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Epigenetic clocks estimate the biological age of a given tissue based on DNA methylation and are potential health biomarkers. This study leveraged the Extremely Low Gestational Age Newborn (ELGAN) study (n = 265) to evaluate associations between umbilical cord tissue concentrations of 11 metals as single exposures as well as mixtures in relation to (1) placental epigenetic gestational age acceleration (eGAA) and the (2) methylation status of the Robust Placental Clock (RPC) CpGs. Linear mixed effect regression models were stratified by infant sex. Both copper (Cu) and manganese (Mn) were significantly associated with a decelerated placental eGA of \u22120.98 (95% confidence interval (CI): \u22121.89, \u22120.07) and \u22120.90 weeks (95% CI: \u22121.78, \u22120.01), respectively, in male infants. Cu and Mn levels were also associated with methylation at RPC CpGs within genes related to processes including energy homeostasis and inflammatory response in placenta. Overall, these findings suggest that prenatal exposures to Cu and Mn impact placental eGAA in a sex-dependent manner in ELGANs, and future work could examine eGAA as a potential mechanism mediating in utero metal exposures and later life consequences.<\/jats:p>","DOI":"10.3390\/cells14040306","type":"journal-article","created":{"date-parts":[[2025,2,18]],"date-time":"2025-02-18T12:16:37Z","timestamp":1739880997000},"page":"306","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Prenatal Exposure to Metals Is Associated with Placental Decelerated Epigenetic Gestational Age in a Sex-Dependent Manner in Infants Born Extremely Preterm"],"prefix":"10.3390","volume":"14","author":[{"given":"Katelyn K.","family":"Huff","sequence":"first","affiliation":[{"name":"Curriculum in Toxicology and Environmental Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA"},{"name":"Institute for Environmental Health Solutions, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle R.","family":"Roell","sequence":"additional","affiliation":[{"name":"Institute for Environmental Health Solutions, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA"},{"name":"Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6056-923X","authenticated-orcid":false,"given":"Lauren A.","family":"Eaves","sequence":"additional","affiliation":[{"name":"Institute for Environmental Health Solutions, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA"},{"name":"Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6692-911X","authenticated-orcid":false,"given":"Thomas Michael","family":"O\u2019Shea","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0899-9018","authenticated-orcid":false,"given":"Rebecca C.","family":"Fry","sequence":"additional","affiliation":[{"name":"Curriculum in Toxicology and Environmental Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA"},{"name":"Institute for Environmental Health Solutions, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA"},{"name":"Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Okereafor, U., Makhatha, M., Mekuto, L., Uche-Okereafor, N., Sebola, T., and Mavumengwana, V. 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