{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T04:03:28Z","timestamp":1784693008639,"version":"3.55.0"},"reference-count":73,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T00:00:00Z","timestamp":1753833600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung and Blood Institute","doi-asserted-by":"crossref","award":["R01HL166455"],"award-info":[{"award-number":["R01HL166455"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["P30 ES019776"],"award-info":[{"award-number":["P30 ES019776"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["R01 ES031980"],"award-info":[{"award-number":["R01 ES031980"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Emory Integrated Genomics Core"},{"name":"Emory University School of Medicine and is"},{"name":"Emory Integrated Core Facilities"}],"content-domain":{"domain":["www.atsjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats: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 coexposure to Cd and As at levels relevant to human intake inhibits branching morphogenesis, yet cell type\u2013specific mechanisms remain elusive. Here, we examined early embryonic (Embryonic Day [E]12) lungs from mice exposed prenatally to either 0 (control) or 250 (treated) ppb of both Cd and As. Through single-cell multiome sequencing (single-cell transposase-accessible chromatin with high-throughput sequencing + single-cell RNA sequencing) and high-resolution metabolomics, we present a multifaceted landscape of Cd- and As-induced molecular and cellular disruption. We identified 19 cell states that exhibited 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+\u2009mesenchymal 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 they provide insights into the factors central to cell resilience during this vulnerable stage of lung development.<\/jats:p>","DOI":"10.1165\/rcmb.2024-0563oc","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T18:05:29Z","timestamp":1753898729000},"page":"106-118","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":2,"title":["Single-Cell Multiome Impact of Prenatal Heavy Metal Exposure on Early Airway Development"],"prefix":"10.1093","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-2503-752X","authenticated-orcid":false,"given":"Boris","family":"Minasenko","sequence":"first","affiliation":[{"name":"Gangarosa Department of Environmental Health"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongxue","family":"Wang","sequence":"additional","affiliation":[{"name":"Gangarosa Department of Environmental Health"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Bioinformatics, Rollins School of Public Health"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0833-6168","authenticated-orcid":false,"given":"ViLinh","family":"Tran","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine , School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5979-2821","authenticated-orcid":false,"given":"Theresa W","family":"Gauthier","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, School of Medicine, Emory University , Atlanta, Georgia; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4566-150X","authenticated-orcid":false,"given":"Carmen J","family":"Marsit","sequence":"additional","affiliation":[{"name":"Gangarosa Department of Environmental Health"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2090-0677","authenticated-orcid":false,"given":"Dean P","family":"Jones","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine , School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0211-177X","authenticated-orcid":false,"given":"Young-Mi","family":"Go","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine , School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2902-122X","authenticated-orcid":false,"given":"Cherry","family":"Wongtrakool","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine , School of Medicine, and"},{"name":"Atlanta VA Healthcare System , Decatur, Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8704-1512","authenticated-orcid":false,"given":"Chang","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Bioinformatics, Rollins School of Public Health"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2747-9085","authenticated-orcid":false,"given":"Xin","family":"Hu","sequence":"additional","affiliation":[{"name":"Gangarosa Department of Environmental Health"},{"name":"Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine , School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,7,30]]},"reference":[{"key":"2026021011164792000_bib1","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/S0070-2153(10)90003-3","article-title":"Lung organogenesis","volume":"90","author":"Warburton","year":"2010","journal-title":"Curr Top Dev Biol"},{"key":"2026021011164792000_bib2","doi-asserted-by":"crossref","first-page":"L611","DOI":"10.1152\/ajplung.00038.2007","article-title":"Nicotine alters lung branching morphogenesis through the \u03b17 nicotinic acetylcholine receptor","volume":"293","author":"Wongtrakool","year":"2007","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026021011164792000_bib3","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1165\/rcmb.2011-0028OC","article-title":"Prenatal nicotine exposure alters lung function and airway geometry through \u03b17 nicotinic receptors","volume":"46","author":"Wongtrakool","year":"2012","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026021011164792000_bib4","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1165\/rcmb.2024-0123LE","article-title":"Pyrimidine biosynthesis in branching morphogenesis defects induced by prenatal heavy metal exposure","volume":"71","author":"Wongtrakool","year":"2024","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026021011164792000_bib5","volume-title":"CERCLA priority list of hazardous substances.","author":"Centers for Disease Control and Prevention","year":"2007"},{"key":"2026021011164792000_bib6","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1186\/s12889-015-2379-9","article-title":"Geographic clustering of elevated blood heavy metal levels in pregnant women","volume":"15","author":"King","year":"2015","journal-title":"BMC Public Health"},{"key":"2026021011164792000_bib7","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/S0378-4274(02)00381-8","article-title":"A global perspective on cadmium pollution and toxicity in non-occupationally exposed population","volume":"137","author":"Satarug","year":"2003","journal-title":"Toxicol Lett"},{"key":"2026021011164792000_bib8","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1289\/ehp.1205875","article-title":"The broad scope of health effects from chronic arsenic exposure: update on a worldwide public health problem","volume":"121","author":"Naujokas","year":"2013","journal-title":"Environ Health Perspect"},{"key":"2026021011164792000_bib9","doi-asserted-by":"crossref","first-page":"e948","DOI":"10.1161\/CIR.0000000000000773","article-title":"Cardiovascular health in American Indians and Alaska Natives: a scientific statement from the American Heart Association","volume":"141","author":"Breathett","year":"2020","journal-title":"Circulation"},{"key":"2026021011164792000_bib10","doi-asserted-by":"crossref","first-page":"2727","DOI":"10.3390\/ijerph16152727","article-title":"Quantification of elemental contaminants in unregulated water across Western Navajo Nation","volume":"16","author":"Credo","year":"2019","journal-title":"Int J Environ Res Public Health"},{"key":"2026021011164792000_bib11","doi-asserted-by":"crossref","first-page":"127001","DOI":"10.1289\/EHP7313","article-title":"Inequalities in public water arsenic concentrations in counties and community water systems across the United States, 2006\u20132011","volume":"128","author":"Nigra","year":"2020","journal-title":"Environ Health Perspect"},{"key":"2026021011164792000_bib12","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.envres.2016.11.008","article-title":"Arsenic levels among pregnant women and newborns in Canada: results from the Maternal-Infant Research on Environmental Chemicals (MIREC) cohort","volume":"153","author":"Ettinger","year":"2017","journal-title":"Environ Res"},{"key":"2026021011164792000_bib13","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1186\/1471-2458-13-841","article-title":"Lead, mercury and cadmium in umbilical cord blood and its association with parental epidemiological variables and birth factors","volume":"13","author":"Garc\u00eda-Esquinas","year":"2013","journal-title":"BMC Public Health"},{"key":"2026021011164792000_bib14","doi-asserted-by":"crossref","first-page":"5336","DOI":"10.1007\/s11356-017-0874-5","article-title":"Children\u2019s environmental chemical exposures in the USA, NHANES 2003-2012","volume":"25","author":"Hendryx","year":"2018","journal-title":"Environ Sci Pollut Res Int"},{"key":"2026021011164792000_bib15","volume-title":"National report on human exposure to environmental chemicals.","author":"Centers for Disease Control and