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

Single-Cell Multiome Impact of Prenatal Heavy Metal Exposure on Early Airway Development | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Single-Cell Multiome Impact of Prenatal Heavy Metal Exposure on Early Airway Development Xin Hu, Boris Minasenko, Dongxue Wang, Jessica Chan, ViLinh Ly, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5389961/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Prenatal exposure to environmental hazards such as 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 significant risks to pregnant women in 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. In this study, 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 governing cell resilience during this critical, vulnerable stage of lung development. Health sciences/Risk factors Biological sciences/Developmental biology/Differentiation Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementalMaterial.docx Supplemental material Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5389961","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":374167581,"identity":"a8ef2d92-69c4-40d8-9ee5-30d1d3bc5ce8","order_by":0,"name":"Xin 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As two of the most common and toxic heavy metals, Cd and As pose significant risks to pregnant women in 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. In this study, 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. 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