Page 154 - 2014 Printable Abstract Book
P. 154
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(PS2-32) Non-targeted low dose radiation-induced carcinogenesis: a review. Julie J. Burtt ; Robert
1
2
1
Lafrenie ; and Patsy Thompson, Canadian Nuclear Safety Commission, Ottawa, Canada and Northeast
2
Cancer Center, Sudbury, Canada
Exposure to ionizing radiation is associated with an increased risk of developing some types of
cancer. However, the contribution of low dose ionizing radiation to cancer risk is far less clear. Cancer is a
complex group of diseases and the risk of only a subset seem to be enhanced by radiation exposure. Many
believe that any increase in radiation exposure proportionately increases the risk of developing cancer,
supporting a stochastic risk model. However, there is also some evidence to suggest a threshold dose of
radiation is required to increase cancer risk. This paper reviews the weight of evidence associated with
the risk of developing cancer in response to radiation-induced non-targeted DNA damage at low doses
and low dose-rates. Non-targeted effects such as the bystander effect and increased genomic instability
have been shown to induce variations in gene expression. These effects can be dependent on cell type,
the growth state of the cell, the type of radiation, and the biological endpoint being measured. Variations
in gene expression are not always observed and may occur solely in genetically susceptible people, that
is, individuals with pre-existing initiated or promoted cancer cells. In conclusion, there is growing support
for a possible low dose radiation-induced cancer progression mechanism caused by bystander-induced
genomic instability. An evolution in the understanding of the biological effects of low dose ionizing
radiation is critical to determine the true risk of low dose exposure.
(PS2-33) Investigation of micronucleus induction in hMTH1 knockdown TK6 cells exposed to UVA, UVB
or UVC. Asal Fotouhi; Nicola Cornella; Mehrafarin Ramezani; Andrzej Wojcik; and Siamak Haghdoost,
MBW Stockholms University, Stockholm, Sweden
Aim: To study the protective role of the hMTH1 protein against the cytogenetic effect of UVA,
UVB and UVC in human lymphoblastoid cells TK6. Ultraviolet radiation (UVR) is a known carcinogen and
mutagen causing harmful effects such as skin cancer and sun burn. UVR is able to induce mutagenicity by
production of reactive oxygen species (ROS) and pyrimidine dimers. ROS can in turn attack nucleotides in
the DNA (dNs) or in the nucleotide pool (dNTPs) giving rise to oxidized nucleotides (for example; 8-oxo-
dNs in DNA or 8-oxo-dNTP in the nucleotide pool). Oxidized dN or dNTPs (after incorporation during DNA
replication) can lead to mutations after next DNA replication. The cell is, however, equipped with repair
mechanisms to avoid and protect against damages. One such repair mechanism is the nucleotide pool
sanitization protein, hMTH1. This protein is able to dephosphorylate oxidized dNTPs such as 2-OH-dATP
and 8-oxo-dGTP in the pool into 2-OH-dAMP and 8-oxo-dGMP. These are no longer a substrate for the
DNA during DNA replication and are thereby excreted from the cell to the extracellular milieu. We have
previously focused on the mutagenicity of UVR induced in cells. Now we study the cytogenetic effect of
UVR on cells with reduced level of hMTH1. The cells used are human B lymphoblastoid TK6 cells that were
transfected with shRNA against hMTH1 (hMTH1-knockdown). The cells were exposed to UVA, UVB or UVC,
incubated for different incubation times with cytochalasin B and analyzed for micronucleus frequency and
replication index. We observed a significant increase of micronuclei with UVA exposure but no significant
increase with UVB or UVC exposure in hMTH1-knockdown and non-transfected cells. There is a significant
decrease of replication index when cells are exposed to UVA, partly for UVB but not for UVC. This suggests
that ROS might be a significant micronucleus inducer after UVA. No significant difference was observed
between cells with normal level of hMTH1 and reduced level of hMTH1 which suggests that hMTH1 has
no protective role in UVR-induced cytogenetic damage.