Prevension","year":"2001"},{"key":"2026021011164792000_bib16","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1007\/s40572-018-0184-1","article-title":"Long-term health effects and underlying biological mechanisms of developmental exposure to arsenic","volume":"5","author":"Smeester","year":"2018","journal-title":"Curr Environ Health Rep"},{"key":"2026021011164792000_bib17","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1007\/s00420-010-0591-6","article-title":"Lung function in adults following in utero and childhood exposure to arsenic in drinking water: preliminary findings","volume":"84","author":"Dauphin\u00e9","year":"2011","journal-title":"Int Arch Occup Environ Health"},{"key":"2026021011164792000_bib18","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1289\/ehp.1103711","article-title":"Maternal cadmium exposure during pregnancy and size at birth: a prospective cohort study","volume":"120","author":"Kippler","year":"2012","journal-title":"Environ Health Perspect"},{"key":"2026021011164792000_bib19","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.envres.2014.04.008","article-title":"Blood cadmium levels are associated with a decline in lung function in males","volume":"132","author":"Oh","year":"2014","journal-title":"Environ Res"},{"key":"2026021011164792000_bib20","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1111\/pai.13397","article-title":"Foetal exposure to heavy metals and risk of atopic diseases in early childhood","volume":"32","author":"Pesce","year":"2021","journal-title":"Pediatr Allergy Immunol"},{"key":"2026021011164792000_bib21","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1289\/ehp.1205590","article-title":"In utero exposure to arsenic alters lung development and genes related to immune and mucociliary function in mice","volume":"121","author":"Ramsey","year":"2013","journal-title":"Environ Health Perspect"},{"key":"2026021011164792000_bib22","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/2050-6511-14-13","article-title":"In utero exposure to low dose arsenic via drinking water impairs early life lung mechanics in mice","volume":"14","author":"Ramsey","year":"2013","journal-title":"BMC Pharmacol Toxicol"},{"key":"2026021011164792000_bib23","doi-asserted-by":"crossref","first-page":"104993","DOI":"10.1016\/j.envint.2019.104993","article-title":"Combined exposure to lead, cadmium, mercury, and arsenic and kidney health in adolescents age 12\u201319 in NHANES 2009\u20132014","volume":"131","author":"Sanders","year":"2019","journal-title":"Environ Int"},{"key":"2026021011164792000_bib24","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1038\/s41467-021-21865-2","article-title":"Single cell transcriptomic analysis of murine lung development on hyperoxia-induced damage","volume":"12","author":"Hurskainen","year":"2021","journal-title":"Nat Commun"},{"key":"2026021011164792000_bib25","doi-asserted-by":"crossref","first-page":"dev199512","DOI":"10.1242\/dev.199512","article-title":"A single-cell atlas of mouse lung development","volume":"148","author":"Negretti","year":"2021","journal-title":"Development"},{"key":"2026021011164792000_bib26","doi-asserted-by":"crossref","first-page":"4841","DOI":"10.1016\/j.cell.2022.11.005","article-title":"A human fetal lung cell atlas uncovers proximal-distal gradients of differentiation and key regulators of epithelial fates","volume":"185","author":"He","year":"2022","journal-title":"Cell"},{"key":"2026021011164792000_bib27","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1164\/rccm.202210-2015OC","article-title":"Single cell multiomics identifies cells and genetic networks underlying alveolar capillary dysplasia","volume":"208","author":"Guo","year":"2023","journal-title":"Am J Respir Crit Care Med"},{"key":"2026021011164792000_bib28","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1089\/ars.2019.8006","article-title":"Omics integration for mitochondria systems biology","volume":"32","author":"Hu","year":"2020","journal-title":"Antioxid Redox Signal"},{"key":"2026021011164792000_bib29","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1021\/acs.chemrestox.7b00309","article-title":"Dose and diet \u2013 sources of arsenic intake in mouse in utero exposure scenarios","volume":"31","author":"Murko","year":"2018","journal-title":"Chem Res Toxicol"},{"key":"2026021011164792000_bib30","unstructured":"Minasenko\n              B\n            , HuX. Single-cell multiome impact of prenatal heavy metal exposure on early airway development. UNC Dataverse, V1; 2024 [accessed 2025 Aug 5]. Available from: https:\/\/doi.org\/10.15139\/S3\/RCDYWC."