PMID- 36493891 OWN - NLM STAT- MEDLINE DCOM- 20230111 LR - 20240202 IS - 1879-1298 (Electronic) IS - 0045-6535 (Print) IS - 0045-6535 (Linking) VI - 313 DP - 2023 Feb TI - Metal mixtures modeling identifies birth weight-associated gene networks in the placentas of children born extremely preterm. PG - 137469 LID - S0045-6535(22)03962-5 [pii] LID - 10.1016/j.chemosphere.2022.137469 [doi] AB - Prenatal exposure to toxic metals is linked to numerous adverse birth and later-in-life outcomes. These outcomes are tied to disrupted biological processes in fetal-derived tissues including the placenta and umbilical cord yet the precise pathways are understudied in these target tissues. We set out to examine the relationship between metal concentrations in umbilical cord and altered gene expression networks in placental tissue. These novel relationships were investigated in a subset of the Extremely Low Gestational Age Newborn (ELGAN) cohort (n = 226). Prenatal exposure to 11 metals/metalloids was measured using inductively coupled plasma tandem-mass spectrometry (ICP-MS/MS) in cord tissue, ensuring passage through the placental barrier. RNA-sequencing was used to quantify >37,000 mRNA transcripts. Differentially expressed genes (DEGs) were identified with respect to each metal. Weighted gene co-expression analysis identified gene networks modulated by metals. Two innovative mixtures modeling techniques, namely principal components analysis and quantile-based g-computation, were employed to identify genes/gene networks associated with multi-metal exposure. Individually, lead was associated with the strongest genomic response of 191 DEGs. Joint lead and cadmium exposure was related to 657 DEGs, including DNA Methyl Transferase 1 (DNMT1). These genes were enriched for the Eukaryotic Initiation Factor 2 (EIF2) pathway. Four gene networks, each containing genes within a Nuclear Factor kappa-light-chain-enhancer of Activated B Cells (NF-kB)-mediated network, were significantly increased in average expression level in relation to increases in all metal concentrations. All four of these metal mixture-associated gene networks were negatively correlated with important predictors of neonatal health including birth weight, placenta weight, and fetal growth. Bringing together novel methodologies from epidemiological mixtures analyses and toxicogenomics, applied to a unique cohort of extremely preterm children, the present study highlighted critical genes and pathways in the placenta dysregulated by prenatal metal mixtures. These represent potential mechanisms underlying the developmental origins of metal-induced disease. CI - Copyright (c) 2022 The Authors. Published by Elsevier Ltd.. All rights reserved. FAU - Eaves, Lauren A AU - Eaves LA AD - Department of Environmental Sciences & Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Institute for Environmental Health Solutions, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. FAU - Bulka, Catherine M AU - Bulka CM AD - Department of Environmental Sciences & Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. FAU - Rager, Julia E AU - Rager JE AD - Department of Environmental Sciences & Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Institute for Environmental Health Solutions, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Curriculum in Toxicology and Environmental Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. FAU - Gardner, Amaree J AU - Gardner AJ AD - Department of Environmental Sciences & Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. FAU - Galusha, Aubrey L AU - Galusha AL AD - Laboratory of Inorganic and Nuclear Chemistry, Wadsworth Center, New York State Department of Health, Empire State Plaza, Albany, NY, USA; Department of Environmental Health Sciences, School of Public Health, University at Albany, Rensselaer, NY, USA. FAU - Parsons, Patrick J AU - Parsons PJ AD - Laboratory of Inorganic and Nuclear Chemistry, Wadsworth Center, New York State Department of Health, Empire State Plaza, Albany, NY, USA; Department of Environmental Health Sciences, School of Public Health, University at Albany, Rensselaer, NY, USA. FAU - O'Shea, T Michael AU - O'Shea TM AD - Department of Pediatrics, School of Medicine, University of North Carolina, Chapel Hill, NC, USA. FAU - Fry, Rebecca C AU - Fry RC AD - Department of Environmental Sciences & Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Institute for Environmental Health Solutions, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Curriculum in Toxicology and Environmental Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Pediatrics, School of Medicine, University of North Carolina, Chapel Hill, NC, USA. Electronic address: rfry@unc.edu. LA - eng GR - U2C ES026542/ES/NIEHS NIH HHS/United States GR - P30 ES010126/ES/NIEHS NIH HHS/United States GR - UH3 OD023348/OD/NIH HHS/United States GR - R01 HD092374/HD/NICHD NIH HHS/United States GR - R01 ES029531/ES/NIEHS NIH HHS/United States GR - P42 ES031007/ES/NIEHS NIH HHS/United States PT - Journal Article DEP - 20221206 PL - England TA - Chemosphere JT - Chemosphere JID - 0320657 RN - 0 (Metals) SB - IM MH - Infant, Newborn MH - Humans MH - Pregnancy MH - Female MH - Child MH - *Placenta/metabolism MH - Birth Weight MH - Gene Regulatory Networks MH - Infant, Extremely Premature MH - *Prenatal Exposure Delayed Effects/metabolism MH - Tandem Mass Spectrometry MH - Maternal Exposure/adverse effects MH - Metals/analysis PMC - PMC10476282 MID - NIHMS1859611 OTO - NOTNLM OT - DOHaD OT - Gene expression OT - Metals OT - Mixtures OT - Placenta OT - Pregnancy COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2022/12/10 06:00 MHDA- 2023/01/12 06:00 PMCR- 2024/02/01 CRDT- 2022/12/09 19:34 PHST- 2022/04/14 00:00 [received] PHST- 2022/11/30 00:00 [revised] PHST- 2022/12/03 00:00 [accepted] PHST- 2022/12/10 06:00 [pubmed] PHST- 2023/01/12 06:00 [medline] PHST- 2022/12/09 19:34 [entrez] PHST- 2024/02/01 00:00 [pmc-release] AID - S0045-6535(22)03962-5 [pii] AID - 10.1016/j.chemosphere.2022.137469 [doi] PST - ppublish SO - Chemosphere. 2023 Feb;313:137469. doi: 10.1016/j.chemosphere.2022.137469. Epub 2022 Dec 6.