酸化的ATM及其下游分子Chk2升高。相比之下，Cdc25A，Chk2的下游目标，减少了1-NP暴露的滋养细胞。自由基清除剂苯基-Nt-丁基硝基（PBN）抑制1-NP诱导的遗传毒性胁迫和滋养细胞周期停滞。动物实验表明，抗氧化剂N-乙酰半胱氨酸（NAC）可以挽救1-NP诱导的胎盘增殖抑制和胎儿IUGR。这些结果提供了证据，表明活性氧（ROS）介导的细胞遗传毒性应激部分促成1-NP诱导的胎盘增殖抑制和胎儿IUGR。DNA双链断裂的另一个指标是在1-NP暴露的滋养细胞中被上调。遗传毒性应激的关键分子磷酸化的ATM及其下游分子Chk2升高。相比之下，Cdc25A，Chk2的下游目标，减少了1-NP暴露的滋养细胞。自由基清除剂苯基-Nt-丁基硝基（PBN）抑制1-NP诱导的遗传毒性胁迫和滋养细胞周期停滞。动物实验表明，抗氧化剂N-乙酰半胱氨酸（NAC）可以挽救1-NP诱导的胎盘增殖抑制和胎儿IUGR。这些结果提供了证据，表明活性氧（ROS）介导的细胞遗传毒性应激部分促成1-NP诱导的胎盘增殖抑制和胎儿IUGR。DNA双链断裂的另一个指标是在1-NP暴露的滋养细胞中被上调。遗传毒性应激的关键分子磷酸化的ATM及其下游分子Chk2升高。相比之下，Cdc25A，Chk2的下游目标，减少了1-NP暴露的滋养细胞。自由基清除剂苯基-Nt-丁基硝基（PBN）抑制1-NP诱导的遗传毒性胁迫和滋养细胞周期停滞。动物实验表明，抗氧化剂N-乙酰半胱氨酸（NAC）可以挽救1-NP诱导的胎盘增殖抑制和胎儿IUGR。这些结果提供了证据，表明活性氧（ROS）介导的细胞遗传毒性应激部分促成1-NP诱导的胎盘增殖抑制和胎儿IUGR。遗传毒性胁迫的关键分子及其下游分子Chk2升高。相比之下，Cdc25A，Chk2的下游目标，减少了1-NP暴露的滋养细胞。自由基清除剂苯基-Nt-丁基硝基（PBN）抑制1-NP诱导的遗传毒性胁迫和滋养细胞周期停滞。动物实验表明，抗氧化剂N-乙酰半胱氨酸（NAC）可以挽救1-NP诱导的胎盘增殖抑制和胎儿IUGR。这些结果提供了证据，表明活性氧（ROS）介导的细胞遗传毒性应激部分促成1-NP诱导的胎盘增殖抑制和胎儿IUGR。遗传毒性胁迫的关键分子及其下游分子Chk2升高。相比之下，Cdc25A，Chk2的下游目标，减少了1-NP暴露的滋养细胞。自由基清除剂苯基-Nt-丁基硝基（PBN）抑制1-NP诱导的遗传毒性胁迫和滋养细胞周期停滞。动物实验表明，抗氧化剂N-乙酰半胱氨酸（NAC）可以挽救1-NP诱导的胎盘增殖抑制和胎儿IUGR。这些结果提供了证据，表明活性氧（ROS）介导的细胞遗传毒性应激部分促成1-NP诱导的胎盘增殖抑制和胎儿IUGR。自由基清除剂，抑制1-NP诱导的遗传毒性胁迫和滋养细胞周期停滞。动物实验表明，抗氧化剂N-乙酰半胱氨酸（NAC）可以挽救1-NP诱导的胎盘增殖抑制和胎儿IUGR。这些结果提供了证据，表明活性氧（ROS）介导的细胞遗传毒性应激部分促成1-NP诱导的胎盘增殖抑制和胎儿IUGR。自由基清除剂，抑制1-NP诱导的遗传毒性胁迫和滋养细胞周期停滞。动物实验表明，抗氧化剂N-乙酰半胱氨酸（NAC）可以挽救1-NP诱导的胎盘增殖抑制和胎儿IUGR。这些结果提供了证据，表明活性氧（ROS）介导的细胞遗传毒性应激部分促成1-NP诱导的胎盘增殖抑制和胎儿IUGR。