Single-Cell Multiome Impact of Prenatal Heavy Metal Exposure on Early Airway Development.

IF 5.3 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Boris Minasenko, Dongxue Wang, Jessica Chan, ViLinh Tran, Theresa W Gauthier, Carmen J Marsit, Dean P Jones, Young-Mi Go, Cherry Wongtrakool, Chang Su, Xin Hu
{"title":"Single-Cell Multiome Impact of Prenatal Heavy Metal Exposure on Early Airway Development.","authors":"Boris Minasenko, Dongxue Wang, Jessica Chan, ViLinh Tran, Theresa W Gauthier, Carmen J Marsit, Dean P Jones, Young-Mi Go, Cherry Wongtrakool, Chang Su, Xin Hu","doi":"10.1165/rcmb.2024-0563OC","DOIUrl":null,"url":null,"abstract":"<p><p>Prenatal exposure to cadmium (Cd) and arsenic (As) can severely impair fetal lung development, leading to lifelong adverse effects. As two of the most common and toxic heavy metals, Cd and As pose risks to many communities through food and water consumption. We have shown that prenatal co-exposure to Cd and As at levels relevant to human intake inhibits branching morphogenesis, yet cell-type-specific mechanisms remain elusive. Here we examined early embryonic lungs (E12) from mice exposed prenatally to either 0 (control) or 250 (treated) ppb of both Cd and As. Through single-cell multiome sequencing (scATAC-seq+scRNA-seq) and high-resolution metabolomics, we present a multifaceted landscape of Cd and As-induced molecular and cellular disruption. We identified 19 cell states exhibiting state-specific changes in gene expression related to cell proliferation and differentiation. Velocity analysis integrating RNA splicing and chromatin kinetics showed profound disruptions in cell fate, particularly affecting differentiation of <sup>Sox2</sup>+ proximal progenitors and <i>Wnt2+</i> mesenchymal progenitors. Gene regulatory network analysis pinpointed the diminished function of <i>Gata6</i> and <i>Gli2</i> as central to these disruptions, which was further confirmed by their reduced protein expression in exposed E12, E14.5 and E17 lungs. Additionally, metabolomic alterations in polyamine, tyrosine and fatty acid biosynthesis correlated with changes in gene expression of catalytic enzymes. These findings demonstrate that Cd and As at levels relevant to human exposure impair early airway formation across multiple regulatory levels, including chromatin accessibility, transcription and cell metabolism, and provide insights into the factors central to cell resilience during this vulnerable stage of lung development.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.3000,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"American Journal of Respiratory Cell and Molecular Biology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1165/rcmb.2024-0563OC","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Prenatal exposure to cadmium (Cd) and arsenic (As) can severely impair fetal lung development, leading to lifelong adverse effects. As two of the most common and toxic heavy metals, Cd and As pose risks to many communities through food and water consumption. We have shown that prenatal co-exposure to Cd and As at levels relevant to human intake inhibits branching morphogenesis, yet cell-type-specific mechanisms remain elusive. Here we examined early embryonic lungs (E12) from mice exposed prenatally to either 0 (control) or 250 (treated) ppb of both Cd and As. Through single-cell multiome sequencing (scATAC-seq+scRNA-seq) and high-resolution metabolomics, we present a multifaceted landscape of Cd and As-induced molecular and cellular disruption. We identified 19 cell states exhibiting state-specific changes in gene expression related to cell proliferation and differentiation. Velocity analysis integrating RNA splicing and chromatin kinetics showed profound disruptions in cell fate, particularly affecting differentiation of Sox2+ proximal progenitors and Wnt2+ mesenchymal progenitors. Gene regulatory network analysis pinpointed the diminished function of Gata6 and Gli2 as central to these disruptions, which was further confirmed by their reduced protein expression in exposed E12, E14.5 and E17 lungs. Additionally, metabolomic alterations in polyamine, tyrosine and fatty acid biosynthesis correlated with changes in gene expression of catalytic enzymes. These findings demonstrate that Cd and As at levels relevant to human exposure impair early airway formation across multiple regulatory levels, including chromatin accessibility, transcription and cell metabolism, and provide insights into the factors central to cell resilience during this vulnerable stage of lung development.

产前重金属暴露对早期气道发育的单细胞多组影响。
产前暴露于镉(Cd)和砷(As)可严重损害胎儿肺部发育,导致终身不良影响。作为两种最常见和最有毒的重金属,镉和砷通过食物和水的消耗对许多社区构成风险。我们已经表明,产前同时暴露于镉和砷的水平与人类摄入量有关,可以抑制分支形态的发生,但细胞类型特异性机制仍然难以捉摸。在这里,我们检查了小鼠在产前暴露于0(对照)或250(处理)ppb的Cd和As的早期胚胎肺(E12)。通过单细胞多组测序(scATAC-seq+scRNA-seq)和高分辨率代谢组学,我们呈现了镉和砷诱导的分子和细胞破坏的多方面景观。我们发现19种细胞状态表现出与细胞增殖和分化相关的基因表达的状态特异性变化。结合RNA剪接和染色质动力学的速度分析显示,细胞命运受到严重破坏,特别是影响Sox2+近端祖细胞和Wnt2+间质祖细胞的分化。基因调控网络分析指出,Gata6和Gli2的功能减弱是这些破坏的核心,这一点在暴露的E12、E14.5和E17肺中得到进一步证实。此外,多胺、酪氨酸和脂肪酸生物合成代谢组学的改变与催化酶基因表达的变化相关。这些研究结果表明,与人体暴露相关的Cd和As水平会通过多个调控水平损害早期气道形成,包括染色质可及性、转录和细胞代谢,并提供了对肺发育脆弱阶段细胞恢复力的核心因素的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
11.20
自引率
3.10%
发文量
370
审稿时长
3-8 weeks
期刊介绍: The American Journal of Respiratory Cell and Molecular Biology publishes papers that report significant and original observations in the area of pulmonary biology. The focus of the Journal includes, but is not limited to, cellular, biochemical, molecular, developmental, genetic, and immunologic studies of lung cells and molecules.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信