POLA1 mediates hexavalent chromium-induced ovarian tumor progression through replication stress and DNA damage response

Hexavalent chromium (Cr(VI)), a recognized environmental carcinogen, yet its role in promoting gynecological malignancies remains mechanistically unclear. Here, we demonstrate that chronic, low-dose hexavalent chromium (Cr(VI)) exposure (0.1 μM) drives ovarian tumorigenesis by inducing replication stress and DNA damage response (DDR) activation. We identify the DNA polymerase α catalytic subunit POLA1 as a critical mediator of this process. In human ovarian cancer SKOV3 cells, long-term Cr(VI) exposure (4–8 weeks) triggered S-phase accumulation, γH2AX elevation, and ATR/ATM activation, events dependent on POLA1 recruitment to chromatin. Crucially, genetic ablation of POLA1 reversed Cr(VI)-induced replication stress and suppressed tumor proliferation both in vitro and in vivo . These findings reveal a novel Cr(VI)-POLA1-DNA damage axis in environmental carcinogenesis, highlighting POLA1 as a potential target for preventive intervention in metal-induced malignancies.