Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, School of Public Health, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
Toxicology. 2022 May 30;474:153225. doi: 10.1016/j.tox.2022.153225. Epub 2022 Jun 1.
It is well understood that exposure to particulate matter (PM) can have adverse effects on the nervous system. When pregnant women are exposed to PM, their fetuses are also affected through the placenta. However, the mechanisms by which fetal brain development is regulated between mother and fetus remain unclear. C57BL/6J pregnant mice were exposed to PM at embryonic day (E) 2.5, 5.5, 8.5, 11.5, 14.5, and 17.5 via nasal drip at three doses (3, 6, 12 mg/kg of body weight) or PBS control. Neurobehavioral changes in the offspring were examined at 5-6-week-old by open field test (OFT) and elevated plus maze (EPM). The maternal and fetal brain and placenta were collected at E18.5, and molecular signal changes were explored using transcriptome analysis. We found that both male and female low-dose pups and male middle-dose pups traveled a significantly longer distance than controls in EPM tests. Both male and female low-dose pups showed a higher frequency of entering the center area and female low-dose pups exhibited a higher percentage of distance moved in the center area than controls in OFT tests. Gene expression in the maternal brain, fetal brain, and placenta at E18.5 was altered. Differentially expressed genes were enriched in the neuroactive ligand-receptor interaction pathway in all three tissue types. Pathway analysis revealed that the PI3K-Akt and PKC signaling was dysregulated in the fetal brain in the high-dose group compared with the control group. The pathways play a role in neuronal survival and apoptosis. Furthermore, there is a dose-dependent increase in Caspase-6, neuronal apoptosis and neurodegeneration biomarker, levels in E18.5 fetal brain (P = 0.06). In conclusion, our study demonstrated that prenatal PM exposure enhanced exploration and locomotor activity in adolescent offspring and altered molecular events in maternal brain, fetal brain, and placenta. The connections of these changes warrant further investigations.
众所周知，颗粒物（PM）暴露会对神经系统产生不良影响。当孕妇暴露于 PM 中时，其胎儿会通过胎盘受到影响。然而，母子之间调节胎儿大脑发育的机制尚不清楚。C57BL/6J 孕鼠在胚胎期（E）2.5、5.5、8.5、11.5、14.5 和 17.5 时通过鼻腔滴注暴露于 PM，剂量为 3、6 和 12mg/kg 体重，或用 PBS 对照。在 5-6 周龄时，通过旷场试验（OFT）和高架十字迷宫（EPM）检查后代的神经行为变化。在 E18.5 时收集母脑、胎脑和胎盘，并用转录组分析探索分子信号变化。我们发现，低剂量雄性和雌性幼鼠以及中剂量雄性幼鼠在 EPM 测试中比对照组走的距离明显更长。在 OFT 测试中，低剂量雄性和雌性幼鼠的进入中央区域的频率更高，低剂量雌性幼鼠的中央区域移动距离百分比更高。E18.5 时母脑、胎脑和胎盘的基因表达发生改变。在所有三种组织类型中，差异表达基因都富集在神经活性配体-受体相互作用途径中。通路分析显示，与对照组相比，高剂量组胎脑中的 PI3K-Akt 和 PKC 信号通路失调。这些通路在神经元存活和凋亡中起作用。此外，E18.5 胎脑中 Caspase-6（神经元凋亡和神经退行性变生物标志物）水平呈剂量依赖性增加（P=0.06）。总之，我们的研究表明，产前 PM 暴露增强了青少年后代的探索和运动活动，并改变了母脑、胎脑和胎盘的分子事件。这些变化的联系值得进一步研究。
