{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T03:49:59Z","timestamp":1790567399396,"version":"4.1.0"},"reference-count":76,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,4,23]],"date-time":"2023-04-23T00:00:00Z","timestamp":1682208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"NIH","doi-asserted-by":"publisher","award":["HL125734"],"award-info":[{"award-number":["HL125734"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"NIH","doi-asserted-by":"publisher","award":["HL155742"],"award-info":[{"award-number":["HL155742"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"NIH","doi-asserted-by":"publisher","award":["HL139634"],"award-info":[{"award-number":["HL139634"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"NIH","doi-asserted-by":"publisher","award":["HL073373"],"award-info":[{"award-number":["HL073373"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"NIH","doi-asserted-by":"publisher","award":["HL083069"],"award-info":[{"award-number":["HL083069"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Intrauterine smoke (IUS) exposure during early childhood has been associated with a number of negative health consequences, including reduced lung function and asthma susceptibility. The biological mechanisms underlying these associations have not been established. MicroRNAs regulate the expression of numerous genes involved in lung development. Thus, investigation of the impact of IUS on miRNA expression during human lung development may elucidate the impact of IUS on post-natal respiratory outcomes. We sought to investigate the effect of IUS exposure on miRNA expression during early lung development. We hypothesized that miRNA\u2013mRNA networks are dysregulated by IUS during human lung development and that these miRNAs may be associated with future risk of asthma and allergy. Human fetal lung samples from a prenatal tissue retrieval program were tested for differential miRNA expression with IUS exposure (measured using placental cotinine concentration). RNA was extracted and miRNA-sequencing was performed. We performed differential expression using IUS exposure, with covariate adjustment. We also considered the above model with an additional sex-by-IUS interaction term, allowing IUS effects to differ by male and female samples. Using paired gene expression profiles, we created sex-stratified miRNA\u2013mRNA correlation networks predictive of IUS using DIABLO. We additionally evaluated whether miRNAs were associated with asthma and allergy outcomes in a cohort of childhood asthma. We profiled pseudoglandular lung miRNA in n = 298 samples, 139 (47%) of which had evidence of IUS exposure. Of 515 miRNAs, 25 were significantly associated with intrauterine smoke exposure (q-value &lt; 0.10). The IUS associated miRNAs were correlated with well-known asthma genes (e.g., ORM1-Like Protein 3, ORDML3) and enriched in disease-relevant pathways (oxidative stress). Eleven IUS-miRNAs were also correlated with clinical measures (e.g., Immunoglobulin E andlungfunction) in children with asthma, further supporting their likely disease relevance. Lastly, we found substantial differences in IUS effects by sex, finding 95 significant IUS-miRNAs in male samples, but only four miRNAs in female samples. The miRNA\u2013mRNA correlation networks were predictive of IUS (AUC = 0.78 in males and 0.86 in females) and suggested that IUS-miRNAs are involved in regulation of disease-relevant genes (e.g., A disintegrin and metalloproteinase domain 19 (ADAM19), LBH regulator of WNT signaling (LBH)) and sex hormone signaling (Coactivator associated methyltransferase 1(CARM1)). Our study demonstrated differential expression of miRNAs by IUS during early prenatal human lung development, which may be modified by sex. Based on their gene targets and correlation to clinical asthma and atopy outcomes, these IUS-miRNAs may be relevant for subsequent allergy and asthma risk. Our study provides insight into the impact of IUS in human fetal lung transcriptional networks and on the developmental origins of asthma and allergic disorders.<\/jats:p>","DOI":"10.3390\/ijms24097727","type":"journal-article","created":{"date-parts":[[2023,4,24]],"date-time":"2023-04-24T04:01:23Z","timestamp":1682308883000},"page":"7727","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Intrauterine Smoke Exposure, microRNA Expression during Human Lung Development, and Childhood Asthma"],"prefix":"10.3390","volume":"24","author":[{"given":"Lynne","family":"Rosenberg","sequence":"first","affiliation":[{"name":"Department of Pediatrics and Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1079-0045","authenticated-orcid":false,"given":"Cuining","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado-Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3036-2080","authenticated-orcid":false,"given":"Rinku","family":"Sharma","sequence":"additional","affiliation":[{"name":"Channing Division of Network Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9418-4917","authenticated-orcid":false,"given":"Cheyret","family":"Wood","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado-Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carrie A.","family":"Vyhlidal","sequence":"additional","affiliation":[{"name":"Children\u2019s Mercy Hospital and Clinics, Kansas City, MO 64108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Gaedigk","sequence":"additional","affiliation":[{"name":"Children\u2019s Mercy Hospital and Clinics, Kansas City, MO 64108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9887-312X","authenticated-orcid":false,"given":"Alvin T.","family":"Kho","sequence":"additional","affiliation":[{"name":"Channing Division of Network Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John P.","family":"Ziniti","sequence":"additional","affiliation":[{"name":"Channing Division of Network Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6139-5320","authenticated-orcid":false,"given":"Juan C.","family":"Celed\u00f3n","sequence":"additional","affiliation":[{"name":"Division of Pediatric Pulmonary Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelan G.","family":"Tantisira","sequence":"additional","affiliation":[{"name":"Division of Pediatric Respiratory Medicine, Rady Children\u2019s Hospital, University of California, San Diego, CA 92123, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott T.","family":"Weiss","sequence":"additional","affiliation":[{"name":"Channing Division of Network Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"McGeachie","sequence":"additional","affiliation":[{"name":"Channing Division of Network Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3725-5459","authenticated-orcid":false,"given":"Katerina","family":"Kechris","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado-Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunita","family":"Sharma","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, 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