The associations between prenatal rare earth elements exposure and preterm birth: integrate insights from birth cohort and in vitro study

Rare earth elements (REEs) are emerging environmental contaminants, yet their effects on preterm birth (PTB) remain poorly understood. This study integrates epidemiological and mechanistic evidence to evaluate REEs-associated PTB risk and potential biological pathways. We analyzed 4,897 mother-child pairs from a large cohort in China and 13 REEs in maternal urine were measured. PTB risk was assessed via logistic regression and weighted quantile sum (WQS) models. HTR-8/SVneo trophoblasts were used to evaluate cell invasion (Transwell assays), matrix metalloproteinase-9(MMP-9)/ tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) expression (western blot), and transcriptomic profiles (RNA-seq) after REEs treatment. Median concentrations (0.006-0.065 μg/g creatinine) and detection frequencies (90-100 %) of 12 REEs were higher in PTB cases (P < 0.05). Each log₂-unit increase in individual and mixture of REEs exposure elevated PTB risk by 18-51 % after adjusting for covariates. Cerium (Ce), praseodymium (Pr) and gadolinium (Gd) were the primary contributors. Environmentally-relevant REEs concentrations (0.5-100 μg/L) treatment enhanced trophoblast invasion by 2.7-19.2 folds, accompanied by MMP-9 upregulation and TIMP-1 suppression in dose-dependently. Transcriptome analysis revealed 1,425 shared differentially expressed genes, prominently affecting ribosome biogenesis and oxidative phosphorylation pathways. These findings establish REEs as hazardous environmental contaminants impacting maternal-fetal health, providing crucial evidence for reevaluating exposure guidelines.