Reactive oxygen species-mediated cellular genotoxic stress is involved in 1-nitropyrene-induced trophoblast cycle arrest and fetal growth restriction
Reactive oxygen species-mediated cellular genotoxic stress is involved in 1-nitropyrene-induced trophoblast cycle arrest and fetal growth restriction
复制标题
活性氧介导的细胞基因毒性应激参与 1-硝基芘诱导的滋养层周期停滞和胎儿生长受限。
DOI：
10.1016/j.envpol.2020.113984
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
De-Xiang Xu
中科院分区：
文献类型：
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作者：
Bo Wang;Shen Xu;Xue Lu;Li Ma;Lan Gao;Shan-Yu Zhang;Ran Li;Lin Fu;Hua Wang;Guo-Ping Sun;De-Xiang Xu
1-硝基芘（1-NP）是柴油机排气源细颗粒物（PM2.5）的关键组分。我们最近的研究表明，妊娠期1-NP暴露导致胎盘增殖抑制和胎儿宫内生长受限（IUGR）。本研究旨在探讨遗传毒性应激在1-NP诱导的胎盘增殖抑制和胎儿IUGR中的作用。将人滋养层细胞暴露于1-NP（10 μM）。在1-NP暴露的胎盘滋养层细胞中，生长指数降低，PCNA下调。超过90%的1-NP暴露的滋养细胞被阻滞在G 0/G1或G2/M期。CDK 1和细胞周期蛋白B，两个G2/M周期相关蛋白，和CDK 2，一个G 0/G1周期相关蛋白，在1-NP暴露的滋养细胞减少。磷酸化Rb，CDK 2的下游分子，在1-NP暴露的滋养层细胞中被抑制。此外，在1-NP暴露的滋养层细胞中观察到DNA双链断裂，并且另一种DNA双链断裂的指标γ-H2 AX上调。磷酸化ATM，一个关键的基因毒性应激分子，及其下游分子Chk 2的升高。相比之下，Cdc 25 A，Chk 2的下游靶点，在1-NP暴露的滋养层细胞中减少。苯基-N-叔丁基硝酮（PBN），自由基清除剂，抑制1-NP诱导的遗传毒性应激和滋养细胞周期阻滞。动物实验表明，抗氧化剂N-乙酰半胱氨酸（NAC）可解除1-NP对小鼠胎盘增殖的抑制作用和胎儿宫内发育迟缓。这些结果提供的证据表明，活性氧（ROS）介导的细胞遗传毒性应激部分有助于1-NP诱导的胎盘增殖抑制和胎儿IUGR。
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.