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Heavy metals stimulate human LINE-1 retrotransposition.

Kale SP, Moore L, Deininger PL, Roy-Engel AM - Int J Environ Res Public Health (2005)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Dept. of Biology, Xavier University of Louisiana, 1 Drexel Dr. New Orleans, LA 70125, USA.

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.

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Related in: MedlinePlus

Proposed model for how metal stimulation of mobile elements may impact genetic stability.The balance between normal cells and altered or mutated cells is depicted as an equilibrium. External and internal components can affect the outcome of this equilibrium. Normal cells are consistently being mutated or altered by external factors, such as UV light, etc. The damage generated can be either repaired or progress to two outcomes: (1) Apoptosis to eliminate the damaged cell or (2) Disease/cancerous cell. We propose that heavy metals shift the equilibrium through the increase of retroelement activity potentially leading to the accumulation of more mutated cells.
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f4-ijerph-02-00014: Proposed model for how metal stimulation of mobile elements may impact genetic stability.The balance between normal cells and altered or mutated cells is depicted as an equilibrium. External and internal components can affect the outcome of this equilibrium. Normal cells are consistently being mutated or altered by external factors, such as UV light, etc. The damage generated can be either repaired or progress to two outcomes: (1) Apoptosis to eliminate the damaged cell or (2) Disease/cancerous cell. We propose that heavy metals shift the equilibrium through the increase of retroelement activity potentially leading to the accumulation of more mutated cells.

Mentions: We present a model of the role the environment and mobile elements have on the generation of diseases and cancer (Figure 4). The integrity of the cellular homeostasis is constantly being assaulted by external components including environmental agents, such as oxidants, heavy metals, UV radiation, etc. The cell presents a complex system of regulatory and protective pathways to either correct (ie. DNA repair pathways) or prevent the continuation of an unrepaired event (cell cycle arrest and apoptosis). A “healthy” or disease free state is maintained as long as there is a balance of these external effects and the cellular controls. Mobile element activity is among the factors that influence this balance. For example, reports demonstrate that methylation of mobile elements maintains their expression under control [31, 42–43]. If the regulation by methylation is eliminated, the increase in expression of repeats leads cells to have an increased genetic instability with disastrous consequences [44]. Thus, external factors, such as heavy metals, affect the regulation of mobile element activity, allowing for an increase in altered cells. Mobile element activity may continue to be high in these cells, accumulating even more defects that in conjunction with inactivation of tumour suppressors, etc. may lead to a cancerous state.


Heavy metals stimulate human LINE-1 retrotransposition.

Kale SP, Moore L, Deininger PL, Roy-Engel AM - Int J Environ Res Public Health (2005)

Proposed model for how metal stimulation of mobile elements may impact genetic stability.The balance between normal cells and altered or mutated cells is depicted as an equilibrium. External and internal components can affect the outcome of this equilibrium. Normal cells are consistently being mutated or altered by external factors, such as UV light, etc. The damage generated can be either repaired or progress to two outcomes: (1) Apoptosis to eliminate the damaged cell or (2) Disease/cancerous cell. We propose that heavy metals shift the equilibrium through the increase of retroelement activity potentially leading to the accumulation of more mutated cells.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3814692&req=5

f4-ijerph-02-00014: Proposed model for how metal stimulation of mobile elements may impact genetic stability.The balance between normal cells and altered or mutated cells is depicted as an equilibrium. External and internal components can affect the outcome of this equilibrium. Normal cells are consistently being mutated or altered by external factors, such as UV light, etc. The damage generated can be either repaired or progress to two outcomes: (1) Apoptosis to eliminate the damaged cell or (2) Disease/cancerous cell. We propose that heavy metals shift the equilibrium through the increase of retroelement activity potentially leading to the accumulation of more mutated cells.
Mentions: We present a model of the role the environment and mobile elements have on the generation of diseases and cancer (Figure 4). The integrity of the cellular homeostasis is constantly being assaulted by external components including environmental agents, such as oxidants, heavy metals, UV radiation, etc. The cell presents a complex system of regulatory and protective pathways to either correct (ie. DNA repair pathways) or prevent the continuation of an unrepaired event (cell cycle arrest and apoptosis). A “healthy” or disease free state is maintained as long as there is a balance of these external effects and the cellular controls. Mobile element activity is among the factors that influence this balance. For example, reports demonstrate that methylation of mobile elements maintains their expression under control [31, 42–43]. If the regulation by methylation is eliminated, the increase in expression of repeats leads cells to have an increased genetic instability with disastrous consequences [44]. Thus, external factors, such as heavy metals, affect the regulation of mobile element activity, allowing for an increase in altered cells. Mobile element activity may continue to be high in these cells, accumulating even more defects that in conjunction with inactivation of tumour suppressors, etc. may lead to a cancerous state.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Dept. of Biology, Xavier University of Louisiana, 1 Drexel Dr. New Orleans, LA 70125, USA.

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.

Show MeSH
Related in: MedlinePlus