The Adaptive Response in Radiobiology: Evolving Insights and Implications

Abstract

The first of the regularly reproducible experiments to show that very low doses of ionizing radiation, like very low doses of chemical agents, could induce mechanisms whereby cells become better fit to cope with subsequent exposures to high doses were carried out on the induction of chromosome aberrations in cultures of human lymphocytes. If cells that had been exposed to a very low dose (1 cGy) of X rays were subsequently exposed to a relatively high dose (1 Gy), approximately half as many chromosome breaks were induced. Subsequent experiments showed that this adaptive response to low doses requires a certain minimal dose before it becomes active; occurs only within a relatively small window of dose; is dose-rate dependent; and depends on the genetic constitution of the people or animals exposed, with some being unresponsive. It was further shown that the response to the low-dose preexposure was not instantaneous but took approximately 4 to 6 hr to become fully active, and could be prevented if during this period protein synthesis was inhibited, i.e., a necessary protein (enzyme) was being induced. In fact, subsequent experiments with two-dimensional gel electrophoresis showed new proteins in cells irradiated with 1 to 2 cGy. The adaptation induced by low doses of radiation was therefore attributed to the induction of a novel efficient chromosome break repair mechanism that if active at the time of challenge with high doses would lead to less residual damage. This hypothesis was strengthened by a series of experiments in which it was found that inhibitors of poly(ADP-ribose)polymerase, an enzyme implicated in DNA strand break rejoining, could prevent the adaptive response. Although the phenomenon is well established in cellular systems, it is still problematical as to whether or not it will have any utility in establishing risks of ionizing radiation to humans. Newer experiments have now been carried out on the mechanisms underlying the effect and whether or not the effect can manifest itself as a decrease in the number of induced cancers and radiation-induced mortality. Experiments with restriction enzymes now indicate that doublestrand breaks in DNA can be triggering events in adaptation. In addition, preliminary experiments on the survival of whole-body irradiated mice have shown that multiple exposures to low adapting doses can have profound effects on survival, and other experiments have shown that adaptation can affect the induction of thymic lymphoma in irradiated mice. It therefore appears that the initial experiments behind the adaptive response have led to a vigorous worldwide effort to understand the basic mechanisms behind it. This effort is stimulated both by a desire to understand the basic cell biology behind the response and a desire to see if indeed this phenomenon affects the estimation of risks of low-level radiation exposure.Environ Health Perspect 106(Suppl 1):277-283 (1998). http.//ehpnetl.niehs.nih.gov/1998/Suppl-1/277-283wolff/abstract.html

Chromosomal Radiosensitivity in Secondary‐Progressive Multiple Sclerosis Patients

“…That lymphocytes of MS patients have a better repair capacity, as observed with the LDR MN assay and the DRS index, confirms that the LDR MN assay may indeed be a more suitable/sensitive biomarker to identify small differences in repair capacity. One possible explanation for the radioresistance observed in the lymphocytes of MS patients with the LDR MN assay could be that a mechanism similar to that of the adaptive response induced by very low doses of irradiation (Cai and Liu 1990, Barquinero et al 1995, Wolf 1998, Thierens et al 2000, Sasaki et al 2002, Marples 1996 occurs in multiple sclerosis, in this case triggered by the oxidative stress. In fact transient adaptation to in vitro oxidative stress of hydrogen peroxide (H 2 O 2 ) exposure has already been reported in mammalian cells (Wiese et al 1995, Davies-Kelvin 1999.…”

Adaptive response: stimulated DNA repair or decreased damage fixation?

“…The nature of the signal remains unknown. Its target probably is, among others, protein synthesis, since cyclohexamide abolishes the response and new proteins are synthesized in primed cells (reviewed by Wolff 1998). Consistent with this assumption, the response needs at least 3 -4 h to develop.…”

Carcinogenesis. Improved knowledge and new concepts

“…Divers types de cancers radio-induits (par exemple les cancers du sein) apparaissent à l'â ge où ils surviennent normalement chez des sujets non irradié s, ce qui illustre l'interaction entre facteurs endogè nes (hormones) et exogè nes ; chez les femmes dont le sein a é té irradié , le risque de cancer du sein est moindre si des alkylants ont é té administré s au cours du traitement, car ceux-ci lè sent l'ovaire, ré duisant la sé cré -tion hormonale ; -l'influence de la dose : plus celle-ci est é levé e, plus l'incidence des cancers est grande et, en moyenne, le dé lai court. Contrairement à ce qui é tait cru, il y a peu encore, mê me si l'endommagement initial de l'ADN est proportionnel à la dose de gé notoxique, l'effet final ne l'est pas, les faibles doses peuvent n'avoir qu'un trè s faible effet cancé rogè ne [2] ; elles peuvent mê me avoir un effet protecteur vis-à -vis des expositions ulté rieures en activant les dé fenses [60,232]. Elles peuvent aussi ré duire les consé quences des expositions pré cé dentes en provoquant l'apoptose des cellules pré né oplasiques [19,169].…”

“…Une irradiation avec des UV ou des rayons X à dose faible (< 100 mGy), ou dé livré e à faible dé bit (< 100 mGy/h) [226,227] ou fractionné e [184] est moins mutagè ne qu'une irradiation aiguë , vraisemblablement en raison d'une meilleure ré paration des lé sions de l'ADN. La capacité de ré paration est influencé e par les irradiations pré alables (ré action d'adaptation) [232] et les informations venues des cellules voisines (effet bystander : Mothersill et Seymour ; Belyakov et al [23,157]). …”