},{"key":"2026021011164792000_bib31","doi-asserted-by":"crossref","first-page":"5233","DOI":"10.1038\/s41598-019-41695-z","article-title":"From Louvain to Leiden: guaranteeing well-connected communities","volume":"9","author":"Traag","year":"2019","journal-title":"Sci Rep"},{"key":"2026021011164792000_bib32","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1186\/s13059-020-02210-0","article-title":"Single-cell transcriptome profiling of an adult human cell atlas of 15 major organs","volume":"21","author":"He","year":"2020","journal-title":"Genome Biol"},{"key":"2026021011164792000_bib33","doi-asserted-by":"crossref","first-page":"4566","DOI":"10.1038\/s41467-023-40173-5","article-title":"Guided construction of single cell reference for human and mouse lung","volume":"14","author":"Guo","year":"2023","journal-title":"Nat Commun"},{"key":"2026021011164792000_bib34","doi-asserted-by":"crossref","first-page":"eabc3172","DOI":"10.1126\/science.abc3172","article-title":"Genomic, epigenomic, and biophysical cues controlling the emergence of the lung alveolus","volume":"371","author":"Zepp","year":"2021","journal-title":"Science"},{"key":"2026021011164792000_bib35","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1007\/978-3-642-04898-2_253","volume-title":"International encyclopedia of statistical science.","author":"Sprent","year":"2011"},{"key":"2026021011164792000_bib36","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026021011164792000_bib37","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1038\/s41587-022-01476-y","article-title":"Multi-omic single-cell velocity models epigenome-transcriptome interactions and improves cell fate prediction","volume":"41","author":"Li","year":"2023","journal-title":"Nat Biotechnol"},{"key":"2026021011164792000_bib38","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1038\/s41592-023-01938-4","article-title":"SCENIC+: single-cell multiomic inference of enhancers and gene regulatory networks","volume":"20","author":"Bravo Gonz\u00e1lez-Blas","year":"2023","journal-title":"Nat Methods"},{"key":"2026021011164792000_bib39","doi-asserted-by":"crossref","first-page":"2417","DOI":"10.1016\/j.bbagen.2018.04.009","article-title":"Selenium supplementation prevents metabolic and transcriptomic responses to cadmium in mouse lung","volume":"1862","author":"Hu","year":"2018","journal-title":"Biochim Biophys Acta Gen Subj"},{"key":"2026021011164792000_bib40","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1093\/jn\/nxy036","article-title":"Selenium supplementation alters hepatic energy and fatty acid metabolism in mice","volume":"148","author":"Hu","year":"2018","journal-title":"J Nutr"},{"key":"2026021011164792000_bib41","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.freeradbiomed.2018.12.005","article-title":"Low-dose cadmium disrupts mitochondrial citric acid cycle and lipid metabolism in mouse lung","volume":"131","author":"Hu","year":"2019","journal-title":"Free Radic Biol Med"},{"key":"2026021011164792000_bib42","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1016\/j.ajpath.2019.04.013","article-title":"Environmental cadmium enhances lung injury by respiratory syncytial virus infection","volume":"189","author":"Hu","year":"2019","journal-title":"Am J Pathol"},{"key":"2026021011164792000_bib43","doi-asserted-by":"crossref","first-page":"vbaf088","DOI":"10.1093\/bioadv\/vbaf088","article-title":"Rodin: a streamlined metabolomics data analysis and visualization tool","volume":"5","author":"Minasenko","year":"2025","journal-title":"Bioinform Adv"},{"key":"2026021011164792000_bib44","doi-asserted-by":"crossref","first-page":"D801","DOI":"10.1093\/nar\/gks1065","article-title":"HMDB 3.0\u2014the human metabolome database in 2013","volume":"41","author":"Wishart","year":"2013","journal-title":"Nucleic Acids Res"},{"key":"2026021011164792000_bib45","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1513\/pats.200801-006AW","article-title":"Lung epithelial progenitor cells: lessons from development","volume":"5","author":"Rawlins","year":"2008","journal-title":"Proc Am Thorac Soc"},{"key":"2026021011164792000_bib46","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1186\/s12931-022-02213-4","article-title":"The FoxP1 gene regulates lung function, production of matrix metalloproteinases and inflammatory mediators, and viability of lung