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We hypothesized that PAE leads to alterations in the placental expression of genes related to iron metabolism and inflammation that play functional roles in the teratogenic effects of alcohol on iron homeostasis. A total of 126 heavy-drinking women (\u22651 oz (30 mL) absolute alcohol\/day (~1.67 standard drinks\/day) or women reporting binge drinking (\u22652 drinks\/occasion)) and 80 control women (&lt;0.5 oz AA per day, no binging) in Cape Town, South Africa were interviewed prenatally regarding demographics, and alcohol, smoking, and drug use around conception and during pregnancy. Prenatal\/maternal and infant hemoglobin and ferritin were measured. Whole-transcriptome RNA sequencing analysis was performed on flash-frozen transplacental tissue samples. Gene sets related to iron metabolism (n = 398) and inflammation (n = 467) were constructed by searching the Molecular Signatures Database for related ontology terms. Principal component analysis (PCA) yielded 59 factors for each theme. In multivariable regression models, PAE was related to 2 iron metabolism PCA factors (PCs) and 5 inflammation PCs, among which 2 iron metabolism and 4 inflammation factors were related to at least 1 key maternal or infant iron outcome. In causal inference analyses based on marginal structural models and the product method, the alterations in the expression profile of genes with functions in immune cell regulation, cytokine activity, angiogenesis, hematopoiesis, and ubiquitous cell processes appeared to partially mediate the relation of prenatal drinking frequency (days\/week) around conception to a lower maternal hemoglobin-to-log(ferritin) ratio (proportion mediation = 51.35%). These findings suggest that placental inflammation may be partly responsible for the differences in alcohol-related iron homeostasis patterns between pregnant and non-pregnant adults.<\/jats:p>","DOI":"10.3390\/nu15194105","type":"journal-article","created":{"date-parts":[[2023,9,24]],"date-time":"2023-09-24T10:46:21Z","timestamp":1695552381000},"page":"4105","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Alterations in Placental Inflammation-Related Gene Expression Partially Mediate the Effects of Prenatal Alcohol Consumption on Maternal Iron Homeostasis"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5183-3043","authenticated-orcid":false,"given":"Jacqueline J.","family":"Masehi-Lano","sequence":"first","affiliation":[{"name":"Institute of Human Nutrition and Departments of Emergency Medicine and Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maya","family":"Deyssenroth","sequence":"additional","affiliation":[{"name":"Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY 10032, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9768-2671","authenticated-orcid":false,"given":"Sandra W.","family":"Jacobson","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI 48201, USA"},{"name":"Department of Human Biology, University of Cape Town Faculty of Health Sciences, Cape Town 7925, South Africa"},{"name":"Department of Psychiatry and Mental Health, University of Cape Town Faculty of Health Sciences, Cape Town 7925, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph L.","family":"Jacobson","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI 48201, USA"},{"name":"Department of Human Biology, University of Cape Town Faculty of Health Sciences, Cape Town 7925, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher D.","family":"Molteno","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Mental Health, University of Cape Town Faculty of Health Sciences, Cape Town 7925, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neil C.","family":"Dodge","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI 48201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helen C.","family":"Wainwright","sequence":"additional","affiliation":[{"name":"Department of Pathology, National Health Laboratory Service, Cape Town 7925, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ernesta M.","family":"Meintjes","sequence":"additional","affiliation":[{"name":"Department of Human Biology, University of Cape Town Faculty of Health Sciences, Cape Town 7925, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Corina","family":"Lesseur","sequence":"additional","affiliation":[{"name":"Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haoxiang","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qian","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ke","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R. Colin","family":"Carter","sequence":"additional","affiliation":[{"name":"Institute of Human Nutrition and Departments of Emergency Medicine and Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA"},{"name":"Department of Human Biology, University of Cape Town Faculty of Health Sciences, Cape Town 7925, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1542\/peds.2013-3319","article-title":"Prevalence and characteristics of fetal alcohol spectrum disorders","volume":"134","author":"May","year":"2014","journal-title":"Pediatrics"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e20154256","DOI":"10.1542\/peds.2015-4256","article-title":"Updated clinical guidelines for diagnosing fetal alcohol spectrum disorders","volume":"138","author":"Hoyme","year":"2016","journal-title":"Pediatrics"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1542\/peds.2004-0259","article-title":"A practical clinical approach to diagnosis of fetal alcohol spectrum disorders: Clarification of the 1996 Institute of Medicine criteria","volume":"115","author":"Hoyme","year":"2005","journal-title":"Pediatrics"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e290","DOI":"10.1016\/S2214-109X(17)30021-9","article-title":"Estimation of national, regional, and global prevalence of alcohol use during pregnancy and fetal alcohol syndrome: A systematic review and meta-analysis","volume":"5","author":"Popova","year":"2017","journal-title":"Lancet Glob. 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