{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T12:15:46Z","timestamp":1788437746978,"version":"build-2803163510"},"reference-count":52,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P20GM103466"],"award-info":[{"award-number":["P20GM103466"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"award":["P20GM103466"],"award-info":[{"award-number":["P20GM103466"]}],"id":[{"id":"https:\/\/ror.org\/04q48ey07","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Curr. Issues Mol. Biol.","CIMB"],"abstract":"<jats:p>Background: Opioid use during pregnancy is linked to preterm birth, fetal growth restriction, and Neonatal Opioid Withdrawal Syndrome. While the placenta is the primary regulator of the uterine environment, the precise molecular mechanisms by which opioids dismantle placental function remain poorly defined. Methods: The transcriptomic landscape of opioid-exposed human placentas from a unique Hawai\u2019i-based cohort was characterized. Results: Transcriptional signatures were defined by genes involved in translational inhibition and metabolic attenuation. Integrative network modeling predicted a prominent stress-signaling hub centered on p38 Mitogen-Activated Protein Kinase and Extracellular Signal-Related Kinase 1\/2, paralleling a broad suppression of ribosomal protein transcripts (Ribosomal Protein 27S, -29, and -39). This response was further characterized by the inhibition of the Myelecytomatosis Proto-Oncogene regulatory hub, predicting a loss of mitochondrial phosphate transport through associated genes (via Solute Carrier Family 25A3) and cell-cycle progression (via S-Phase Kinase-Associated Protein 1). Additionally, the genes in this model suggested upregulation of antisense regulatory brakes, such as RAP2C Antisense RNA 1, which might further reinforce this inhibitory state. Conclusion: The findings suggest that prenatal opioid exposure is associated with the disruption of placental homeostasis. This may be coordinated by protein synthesis and bioenergetic flux, as inferred from the modeled eukaryotic Translation Initiation Factor-mediated Integrated Stress Response. These findings establish a localized, clinical baseline of human placental stress, highlighting candidate molecular regulatory nodes to guide future mechanistic studies and biomarker discovery in exposed pregnancies.<\/jats:p>","DOI":"10.3390\/cimb48090900","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T11:08:53Z","timestamp":1788433733000},"page":"900","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Transcriptomic Reprogramming of the Human Placenta Following Maternal Opioid Exposure: Identification of Altered Metabolic and Translational Pathways"],"prefix":"10.3390","volume":"48","author":[{"given":"Po\u2019okela K.","family":"Ng","sequence":"first","affiliation":[{"name":"Department of Natural Sciences and Mathematics, Chaminade University of Honolulu, Honolulu, HI 96816, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8652-2904","authenticated-orcid":false,"given":"Vedbar S.","family":"Khadka","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences, John A. Burns School of Medicine, University of Hawai\u2019i, 651 Ilalo St, Honolulu, HI 96813, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-2877-9137","authenticated-orcid":false,"given":"Connor","family":"Howe","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology, and Women\u2019s Health, John A. Burns School of Medicine, University of Hawai\u2019i, 1319 Punahou St, Honolulu, HI 96826, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Riel","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology, and Women\u2019s Health, John A. Burns School of Medicine, University of Hawai\u2019i, 1319 Punahou St, Honolulu, HI 96826, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Men-Jean","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology and Reproductive Health, Rutgers University, 185 South Orange Avenue, MSB E-506, Newark, NJ 07101-1709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6361-998X","authenticated-orcid":false,"given":"Claire E.","family":"Kendal-Wright","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology, and Women\u2019s Health, John A. Burns School of Medicine, University of Hawai\u2019i, 1319 Punahou St, Honolulu, HI 96826, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"key":"ref_1","unstructured":"Centers for Disease Control and Prevention (2026, January 28). Provisional Drug Overdose Death Counts; Updated 15 May 2025, Available online: https:\/\/www.cdc.gov\/nchs\/nvss\/vsrr\/drug-overdose-data.htm."