epithelia","volume":"23","author":"Andreas","year":"2022","journal-title":"Respir Res"},{"key":"2026021011164792000_bib47","doi-asserted-by":"crossref","first-page":"27488","DOI":"10.1074\/jbc.M100636200","article-title":"Characterization of a new subfamily of winged-helix\/forkhead (Fox) genes that are expressed in the lung and act as transcriptional repressors","volume":"276","author":"Shu","year":"2001","journal-title":"J Biol Chem"},{"key":"2026021011164792000_bib48","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1136\/thoraxjnl-2013-204608","article-title":"Epithelial-mesenchymal transition in lung development and disease: does it exist and is it important?","volume":"69","author":"Bartis","year":"2014","journal-title":"Thorax"},{"key":"2026021011164792000_bib49","doi-asserted-by":"crossref","first-page":"2233","DOI":"10.1242\/dev.129.9.2233","article-title":"GATA6 regulates differentiation of distal lung epithelium","volume":"129","author":"Yang","year":"2002","journal-title":"Development"},{"key":"2026021011164792000_bib50","doi-asserted-by":"crossref","first-page":"3529","DOI":"10.1210\/en.2016-1286","article-title":"Up-regulation of 11\u03b2-hydroxysteroid dehydrogenase type 2 expression by Hedgehog ligand contributes to the conversion of cortisol into cortisone","volume":"157","author":"Zhu","year":"2016","journal-title":"Endocrinology"},{"key":"2026021011164792000_bib51","doi-asserted-by":"crossref","first-page":"3037","DOI":"10.1242\/dev.132829","article-title":"Slit-Robo signaling","volume":"143","author":"Blockus","year":"2016","journal-title":"Development"},{"key":"2026021011164792000_bib52","doi-asserted-by":"crossref","first-page":"2167","DOI":"10.1523\/JNEUROSCI.5254-10.2011","article-title":"The UNC5C netrin receptor regulates dorsal guidance of mouse hindbrain axons","volume":"31","author":"Kim","year":"2011","journal-title":"J Neurosci"},{"key":"2026021011164792000_bib53","doi-asserted-by":"crossref","first-page":"3349","DOI":"10.1038\/s41467-018-05559-w","article-title":"ZCCHC3 is a co-sensor of cGAS for dsDNA recognition in innate immune response","volume":"9","author":"Lian","year":"2018","journal-title":"Nat Commun"},{"key":"2026021011164792000_bib54","doi-asserted-by":"crossref","first-page":"e13308","DOI":"10.7554\/eLife.13308","article-title":"Hedgehog signaling is a potent regulator of liver lipid metabolism and reveals a GLI-code associated with steatosis","volume":"5","author":"Matz-Soja","year":"2016","journal-title":"Elife"},{"key":"2026021011164792000_bib55","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1158\/0008-5472.CAN-20-0652","article-title":"A transcriptional regulatory loop of master regulator transcription factors, PPARG, and fatty acid synthesis promotes esophageal adenocarcinoma","volume":"81","author":"Ma","year":"2021","journal-title":"Cancer Res"},{"key":"2026021011164792000_bib56","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1289\/EHP108","article-title":"Health risk assessment of dietary cadmium intake: do current guidelines indicate how much is safe?","volume":"125","author":"Satarug","year":"2017","journal-title":"Environ Health Perspect"},{"key":"2026021011164792000_bib57","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1038\/nature13173","article-title":"Reconstructing lineage hierarchies of the distal lung epithelium using single-cell RNA-seq","volume":"509","author":"Treutlein","year":"2014","journal-title":"Nature"},{"key":"2026021011164792000_bib58","doi-asserted-by":"crossref","first-page":"L5","DOI":"10.1152\/ajplung.00269.2022","article-title":"Remarkable sex-specific differences at single-cell resolution in neonatal hyperoxic lung injury","volume":"324","author":"Cantu","year":"2023","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026021011164792000_bib59","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.molcel.2013.02.018","article-title":"Nkx2-1 represses a latent gastric differentiation program in lung adenocarcinoma","volume":"50","author":"Snyder","year":"2013","journal-title":"Mol Cell"},{"key":"2026021011164792000_bib60","doi-asserted-by":"crossref","first-page":"E4456","DOI":"10.1073\/pnas.1311847110","article-title":"Sox9 plays multiple roles in the lung epithelium during branching morphogenesis","volume":"110","author":"Rockich","year":"2013","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026021011164792000_bib61","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1038\/s42003-021-02118-w","article-title":"Wnt signaling in lung