Radiation-induced versus endogenous DNA damage: possible effect of inducible protective responses in mitigating endogenous damage

Abstract

<jats:p> Ionizing radiation (IR) causes damage to DNA that is apparently proportional to absorbed dose. The incidence of radiation-induced cancer in humans unequivocally rises with the value of absorbed doses above about 300 mGy, in a seemingly linear fashion. Extrapolation of this linear correlation down to zero-dose constitutes the linear-no-threshold (LNT) hypothesis of radiation-induced cancer incidence. The corresponding dose-risk correlation, however, is questionable at doses lower than 300 mGy. Non-radiation induced DNA damage and, in consequence, oncogenic transformation in non-irradiated cells arises from a variety of sources, mainly from weak endogenous carcinogens such as reactive oxygen species (ROS) as well as from micronutrient deficiencies and environmental toxins. In order to relate the low probability of radiation-induced cancer to the relatively high incidence of non-radiation carcinogenesis, especially at low-dose irradiation, the quantitative and qualitative differences between the DNA damages from non-radiation and radiation sources need to be addressed and put into context of physiological mechanisms of cellular protection. </jats:p><jats:p> This paper summarizes a co-operative approach by the authors to answer the questions on the quantitative and qualitative DNA damages from non-radiation sources, largely endogenous ROS, and following exposure to low doses of IR. The analysis relies on published data and justified assumptions and considers the physiological capacity of mammalian cells to protect themselves constantly by preventing and repairing DNA damage. Furthermore, damaged cells are susceptible to removal by apoptosis or the immune system. The results suggest that the various forms of non-radiation DNA damage in tissues far outweigh corresponding DNA damage from low-dose radiation exposure at the level of, and well above, background radiation. </jats:p><jats:p> These data are examined within the context of low-dose radiation induction of cellular signaling that may stimulate cellular protection systems over hours to weeks against accumulation of DNA damage. The particular focus is the hypothesis that these enhanced and persisting protective responses reduce the steady state level of nonradiation DNA damage, thereby reducing deleterious outcomes such as cancer and aging. </jats:p><jats:p> The emerging model urgently needs rigorous experimental testing, since it suggests, importantly, that the LNT hypothesis is invalid for complex adaptive systems such as mammalian organisms. </jats:p>

Combined action of X-rays and nonylphenol on mouse sperm

“…The hormetic effect of low-dose radiation may be explained by its increase of biosystem efficiency [53]. Pollycove and Feinendegen [54] show that low dose radiation induces DNA damage and stimulates physiological mechanisms which repair and remove damage. The above may explain the reduced DNA damage observed after exposure to a lower dose of X-rays (0.05 Gy) alone and in combination with NP (0.05 Gy + 25 mg/kg bw NP).…”

Treatment of Radiation Injury

“…Endogenous free radicals, which are collectively named reactive oxygen species (ROS), arise from mitochondrial oxidative metabolism and other reactions in cells. 1 The estimated average generation rate is around 10 9 ROS per cell per day, 2 which results in 10 6 oxidative DNA damage, 10 5 DNA single-strand breaks, and 0.1 DNA double-strand breaks per cell per day. 1 Additionally, cellular and molecular targets leading to broader issues of signaling and concerns regarding systemic responses to radiation injuries have been investigated, as well as three temporal categories of acute, subacute, and late (chronic), and these are uninterrupted.…”

“…1 The estimated average generation rate is around 10 9 ROS per cell per day, 2 which results in 10 6 oxidative DNA damage, 10 5 DNA single-strand breaks, and 0.1 DNA double-strand breaks per cell per day. 1 Additionally, cellular and molecular targets leading to broader issues of signaling and concerns regarding systemic responses to radiation injuries have been investigated, as well as three temporal categories of acute, subacute, and late (chronic), and these are uninterrupted. 3 Decreased proliferation, adhesion, and an increased apoptotic cell ratio of fibroblasts occur after whole-body irradiation.…”

Effects of genistein following fractionated lung irradiation in mice

“…The hydroxyl radical is highly reactive and reacts within 10 -9 s of generation. Superoxide anions and hydrogen peroxide are relatively stable and can persist for 10 1 -10 2 s in water, however the amounts of these radicals produced by radiation (depending on dose) is much lower than those produced by normal cellular metabolism [109]. In addition to the rapid burst of ROS following radiation there is a prolonged increase in ROS up to several days post irradiation [14].…”