152 | P a g e
(PS2-32) Non-targeted low dose radiation-induced carcinogenesis: a review. Julie J. Burtt ; Robert
1
2
1
Lafrenie ; and Patsy Thompson, Canadian Nuclear Safety Commission, Ottawa, Canada and Northeast
2
Cancer Center, Sudbury, Canada
Exposure to ionizing radiation is associated with an increased risk of developing some types of
cancer. However, the contribution of low dose ionizing radiation to cancer risk is far less clear. Cancer is a
complex group of diseases and the risk of only a subset seem to be enhanced by radiation exposure. Many
believe that any increase in radiation exposure proportionately increases the risk of developing cancer,
supporting a stochastic risk model. However, there is also some evidence to suggest a threshold dose of
radiation is required to increase cancer risk. This paper reviews the weight of evidence associated with
the risk of developing cancer in response to radiation-induced non-targeted DNA damage at low doses
and low dose-rates. Non-targeted effects such as the bystander effect and increased genomic instability
have been shown to induce variations in gene expression. These effects can be dependent on cell type,
the growth state of the cell, the type of radiation, and the biological endpoint being measured. Variations
in gene expression are not always observed and may occur solely in genetically susceptible people, that
is, individuals with pre-existing initiated or promoted cancer cells. In conclusion, there is growing support
for a possible low dose radiation-induced cancer progression mechanism caused by bystander-induced
genomic instability. An evolution in the understanding of the biological effects of low dose ionizing
radiation is critical to determine the true risk of low dose exposure.
(PS2-33) Investigation of micronucleus induction in hMTH1 knockdown TK6 cells exposed to UVA, UVB
or UVC. Asal Fotouhi; Nicola Cornella; Mehrafarin Ramezani; Andrzej Wojcik; and Siamak Haghdoost,
MBW Stockholms University, Stockholm, Sweden
Aim: To study the protective role of the hMTH1 protein against the cytogenetic effect of UVA,
UVB and UVC in human lymphoblastoid cells TK6. Ultraviolet radiation (UVR) is a known carcinogen and
mutagen causing harmful effects such as skin cancer and sun burn. UVR is able to induce mutagenicity by
production of reactive oxygen species (ROS) and pyrimidine dimers. ROS can in turn attack nucleotides in
the DNA (dNs) or in the nucleotide pool (dNTPs) giving rise to oxidized nucleotides (for example; 8-oxo-
dNs in DNA or 8-oxo-dNTP in the nucleotide pool). Oxidized dN or dNTPs (after incorporation during DNA
replication) can lead to mutations after next DNA replication. The cell is, however, equipped with repair
mechanisms to avoid and protect against damages. One such repair mechanism is the nucleotide pool
sanitization protein, hMTH1. This protein is able to dephosphorylate oxidized dNTPs such as 2-OH-dATP
and 8-oxo-dGTP in the pool into 2-OH-dAMP and 8-oxo-dGMP. These are no longer a substrate for the
DNA during DNA replication and are thereby excreted from the cell to the extracellular milieu. We have
previously focused on the mutagenicity of UVR induced in cells. Now we study the cytogenetic effect of
UVR on cells with reduced level of hMTH1. The cells used are human B lymphoblastoid TK6 cells that were
transfected with shRNA against hMTH1 (hMTH1-knockdown). The cells were exposed to UVA, UVB or UVC,
incubated for different incubation times with cytochalasin B and analyzed for micronucleus frequency and
replication index. We observed a significant increase of micronuclei with UVA exposure but no significant
increase with UVB or UVC exposure in hMTH1-knockdown and non-transfected cells. There is a significant
decrease of replication index when cells are exposed to UVA, partly for UVB but not for UVC. This suggests
that ROS might be a significant micronucleus inducer after UVA. No significant difference was observed
between cells with normal level of hMTH1 and reduced level of hMTH1 which suggests that hMTH1 has
no protective role in UVR-induced cytogenetic damage.
152 | P a g e