development, regeneration, and disease progression","volume":"4","author":"Aros","year":"2021","journal-title":"Commun Biol"},{"key":"2026021011164792000_bib62","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1186\/1471-2164-12-173","article-title":"Comparative genomic analyses identify common molecular pathways modulated upon exposure to low doses of arsenic and cadmium","volume":"12","author":"Benton","year":"2011","journal-title":"BMC Genomics"},{"key":"2026021011164792000_bib63","volume-title":"Toxicological profile for cadmium.","author":"Faroon","year":"2012"},{"key":"2026021011164792000_bib64","volume-title":"Toxicological profile for arsenic.","author":"Chou","year":"2007"},{"key":"2026021011164792000_bib65","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1289\/ehp.1002114","article-title":"An emerging role for epigenetic dysregulation in arsenic toxicity and carcinogenesis","volume":"119","author":"Ren","year":"2011","journal-title":"Environ Health Perspect"},{"key":"2026021011164792000_bib66","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1006\/bbrc.2000.2601","article-title":"Polyamines: mysterious modulators of cellular functions","volume":"271","author":"Igarashi","year":"2000","journal-title":"Biochem Biophys Res Commun"},{"key":"2026021011164792000_bib67","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1210\/er.2011-0012","article-title":"Polyamines on the reproductive landscape","volume":"32","author":"Lef\u00e8vre","year":"2011","journal-title":"Endocr Rev"},{"key":"2026021011164792000_bib68","doi-asserted-by":"crossref","first-page":"13269","DOI":"10.1038\/srep13269","article-title":"Polyamine biosynthesis is critical for growth and differentiation of the pancreas","volume":"5","author":"Mastracci","year":"2015","journal-title":"Sci Rep"},{"key":"2026021011164792000_bib69","doi-asserted-by":"crossref","first-page":"17294","DOI":"10.3390\/ijms242417294","article-title":"Positive regulation of S-adenosylmethionine on chondrocytic differentiation via stimulation of polyamine production and the gene expression of chondrogenic differentiation factors","volume":"24","author":"Hoang","year":"2023","journal-title":"Int J Mol Sci"},{"key":"2026021011164792000_bib70","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1164\/rccm.200207-744OC","article-title":"Augmentation of endogenous dopamine production increases lung liquid clearance","volume":"169","author":"Adir","year":"2004","journal-title":"Am J Respir Crit Care Med"},{"key":"2026021011164792000_bib71","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1165\/rcmb.2005-0297TR","article-title":"The dopamine paradox in lung and kidney epithelia","volume":"33","author":"Bertorello","year":"2005","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026021011164792000_bib72","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1165\/rcmb.2008-0390OC","article-title":"Gli2 influences proliferation in the developing lung through regulation of cyclin expression","volume":"42","author":"Rutter","year":"2010","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026021011164792000_bib73","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/bs.ctdb.2020.09.004","article-title":"Uncovering cellular networks in branching morphogenesis using single-cell transcriptomics","volume":"143","author":"Goodwin","year":"2021","journal-title":"Curr Top Dev Biol"}],"container-title":["American Journal of Respiratory Cell and Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrcmb\/advance-article-pdf\/doi\/10.1165\/rcmb.2024-0563OC\/66542853\/rcmb.2024-0563oc.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/74\/1\/106\/66542853\/rcmb.2024-0563oc.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/74\/1\/106\/66542853\/rcmb.2024-0563oc.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T16:17:05Z","timestamp":1770740225000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article\/74\/1\/106\/8438548"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,30]]},"references-count":73,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,7,30]]},"published-print":{"date-parts":[[2026,1,1]]}},"URL":"https:\/\/doi.org\/10.1165\/rcmb.2024-0563oc","relation":{},"ISSN":["1535-4989"],"issn-type":[{"value":"1535-4989","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,1]]},"published":{"date-parts":[[2025,7,30]]},"assertion":[{"value":"2024-11-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-29","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}