Subchronic Exposure to Low-Level Lanthanum, Cerium, and Yttrium Mixtures Altered Cell Cycle and Increased Oxidative Stress Pathways in Human LO‑2 Hepatocytes but Did Not Cause Malignant Transformation

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