The Adaptive Response and Protection against Heritable Mutations and Fetal Malformation

Abstract

There are a number of studies that show radiation can cause heritable mutations in the offspring of irradiated organisms. These "germ-line mutations" have been shown to occur in unique sequences of DNA called "minisatellite loci". The high frequencies of spontaneous and induced mutations at minisatellite loci allow mutation induction to be measured at low doses of exposure in a small population, making minisatellite mutation a powerful tool to investigate radiation-induced heritable mutations. However, the biological significance of these mutations is uncertain, and their relationship to health risk or population fitness is unknown. We have adopted this mutation assay to study the role of adaptive response in protecting mice against radiation-induced heritable defects. We have shown that male mice, adapted to radiation with a low dose priming exposure, do not pass on mutations to their offspring caused by a subsequent large radiation exposure to the adapted males. This presentation and paper provide a general overview of radiation-induced mutations in offspring and explain the effect of low dose exposures and the adaptive response on these mutations.It is also known that exposure of pregnant females to high doses of radiation can cause death or malformation (teratogenesis) in developing fetuses. Malformation can only occur during a specialized stage of organ formation known as organogenesis. Studies in rodents show that radiation-induced fetal death and malformation can be significantly reduced when a pregnant female is exposed to a prior low dose of ionizing radiation. The mechanism of this protective effect, through an adaptive response, depends on the stage of organogenesis when the low dose exposures are delivered. To better understand this process, we have investigated the role of an important gene known as p53. Therefore, this report will also discuss fetal effects of ionizing radiation and explain the critical stages of development when fetuses are at risk. Research will be explained that investigates the biological and genetic systems (p53) that protect the developing fetus and discuss the role of low dose radiation adaptive response in these processes.

Cellular Stress Responses, Mitostress and Carnitine Insufficiencies as Critical Determinants in Aging and Neurodegenerative Disorders: Role of Hormesis and Vitagenes

“…The work of Schulz inspired a large number of investigators in diverse fields to assess whether such low dose effects may be a general feature of biological systems. In fact, similar types of dose response observations were subsequently reported by numerous researchers assessing chemicals [101] and radiation [102][103][104][105][106][107][108][109][110][111][112][113] with investigators adopting different names such as the Arndt-Schulz Law, Huppe's Rule, and other terms to describe these similar dose response phenomena. Despite the rather substantial historical literature concerning hormetic dose responses, this concept had a difficult time being incorporated into routine safety assessment and pharmacological investigations, principally because it (1) required more rigorous evaluation in the low dose zone, (2) failure of investigators to understand its clinical significance (3) failure to appreciate the quantitative features of the hormetic dose response (4) failure to understand the limitations of its implications for commercial applications in agriculture as well as medicine, (5) because of the predominant interest in responses at relatively high doses during most of the twentieth century as well as (6) the continuing, yet inappropriate, tendency to associate the concept of hormesis with the medical practice of homeopathy [114][115][116].…”

Radiation-Stimulated Epigenetic Reprogramming of Adaptive-Response Genes in the Lung: An Evolutionary Gift for Mounting Adaptive Protection against Lung Cancer

“…Low doses or low dose rates of low-LET radiation have been demonstrated to do each of the following: (1) protect against spontaneous genomic damage (Feinendegen 2005;Feinendegen et. al 2007); (2) protect against spontaneous and high-radiation-dose-induced mutations (Day et al 2007); (3) protect against neoplastic transformation (Redpath et al 2001;Bauer 2007;Portess et al 2007); (4) protect against high-dose chemical- (Sakai et al 2003) and alpha-radiation-induced (Sanders 2008;Scott et al 2008) cancers; (5) enhance immune system defense against cancer (Liu 2003;Cuttler 2007); (6) suppresses metastasis of existing cancer (Liu 2007); (7) extend tumor latency period (Mitchel 2007); (8) protect against diseases other than cancer (Luckey 1991;Sakai 2006), and (9) protect against heritable mutations and fetal malformation (Boreham et al 2006). A new study (Mancuso et al 2008) has yield data showing that a total-body X-ray dose of 36 mGy suppressed spontaneous brain cancer in brain-cancer-prone mice, although this feature of the data was apparently not recognized by the researchers.…”

Computational Modeling of Signaling Pathways Mediating Cell Cycle Checkpoint Control and Apoptotic Responses to Ionizing Radiation-Induced DNA Damage

“…The underlying assumption that supports LNT model is that a single DNA damage is capable of inducing a tumor. However, laboratory results of IR indicate a J-shaped or hormetic dose response relationship in the low dose region (Cohen 1995;Redpath et al 2001;Boreham et al 2006;Sakai et al 2006;Day et al 2007;Mitchel 2007a, b;Tubiana et al 2006Tubiana et al , 2009. To investigate the conflict between the experimental observations and the LNT model is important because the difference of the regulation costs based on LNT or J-shaped model are dramatic.…”