As one of the environmental risk factors for human health, atmospheric fine particulate matter (PM2.5) contributes to cognitive deterioration in addition to respiratory and cardiovascular injuries. Recently, increasing evidence implicates that PM2.5 inhalation can affect neurological functions in offspring, but the sex-specific outcomes and the underlying biological processes are largely unknown. To observe the influence of prenatal PM2.5 exposure on cognitive performance in offspring, to elucidate the neuronal morphological alterations and possible transcriptional regulation based on mRNA-sequencing (mRNA-Seq) data after birth, and to determine the key components of PM2.5 contributing to the adverse effects. Pregnant C57BL/6J mice were exposed to sterile saline or PM2.5 suspension. Morris water maze test was used to assess the cognitive function in weanling offspring. Microscopic observation was applied to detect neuronal morphogenesis in vivo and in vitro. The cortex tissues from male offspring were collected on postnatal days (PNDs) 1, 7, and 21 for mRNA-Seq analysis. The organic and inorganic components of PM2.5 were separated to assess their contributions using primary cultured neurons. Prenatal PM2.5 exposure impaired spatial learning and memory in weanling male mice, but not female mice. The sex-specific outcomes were associated with mRNA expression profiles of the cortex during postnatal critical windows, and the annotations in Gene Ontology (GO) of differentially expressed genes (DEGs) revealed that the exposure persistently disrupted the expression of genes involved in neuronal features in male offspring. Consistently, axonal growth impairment and dendritic complexity reduction were observed. Importantly, Homeobox A5 (Hoxa5), a critical transcription factor regulating all of the neuronal morphogenesis-associated hub genes on PNDs 1, 7, and 21, significantly decreased in the cortex of male offspring following PM2.5 exposure. In addition, both inorganic and organic components were harmful to axonal and dendritic growth, with organic components exhibiting stronger inhibition than inorganic ones. Prenatal PM2.5 exposure affected spatial learning and memory in male mice by disrupting Hoxa5-mediated neuronal morphogenesis, and the organic components, including polycyclic aromatic hydrocarbons (PAHs), posed more adverse effects than the inorganic components.

中文翻译：

---

产前 PM2.5 暴露会损害雄性小鼠后代的空间学习和记忆：从转录调控到神经元形态发生

作为人类健康的环境风险因素之一，大气细颗粒物 (PM2.5) 除了会导致呼吸系统和心血管损伤外，还会导致认知能力下降。最近，越来越多的证据表明吸入 PM2.5 会影响后代的神经功能，但性别特异性结果和潜在的生物学过程在很大程度上是未知的。观察产前 PM2.5 暴露对后代认知能力的影响，阐明出生后基于 mRNA 测序 (mRNA-Seq) 数据的神经元形态学改变和可能的转录调控，并确定 PM2.5 的关键成分促成不利影响。将怀孕的 C57BL/6J 小鼠暴露于无菌盐水或 PM2.5 悬浮液中。Morris 水迷宫试验用于评估断奶后代的认知功能。应用显微镜观察来检测体内和体外的神经元形态发生。在出生后第 1、7 和 21 天收集雄性后代的皮层组织用于 mRNA-Seq 分析。分离 PM2.5 的有机和无机成分，以使用原代培养的神经元评估它们的贡献。产前 PM2.5 暴露会损害断奶雄性小鼠的空间学习和记忆，但不会损害雌性小鼠。性别特异性结果与出生后关键窗口期间皮质的 mRNA 表达谱相关，基因本体论 (GO) 中差异表达基因 (DEG) 的注释显示，暴露持续破坏了与神经元特征相关的基因表达男性后代。一致地，观察到轴突生长障碍和树突复杂性降低。重要的是，Homeobox A5 (Hoxa5) 是调节 PND 1、7 和 21 上所有神经元形态发生相关中枢基因的关键转录因子，在暴露于 PM2.5 后雄性后代的皮质中显着减少。此外，无机和有机成分均对轴突和树突生长有害，有机成分比无机成分表现出更强的抑制作用。产前 PM2.5 暴露通过破坏 Hoxa5 介导的神经元形态发生来影响雄性小鼠的空间学习和记忆，并且包括多环芳烃 (PAH) 在内的有机成分比无机成分造成更多的不利影响。同源框 A5 (Hoxa5) 是调节 PND 1、7 和 21 上所有神经元形态发生相关中枢基因的关键转录因子，在暴露于 PM2.5 后雄性后代的皮质中显着减少。此外，无机和有机成分均对轴突和树突生长有害，有机成分比无机成分表现出更强的抑制作用。产前 PM2.5 暴露通过破坏 Hoxa5 介导的神经元形态发生来影响雄性小鼠的空间学习和记忆，并且包括多环芳烃 (PAH) 在内的有机成分比无机成分造成更多的不利影响。同源框 A5 (Hoxa5) 是调节 PND 1、7 和 21 上所有神经元形态发生相关中枢基因的关键转录因子，在暴露于 PM2.5 后雄性后代的皮质中显着减少。此外，无机和有机成分均对轴突和树突生长有害，有机成分比无机成分表现出更强的抑制作用。产前 PM2.5 暴露通过破坏 Hoxa5 介导的神经元形态发生来影响雄性小鼠的空间学习和记忆，并且包括多环芳烃 (PAH) 在内的有机成分比无机成分造成更多的不利影响。暴露于 PM2.5 后，雄性后代的大脑皮层显着减少。此外，无机和有机成分均对轴突和树突生长有害，有机成分比无机成分表现出更强的抑制作用。产前 PM2.5 暴露通过破坏 Hoxa5 介导的神经元形态发生来影响雄性小鼠的空间学习和记忆，并且包括多环芳烃 (PAH) 在内的有机成分比无机成分造成更多的不利影响。暴露于 PM2.5 后，雄性后代的大脑皮层显着减少。此外，无机和有机成分均对轴突和树突生长有害，有机成分比无机成分表现出更强的抑制作用。产前 PM2.5 暴露通过破坏 Hoxa5 介导的神经元形态发生来影响雄性小鼠的空间学习和记忆，并且包括多环芳烃 (PAH) 在内的有机成分比无机成分造成更多的不利影响。