BACKGROUND AND AIM: Prenatal exposure to toxic metals (and metalloids) is linked to numerous adverse perinatal and later-in-life outcomes. During pregnancy, metals pass through the placental barrier to reach the developing fetus. In doing so, metals may alter placental functioning; a potential mechanism underlying adverse health outcomes. In this study, we evaluated placental gene expression in relation to cord tissue concentrations of metals/metalloids, individually and in mixtures. METHODS: Matched samples of placenta and cord tissue were collected in the ELGAN cohort (n=251), which enrolled infants delivered 28 weeks’ gestation between 2002-2004. Genome-wide RNA-sequencing of placentas quantified expression levels of 37,000 mRNA transcripts. Concentrations of 8 metals (barium, cadmium, copper, lead, manganese, mercury, strontium, zinc) and 3 metalloids (arsenic, antimony, selenium) were measured in cord tissue using inductively coupled plasma tandem-mass spectrometry. Negative binomial generalized linear models were fit within the DeSeq2 R package to identify differentially expressed genes (false discovery rate 0.1) with respect to each metal/metalloid. To assess metal mixtures, principal components analysis was also conducted. RESULTS:Individually, lead, mercury and manganese were associated with the strongest placental genomic responses, with 181, 64 and 55 differentially expressed genes, respectively. In contrast, arsenic, cadmium, antimony, selenium and strontium individually did not display associations with gene expression levels. However, in a mixtures-based analysis, the principal component that was loaded primarily with arsenic, mercury and manganese was associated with 569 differentially expressed genes. The gene that displayed the most significant association with the metals mixture was DNA Methyl Transferase 1 (DNMT1). CONCLUSIONS:By combining environmental mixtures and high-dimensional -OMICs approaches, we elucidated target genes and potential molecular pathways within the placenta altered by metal/metalloid-exposure. Lead, mercury and manganese were most strongly associated with distinct placental molecular signatures. A multi-metal analysis highlighted a critical gene involved in epigenetic patterning in the placenta. KEYWORDS: Mixtures, Molecular epidemiology, Heavy metals, Pregnancy outcomes, Birth outcomes