产前重金属暴露对呼吸道早期发育的影响
Boris Minasenko1, Dongxue Wang1, Jessica Chan2
1Emory University, Environmental Health, Atlanta, Georgia, United States.
概括
产前暴露于 (Cd) 和 (As) 通过破坏细胞分化和基因调节,损害胎儿肺部发育. 这些重金属会影响多个分子水平,影响早期的气道形成.
科学领域:
- 环境毒理学环境毒理学
- 发展生物学 发展生物学
- 分子毒理学 分子毒理学
背景情况:
- 产前暴露于 (Cd) 和 (As) 对胎儿发育构成重大风险.
- 暴露在重金属中可能导致终身不良健康影响,特别是影响器官生成.
- 了解肺发育过程中Cd和As毒性的细胞类型特定机制至关重要.
研究的目的:
- 在Cd和As的产前共同暴露后,研究早期肺发育中的分子和细胞干扰.
- 确定受Cd和As影响的细胞类型特异性影响和调节途径.
- 阐明Cd和As对基因表达,染色质可访问性和细胞代谢的影响.
主要方法:
- 在胚胎小鼠肺部 (E12) 进行单细胞多基因组测序 (scATAC-seq和scRNA-seq).
- 高分辨率的代谢学来分析代谢变化.
- 基因调控网络分析和速度分析,以评估细胞命运和基因表达动态.
- 对关键调节因子的蛋白质表达分析 (Gata6, Gli2).
主要成果:
- 确定了19个不同的细胞状态,与与增殖和分化相关的基因表达改变.
- 观察到细胞命运的显著干扰,特别是在近位前体和中体前体的分化.
- 确定了Gata6和Gli2的功能下降是发育障碍的核心,由减少的蛋白质水平证实.
- 代谢分析显示了聚胺,氨酸和脂肪酸生物合成途径的改变.
结论:
- 暴露在人体相关水平上的Cd和As通过多层次的干扰损害了早期的肺气道形成.
- 该研究强调了对染色质可访问性,转录和细胞代谢的影响.
- 研究结果提供了关键发育窗口期间细胞弹性机制的见解.
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