Prenatal Cerium Exposure and the Risk of Small-for-Gestational-Age (SGA): Evidence and Early Biomarkers

Abstract Background During pregnancy, the physiological functions of female individuals undergo changes, and their sensitivity to environmental factors is significantly increased. As the most abundant rare earth element, the biological effects of cerium on pregnancy and early placental development remain unclear. Therefore, prenatal exposure to the rare earth element cerium warrants close attention regarding its effects on pregnancy. Methods Pregnant mice were exposed to different doses of cerium nitrate (0, 50, 100, and 200 mg/kg). On gestational day 17 (placental maturation stage), intrauterine pregnancy conditions and placental structural changes were observed. Histopathological alterations in placental tissues were evaluated using hematoxylin and eosin (H&E) staining. Exosomal miRNAs from placental tissues were subjected to miRNA sequencing to identify differentially expressed miRNAs. Gene Ontology (GO) and KEGG enrichment analyses were performed on the dataset. In both in vivo and in vitro models, the expression levels of key components of the MAPK signaling pathway (ARRB2 and p-MAPK14) were determined using qRT-PCR and Western blotting. In human choriocarcinoma cells (JEG-3), cell proliferation under different concentrations of cerium nitrate was assessed using the CCK-8 assay, apoptosis was analyzed by flow cytometry, and IL-6 secretion levels were measured by ELISA. Results Prenatal cerium(Ce) exposure increased the proportion of offspring with SGA-like phenotypes. The study found that cerium accumulated in placental tissues, and was accompanied by placental structural alterations and inflammatory cell infiltration. Quantitative PCR further confirmed the coordinated upregulation of miR-483-3p, its host gene IGF2, and the precursor pri-miR-483 in placental tissues. In vitro experiments showed that Ce treatment inhibited the viability of JEG-3 trophoblast cells and promoted IL-6 expression. Moreover, Ce exposure significantly increased the levels of miR-483-3p secreted via exosomes, upregulated the expression of exosome biogenesis-related proteins, and was accompanied by activation of the MAPK/P38 pathway and increased apoptosis. Conclusion Maternal cerium exposure was associated with placental injury, inflammatory responses, and SGA-like outcomes in rats. These changes were accompanied by activation of p38 MAPK signaling and upregulation of the IGF2/miR-483-3p locus, as well as increased exosomal miR-483-3p release from trophoblast cells. Our findings suggest that exosomal miR-483-3p may have potential as an early indicator of Ce-related placental dysfunction, although further validation is required.