A wide survey of heavy metals-induced in-vitro DNA replication stress characterized by rate-limited replication

Heavy metals (HMs) are environmental pollutants that pose a threat to human health and have been accepted to cause various diseases, including cancer and developmental disorders. DNA replication stress has been identified to be associated with such diseases. However, the effect of HMs exclusively on DNA replication stress is still not well understood. In this study, DNA replication stress induced by thirteen HMs was assessed using a simplified in-vitro DNA replication model. Two parameters, Cte/Ctc reflecting the cycle threshold value alteration and Ke/Kc reflecting the linear phase slope change, were calculated based on the DNA replication amplification curve to evaluate the rate of exponential and linear phases. These parameters were used to detect the replication rate reflecting in-vitro DNA replication stress induced by tested HMs. According to the effective concentrations and rate-limiting degree, HMs were ranked as follows: Hg, Ce > Pb > Zn > Cr > Cd > Co > Fe > Mn, Cu, Bi, Sr, Ni. Additionally, EDTA could relieve the DNA replication stress induced by some HMs. In conclusion, this study highlights the potential danger of HMs themselves on DNA replication and provides new insight into the possible links between HMs and DNA replication-related diseases.