Subchronic Exposure\nto Low-Level Lanthanum, Cerium,\nand Yttrium Mixtures Altered Cell Cycle and Increased Oxidative Stress\nPathways in Human LO‑2 Hepatocytes but Did Not Cause Malignant\nTransformation

Human exposures to rare earth elements are increasing\nwith expanded\nuse in aerospace, precision instruments, and new energy batteries,\nmaterials, and fertilizers. Individually these elements have low toxicity,\nalthough few investigations have examined the health effects of longer-term\nmixture exposures. We used the LO-2 cell line to examine the effects\nof graded exposures to lanthanum, cerium, and yttrium (LCY) mixtures\nat 1-, 100-, and 1000-fold their human background levels (0.31 μg/L\nLa, 0.25 μg/L Ce, and 0.12 μg/L Y) on cell cycle, oxidative\nstress, and nuclear factor erythroid-2-related factor (NRF2) pathway\nbiomarkers, assessing responses every 10 passages up to 100 passages.\nCell migration, concanavalin A, malignant transformation, and tumorigenesis\nin nude mice were also examined. Mixed LCY exposures activated oxidative\nstress and the NRF2 pathway by the 30th passage and increased the\nproportion of cells in the S phase and cell cycle-specific biomarkers\nby the 40th passage. LCY exposures did not cause malignant transformation\nof hepatocytes or induced tumorigenesis in nude mice but enhanced\ncell proliferation, migration, and agglutination. Importantly, LCY\nmixtures with longer-term exposure activated the NRF2 pathway and\naltered the hepatocyte cell cycle at doses far below those used in\nprevious toxicological studies. The consequences of LCY mixtures for\npublic health merit further study.