Impact of Low Dose Ionizing Radiation Induced Genome Instability on Human Health

In modern life, human is under constant exposure to low dose natural or manmade sources of non-ionizing radiations (microwaves, radiowaves, mobile, etc.) and ionizing radiation used for medical or industrial purposes. Ionizing radiation (IR) is known as potent inducer of DNA damages through direct or indirect effcts on DNA molecule. Indirect effect of IR leads to water radiolysis and formation of free radicals and reactive oxygen species (ROS). ROS are a group of highly reactive molecules implicated in the oxidative damage of biological structures. There are accumulating evidences indicating that cell transformation is associated with genome instability leading to an imbalance between the mechanisms of cell-cycle control and mutation rates within the genes. Genome instability can be defined as an enhanced tendency for the genome to acquire mutations; ranging from changes to the nucleotide sequence to chromosomal gain, rearrangements or loss. ROS which gives rise to various types of DNA lesions, including single- strand breaks and double-strand breaks (DSBs), and various types of base damage as well as DNA-DNA and DNA-protein cross links. Radiation induced DSBs represent the most lethal types of DNA damage, leading to cell death, if unrepaired. However, DNA damage response mechanisms may lead to two distinct outcomes: survival and the maintenance of genomic stability. The formation of ROS produces not only DNA strand breakages, but also might act as a signaling event leading to the release of cytokines or epigenetic changes, or trigger DNA repair machinery. All primary lesions induced in the DNA are subjected to cellular repair processes; however, the unrepaired or mis-repaired lesions may give rise to gene mutations and chromosomal aberrations (CA). Although DSBs are considered as serious DNA damage, they may be repaired very effectively by either one of the two different repair mechanisms namely, homologous recombinational repair (HRR) and non-homologous end joining (NHEJ). HRR is able to restore the original sequence of DNA DSB leading to a lower risk of generation of deletions and insertions at the site of DSB. NHEJ is subject to a high risk of generation of de novo mutations at the sites of DSBs. Thus, susceptibility to mutagenesis is a direct consequence of the NHEJ system joining DNA free ends. The biological importance of genomic instability and DNA repair mechanisms in cancer development are particularly well illustrated by several heritable genetic disorders known as chromosome breakage or chromosomal instability syndromes. These chromosome breakage syndromes are characterized by various defects in DNA repair, predisposition to various forms of malignancies and increased radiosensitivity. Therefore, the consequences of genome instability might be various types of ill health such as cancer, infertility and other diseases. Moreover, upon induction of genome instability following low dose IR, other cellular responses such as inherent radiosensitivity, radio-adaptation and bystander effects might be activated which might alter cellular response to radiation. Various molecular mechanisms of genomic instability and their relevance to carcinogenesis, infertility and genetic diseases will be discussed.
Keywords: Low dose ionizing radiation, Genome instability, Cancer, Genetic effects, infertility.