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1097\/GRF.0000000000000098","article-title":"Caring for Opioid-Dependent Pregnant Women: Prenatal and Postpartum Care Considerations","volume":"58","author":"Krans","year":"2015","journal-title":"Clin. Obstet. Gynecol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e547","DOI":"10.1542\/peds.2013-3524","article-title":"Neonatal Abstinence Syndrome","volume":"134","author":"Kocherlakota","year":"2014","journal-title":"Pediatrics"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1089\/pop.2014.0134","article-title":"Neonatal Abstinence Syndrome: Influence of a Combined Inpatient\/Outpatient Methadone Treatment Regimen on the Average Length of Stay of a Medicaid NICU Population","volume":"18","author":"Lee","year":"2015","journal-title":"Popul. Health Manag."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e2023062871","DOI":"10.1542\/peds.2023-062871","article-title":"Advances in the Care of Infants with Prenatal Opioid Exposure and Neonatal Opioid Withdrawal Syndrome","volume":"153","author":"Mascarenhas","year":"2024","journal-title":"Pediatrics"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Morniroli, D., Tiraferri, V., Maiocco, G., De Rose, D.U., Cresi, F., Coscia, A., Mosca, F., and Giann\u00ec, M.L. (2023). Beyond Survival: The Lasting Effects of Premature Birth. Front. Pediatr., 11.","DOI":"10.3389\/fped.2023.1213243"},{"key":"ref_7","first-page":"35","article-title":"Neonatal Abstinence Syndrome after Intrauterine Opioid Exposure: Standards, Cost-Effectiveness of Treatment and Maternal Rights","volume":"17","author":"Brandt","year":"2015","journal-title":"Heroin Addict. Relat. Clin. Probl."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2071","DOI":"10.1111\/j.1360-0443.2010.03120.x","article-title":"Methadone Dose and Neonatal Abstinence Syndrome\u2014Systematic Review and Meta-Analysis","volume":"105","author":"Cleary","year":"2010","journal-title":"Addiction"},{"key":"ref_9","first-page":"33","article-title":"Drug Disposition and Effects in the Fetus","volume":"15","author":"Rurak","year":"1991","journal-title":"J. Dev. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Pandey, R., Pandey Sapkota, N., and Kumar, D. (2017). Neonatal Abstinence Syndrome: Twins Case Series. Front. Pediatr., 5.","DOI":"10.3389\/fped.2017.00242"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"20140066","DOI":"10.1098\/rstb.2014.0066","article-title":"The Placenta: A Multifaceted, Transient Organ","volume":"370","author":"Burton","year":"2015","journal-title":"Philos. Trans. R. Soc. Lond. B Biol. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"True, H.E., Doratt, B.M., Wagner, S., Malherbe, D.C., Shelman, N.R., Boroujeni, M.E., Cockerham, C., O\u2019Brien, J., and Messaoudi, I. (2025). Maternal Opioid Use with and without Hepatitis C Infection Disrupts the Structure and Immune Landscape of the Maternal\u2013Fetal Interface. bioRxiv, bioRxiv:2025.07.30.667651.","DOI":"10.1101\/2025.07.30.667651"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Giovannini, E., Bonasoni, M.P., Pascali, J.P., Bini, C., Pelletti, G., Gualandi, A., Lago, G.D., Mercati, A., Mariotti, B., and Pasini, G.P. (2024). Fetal and Infant Effects of Maternal Opioid Use during Pregnancy: A Literature Review including Clinical, Toxicological, Pharmacogenomic, and Epigenetic Aspects for Forensic Evaluation. Children, 11.","DOI":"10.3390\/children11030278"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1093\/biolre\/ioac003","article-title":"The Placenta as a Target of Opioid Drugs","volume":"106","author":"Rosenfeld","year":"2022","journal-title":"Biol. Reprod."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"125","DOI":"10.2174\/157015908784533842","article-title":"The Effects of Maternally Administered Methadone, Buprenorphine and Naltrexone on Offspring: Review of Human and Animal Data","volume":"6","author":"Farid","year":"2008","journal-title":"Curr. Neuropharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Ciwun, M., Tankiewicz-Kwedlo, A., and Pawlak, D. (2024). Low-Dose Naltrexone as an Adjuvant in Combined Anticancer Therapy. Cancers, 16.","DOI":"10.3390\/cancers16061240"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Zhang, P., Yang, M., Chen, C., Liu, L., Wei, X., and Zeng, S. (2020). Toll-Like Receptor 4 (TLR4)\/Opioid Receptor Pathway Crosstalk and Impact on Opioid Analgesia, Immune Function, and Gastrointestinal Motility. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.01455"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e2412349121","DOI":"10.1073\/pnas.2412349121","article-title":"Effects of Oxycodone on Placental Lineages: Evidence from the Transcriptome Profile of Mouse Trophoblast Giant Cells","volume":"121","author":"Lyu","year":"2024","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Borrelli, K.N., Wachman, E.M., Beierle, J.A., Taglauer, E.S., Jain, M., Bryant, C.D., and Zhang, H. (2022). Effect of Prenatal Opioid Exposure on the Human Placental Methylome. Biomedicines, 10.","DOI":"10.3390\/biomedicines10051150"},{"key":"ref_20","unstructured":"Andrews, S. (2026, February 19). FastQC: A Quality Control Tool for High Throughput Sequence Data. Available online: http:\/\/www.bioinformatics.babraham.ac.uk\/projects\/fastqc\/."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","article-title":"Trimmomatic: A Flexible Trimmer for Illumina Sequence Data","volume":"30","author":"Bolger","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/nmeth.3317","article-title":"HISAT: A Fast Spliced Aligner with Low Memory Requirements","volume":"12","author":"Kim","year":"2015","journal-title":"Nat. Methods"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The Sequence Alignment\/Map Format and SAMtools","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","article-title":"HTSeq\u2014A Python Framework to Work with High-Throughput Sequencing Data","volume":"31","author":"Anders","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated Estimation of Fold Change and Dispersion for RNA-seq Data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1524","DOI":"10.1161\/HYPERTENSIONAHA.124.22923","article-title":"Overexpressed Trophoblast Glycoprotein Contributes to Preeclampsia Development by Inducing Abnormal Trophoblast Migration and Invasion toward the Uterine Spiral Artery","volume":"81","author":"Sun","year":"2024","journal-title":"Hypertension"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2157256","DOI":"10.1080\/14767058.2022.2157256","article-title":"Placental Volume in Pregnant Women with Opioid Use: Prenatal MRI Assessment","volume":"36","author":"Wise","year":"2023","journal-title":"J. Matern. Fetal Neonatal Med."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Kucheryavykh, L., and Kucheryavykh, Y. (2025). The Role of Pyk2 Kinase in Glioblastoma Progression and Therapeutic Targeting. Cancers, 17.","DOI":"10.3390\/cancers17162611"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1016\/j.mod.2006.08.011","article-title":"Essential Function of PTP-PEST during Mouse Embryonic Vascularization, Mesenchyme Formation, Neurogenesis and Early Liver Development","volume":"123","author":"Sirois","year":"2006","journal-title":"Mech. Dev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.placenta.2025.02.012","article-title":"Placental transcriptome analysis in opioid-exposed versus non-opioid exposed pregnancies","volume":"162","author":"Sousa","year":"2025","journal-title":"Placenta"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3610","DOI":"10.1016\/j.ygeno.2021.08.001","article-title":"Maternal Opioid Use Disorder: Placental Transcriptome Analysis for Neonatal Opioid Withdrawal Syndrome","volume":"113","author":"Radhakrishna","year":"2021","journal-title":"Genomics"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.placenta.2020.08.006","article-title":"Maternal Oxycodone Treatment Causes Pathophysiological Changes in the Mouse Placenta","volume":"100","author":"Green","year":"2020","journal-title":"Placenta"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1126\/science.1240925","article-title":"A Long Noncoding RNA Mediates Both Activation and Repression of Immune Response Genes","volume":"341","author":"Carpenter","year":"2013","journal-title":"Science"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.tcb.2012.02.006","article-title":"Bidirectional Crosstalk between Endoplasmic Reticulum Stress and mTOR Signaling","volume":"22","author":"Hall","year":"2012","journal-title":"Trends Cell Biol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Rosario, F.J., Powell, T.L., Gupta, M.B., Cox, L., and Jansson, T. (2020). mTORC1 Transcriptional Regulation of Ribosome Subunits, Protein Synthesis, and Molecular Transport in Primary Human Trophoblast Cells. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.583801"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1970","DOI":"10.1096\/fj.11-190082","article-title":"Evidence of Endoplasmic Reticulum Stress and Protein Synthesis Inhibition in the Placenta of Non-Native Women at High Altitude","volume":"26","author":"Yung","year":"2012","journal-title":"FASEB J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2754","DOI":"10.1016\/j.drudis.2021.07.011","article-title":"Hypoxia and the Integrated Stress Response Promote Pulmonary Hypertension and Preeclampsia: Implications in Drug Development","volume":"26","author":"Hu","year":"2021","journal-title":"Drug Discov. Today"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e12283","DOI":"10.1590\/1414-431x2022e12283","article-title":"Down-Regulation of Autophagy Proteins Is Associated with Higher mTOR Expression in the Placenta of Pregnant Women with Preeclampsia","volume":"55","author":"Weel","year":"2023","journal-title":"Braz. J. Med. Biol. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1038\/s41580-019-0101-y","article-title":"The Proteostasis Network and Its Decline in Ageing","volume":"20","author":"Hipp","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"579","DOI":"10.3390\/biom2040579","article-title":"Pathways for Genome Integrity in G2 Phase of the Cell Cycle","volume":"2","author":"Kousholt","year":"2012","journal-title":"Biomolecules"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"8301","DOI":"10.1038\/s41467-024-52538-5","article-title":"Specific Activation of the Integrated Stress Response Uncovers Regulation of Central Carbon Metabolism and Lipid Droplet Biogenesis","volume":"15","author":"LeBon","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.15252\/embr.201642195","article-title":"The Integrated Stress Response","volume":"17","author":"Koryga","year":"2016","journal-title":"EMBO Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.3390\/cells1041197","article-title":"Adaptive and Pathogenic Responses to Stress by Stem Cells during Development","volume":"1","author":"Mansouri","year":"2012","journal-title":"Cells"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1113\/jphysiol.2005.089326","article-title":"ERK1\/2 and p38 Regulate Trophoblasts Differentiation in Human Term Placenta","volume":"566","author":"Daoud","year":"2005","journal-title":"J. Physiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"R155","DOI":"10.1530\/JME-18-0059","article-title":"Nutrient Sensor Signaling Pathways and Cellular Stress in Fetal Growth Restriction","volume":"62","author":"Hart","year":"2019","journal-title":"J. Mol. Endocrinol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1093\/bioinformatics\/btt703","article-title":"Causal Analysis Approaches in Ingenuity Pathway Analysis","volume":"30","author":"Green","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1080\/14728222.2016.1216980","article-title":"p38 Mitogen Activated Protein Kinase (MAPK): A New Therapeutic Target for Reducing the Risk of Adverse Pregnancy Outcomes","volume":"20","author":"Menon","year":"2016","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1016\/j.bbagrm.2014.03.013","article-title":"Myc and cell cycle control","volume":"1849","author":"Bretones","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.cell.2012.03.003","article-title":"MYC on the Path to Cancer","volume":"149","author":"Dang","year":"2012","journal-title":"Cell"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1038\/416703a","article-title":"Structure of the Cul1\u2013Rbx1\u2013Skp1\u2013F BoxSkp2 SCF Ubiquitin Ligase Complex","volume":"416","author":"Zheng","year":"2002","journal-title":"Nature"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2362","DOI":"10.1016\/j.bbamcr.2016.03.007","article-title":"Discoveries, Metabolic Roles and Diseases of Mitochondrial Carriers: A Review","volume":"1863","author":"Palmieri","year":"2016","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Mol. Cell Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1515\/bc.2009.146","article-title":"Hexose-6-phosphate dehydrogenase in the endoplasmic reticulum","volume":"391","author":"Senesi","year":"2010","journal-title":"Biol. Chem."}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/9\/900\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T11:33:45Z","timestamp":1788435225000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/9\/900"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,3]]},"references-count":52,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["cimb48090900"],"URL":"https:\/\/doi.org\/10.3390\/cimb48090900","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,3]]}}}