Human Lymphocytes Exposed to Low Doses of Ionizing Radiations Become Refractory to High Doses of Radiation as Well as to Chemical Mutagens that Induce Double-strand Breaks in DNA

Wolff, Sheldon M.; Afzal, Veena; Wiencke, John K.; Olivieri, G.; Michaeli, A.

doi:10.1080/09553008814550401

Cited by 266 publications

(86 citation statements)

References 20 publications

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“…Although we have not conducted mechanistic studies to elucidate the cause of the response, there are data from the literature to explain our observed phenomenon. It is possible that nickel induces an adaptive cellular response (35). The study showes that after exposure of cells to a low dose of a DNA damaging agent, cells become resistant to damage from exposure to a high dose of another agent.…”

Section: Discussionmentioning

confidence: 87%

Toxicological interactions between nickel and radiation on chromosome damage and repair.

Heo²,

Chiewchanwit³

1994

Environ Health Perspect

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Carcinogenic nickel compounds are usually found to be weak mutagens; therefore these compounds may not exert their carcinogenic activity through conventional genotoxic mechanisms. On the other hand, the activities of many nickel compounds have not been adequately investigated. We evaluated the genotoxic activities of nickel acetate using conventional chromosome aberration and sister chromatid exchange assays and found that there was no increase of chromosome aberrations or sister chromatid exchanges, although the highest dose (1000 pM) caused mitotic inhibition. In addition,. we investigated its effect on DNA repair using our challenge assay. In this assay, lymphocytes were exposed to 0.1 to 100 pM nickel acetate for 1 hr during the GO phase of the cell cycle. The cells were washed free of the chemical and, 1.5 hr later, were irradiated with two doses of y-rays (75 cGy per dose separated by 60 min). A significant dose-dependent increase of chromosome translocations was observed (p<0.05). The increase is more than expected based on additive effects from exposure to nickel or trays individually. In contrast to the increase of chromosome translocations, there was no increase in chromosome deletions, although there was a nickel dose-dependent reduction of mitotic indices. Our data suggest that pretreatment with nickel interferes with the repair of radiation-induced DNA damage and potentially cause mistakes in DNA repair. Furthermore, we suggest that nickel-induced abnormal DNA repair may be a mechanism for its carcinogenic properties. The DNA repair problems that we observed after exposure to low doses of nickel may be viewed as a type of adaptive response. Contrary to some investigators who showed that adaptive responses may be beneficial, our data indicated that some responses may cause more problems than expected.-Environ Health Perspect 102(Suppl 9): 73-77 (1994)

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Section: Discussionmentioning

confidence: 87%

Toxicological interactions between nickel and radiation on chromosome damage and repair.

Heo²,

Chiewchanwit³

1994

Environ Health Perspect

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“…That is, exposure of cells to low doses of radiomimetic chemicals, alkylating agents, cross-linking agents, or ionizing radiations all could lead to a decrease in the cell's sensitivity to the same agent or any of the others (7).…”

Section: Introductionmentioning

confidence: 99%

The Adaptive Response in Radiobiology: Evolving Insights and Implications

Wolff¹

1998

Environmental Health Perspectives

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105

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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

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“…The present results further enlarge the spectrum of mutagenic agents whose effects are modified by the putative repair mechanism. These agents include alkylating agents (e.g., MNNG [N-methyl-N'-nitro-N-nitrosoquanidine]), crosslinking agents (mitomycin C) and radiomimetic chemicals (bleomycin) (23,24). Furthermore, the observation of an adaptive response to radiation in vivo in multiple types of somatic cells as well as germ cells (8) indicates the potential for modification of radon-induced chromosomal damage in environmentally exposed populations.…”

Section: Discussionmentioning

confidence: 99%

Indications of repair of radon-induced chromosome damage in human lymphocytes: an adaptive response induced by low doses of X-rays.

Wolff

Afzal

Jostes

et al. 1993

Environ Health Perspect

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Naturally occurring radon is a relatively ubiquitous environmental carcinogen to which large numbers of people can be exposed over their lifetimes. The accumulation of radon in homes, therefore, has led to a large program to determine the effects of the densely ionizing a particles that are produced when radon decays. In human lymphocytes, low doses of X-rays can decrease the number of chromatid deletions induced by subsequent high doses of clastogens. This has been attributed to the induction of a repair mechanism by the low-dose exposures. Historically, chromosome aberrations induced by radon have been considered to be relatively irreparable. The present experiments, however, show that if human peripheral blood lymphocytes are irradiated with low doses ofX-rays (2 cGy) at 48 hr of culture, before being exposed to radon at 72 hr ofculture, the yield of chromatid deletions induced by radon is decreased by a factor oftwo. Furthermore, the numbers of aberrations per cell do not follow a Poisson distribution but are overdispersed, as might be expected because high-linear energy transfer (high LET) a particles have a high relative biological effectiveness compared to low-LET radiations such as X-rays or y rays. Pretreatment with a low dose of X-rays decreases the overdispersion and leads to a greater proportion of the cells having no aberrations, or lower numbers of aberrations, than is the case in cells exposed to radon alone. It therefore appears that the putative chromosomal repair mechanism induced by low doses of sparsely ionizing radiation is also effective in reducing cytogenetic damage induced by a particles, which hitherto had been thought to be relatively immune to repair processes.

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Human Lymphocytes Exposed to Low Doses of Ionizing Radiations Become Refractory to High Doses of Radiation as Well as to Chemical Mutagens that Induce Double-strand Breaks in DNA

Cited by 266 publications

References 20 publications

Toxicological interactions between nickel and radiation on chromosome damage and repair.

Toxicological interactions between nickel and radiation on chromosome damage and repair.

The Adaptive Response in Radiobiology: Evolving Insights and Implications

Indications of repair of radon-induced chromosome damage in human lymphocytes: an adaptive response induced by low doses of X-rays.

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