Heavy Metals Stimulate Human LINE-1 Retrotransposition

Abstract

L1 and Alu elements are among the most active retroposons (mobile elements) in the human genome. Several human diseases, including certain forms of breast cancer and leukemia, are associated with L1 and Alu insertions in functionally important areas of the genome. We present data demonstrating that environmental pollutants, such as heavy metals, can stimulate L1 retrotransposition in a tissue culture system using two different types of assays. The response to these agents was equivalent when using a cell line with a stably integrated L1 vector (genomic) or a by introducing the L1 vector by transient transfection (episomal) of the cell. Reproducible results showed that mercury (HgS), cadmium (CdS), and nickel (NiO) increase the activity of L1 by an average of three (3) fold p<0.001. This observation is the first to link several carcinogenic agents with the increased retrotransposition activity of L1 as an alternate mechanism of generating genomic instability contributing to the process of carcinogenesis. Our results demonstrate that mobile element activation must be considered as one of the mechanisms when evaluating genomic damage/instability in response to environmental agents.

Nickel Stimulates L1 Retrotransposition by a Post-transcriptional Mechanism

“…4,64,65 However, we have previously assessed the effect of several heavy metals on cell lines with a stable integration of the reporter plasmid. 35 Our data demonstrate that both assays yield equivalent results. Furthermore, nickel(II) has been reported to influence methylation and gene expression.…”

“…A correction factor was utilized to compensate for the toxic effects of the heavy metals (evidenced as an overall loss of colony formation) when comparing the L1 retrotransposition to the control at different doses. 35 L1 retrotransposition increased with NiCl 2 dose, as reflected by the number of neo R colonies, peaking at about 2.5-fold at 150 μM NiCl 2 in comparison to the untreated (0 μM NiCl 2 ) control. This effect was not seen in cells exposed to CoCl 2 , which showed only decreased retrotransposition as cobalt dosage increased.…”

“…35 Heavy metals, such as nickel and cadmium, are wellknown carcinogens in humans and animal models. [36][37][38][39][40] Although heavy metals are known to be DNA-damaging agents, 41 the molecular mechanisms by which they induce cancer are illdefined.…”

Activation of Human Long Interspersed Nuclear Element 1 Retrotransposition by Benzo(a)pyrene, an Ubiquitous Environmental Carcinogen

“…This increase in endogenous reverse transcriptase activity comes from L1 because it mediates retrotransposition of exogenous AluI element (25). In addition to compounds that damage DNA directly, several heavy metals, considered to be carcinogenic, also stimulate L1 retrotransposition in HeLa cells (46).…”

LINE-1 retrotransposition in human neuroblastoma cells is affected by oxidative stress

“…Several bodies of evidence have shown that some carcinogens and a number of DNA-damaging agents, such as UV, benzo(a)pyrene (Lu et al 2000), cadmium, mercury, nickel (Kale et al 2005), a tryptophan photoproduct 6-formylindolo [3,2-b]carbazole (Okudaira et al 2010) and radiation (Farkash et al 2006) can stimulate retrotransposition in somatic cells.…”