Department of Environment Science, College of Environment and Resource, Research Center of Environment and Health, Shanxi Key Laboratory of Coal-based Emerging Pollutant Identification and Risk Control, Shanxi University, Taiyuan, Shanxi 030006, People's Republic of China.
Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, Shanxi 030032, People's Republic of China.
Proc Natl Acad Sci U S A. 2024 Oct 29;121(44):e2409597121. doi: 10.1073/pnas.2409597121. Epub 2024 Oct 21.
Epidemiological studies show a strong correlation between air pollution and fetal growth restriction (FGR), but existing results are controversial due to inherent limitations, such as causality of specific pollutants, developmental origin, and maternal-fetal transmission. To address this controversy, we first conducted a retrospective analysis of 28,796 newborns and revealed that maternal nitrogen dioxide (NO) exposure during the second trimester was positively associated with FGR, with an adjusted odds ratio of 1.075 (95% confidence interval: 1.020-1.133) per 10 μg/m NO increase for small for gestational age. Then, by establishing an animal model of prenatal NO exposure, we confirmed its adverse effects on embryonic growth and hematopoiesis in the yolk sac and fetal liver, primarily affecting the differentiation of hematopoietic stem and progenitor cells and erythroid maturation. By applying internal exposure analyses coupled with N isotope tracing, we found that maternal NO inhalation induced acquired methemoglobinemia through its byproducts and placental hypoxia in pregnant mice. Importantly, by combining transcriptional profiling, bioinformatics analysis, and RNA binding protein immunoprecipitation (RIP)/chromatin immunoprecipitation (CHIP), we clarified that placental-fetal hypoxia transmission activated hypoxia-inducible factors, disturbed hematopoiesis through the hypoxia-inducible factor 1β-long noncoding RNAs-CCAAT/enhancer binding protein alpha-proinflammatory signaling pathway, ultimately contributing to FGR progression. These findings provide insights for risk prevention and clinical intervention to promote child well-being in NO-polluted areas.
流行病学研究表明，空气污染与胎儿生长受限（FGR）之间存在很强的相关性，但由于特定污染物的因果关系、发育起源和母婴传播等固有局限性，现有结果存在争议。为了解决这一争议，我们首先对 28796 名新生儿进行了回顾性分析，结果表明，母亲在妊娠中期接触二氧化氮（NO）与 FGR 呈正相关，每增加 10μg/m 的 NO，小胎龄的调整比值比为 1.075（95%置信区间：1.020-1.133）。然后，通过建立产前 NO 暴露的动物模型，我们证实了其对卵黄囊和胎肝中胚胎生长和造血的不良影响，主要影响造血干细胞和祖细胞的分化和红细胞成熟。通过应用内暴露分析和 N 同位素示踪，我们发现，母体吸入 NO 会通过其副产物和胎盘缺氧引起获得性高铁血红蛋白血症。重要的是，通过结合转录组学分析、生物信息学分析和 RNA 结合蛋白免疫沉淀（RIP）/染色质免疫沉淀（CHIP），我们阐明了胎盘-胎儿缺氧传递激活了缺氧诱导因子，通过缺氧诱导因子 1β-长链非编码 RNA-CCAAT/增强子结合蛋白α-促炎信号通路扰乱了造血，最终导致 FGR 的进展。这些发现为预防风险和临床干预提供了思路，以促进 NO 污染地区儿童的健康。
