Risk Assessment of Radon in Drinking Water (1999) / Chapter Skim
Currently Skimming:
6 Molecular and Cellular Mechanisms of Radon Induced Carcinogenesis
6 Molecular and Cellular Mechanisms of Radon Induced Carcinogenesis
Pages 105-123
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 105... ...
The process of malignant transformation involves a series of changes that follow, at least roughly, a functional and temporal sequence by which cells gradually and progressively escape from normal tissue control and acquire independence, diversity, and invasive properties (figure 6.1~. Molecular changes associated with radiation carcinogenesis have mainly been investigated after higher doses and dose rates than those experienced from background levels of radon exposure.
|
From page 106... ...
NONHOMOLOGOUS RECOMBINATION ~ , _ ~ RISK ASSESSMENT OF RA:DONIN DRINKING WATER Cellular exposure to radon alpha particles CREACTIVE OXYGEN INTER!
|
From page 107... ...
Stem cells and other proliferative cells of the stomach are major targets of radon alpha particles, but cells of the small intestine are also potential targets. After ingestion of water, radon passes into the small intestine with a half-time of about 15-20 minutes.
|
From page 108... ...
Ion clusters can also produce reactive oxygen intermediates which can damage individual DNA bases, and at high doses, alter intracellular signal transduction, reduce macromolecular synthesis, and trigger processes that resemble those from inflammatory cytokines involved in other kinds of tissue injury. A series of early experiments in the 1950 and 1960s used collimated beams of alpha particles and other kinds of radiation and demonstrated the relative importance of nuclear, cytoplasmic, and extracellular irradiation (Munro 1970b; 1970a; Smith 1964~.
|
From page 109... ...
Low-dose exposure also raises the question of whether radon alpha particles can give rise to radiation hormesis the phenomenon whereby very low radiation doses are stimulatory and beneficial (Ueno and others 1996~. If hormesis occurs through a stimulation of some kind of repair, the low stimulating dose must induce an excess repair capacity that can mend not only the damage caused by the initial dose, but also pre-existing endogenous cellular damage.
|
From page 110... ...
Most mammalian somatic cells are in the prereplicative, Go, phase of the cell cycle and double-strand break repair appears to involve the nonhomologous, or illegitimate, endjoining reactions (Jeggo and others 1995~. In large part, that is because the homologous chromosomes in a diploid Go nucleus are widely separated, so nonhomologous recombination can occur at about 104 times the efficiency of homologous recombination (Godwin and others 1994; Benjamin and
|
From page 111... ...
RadSl-dependent DNA pairing is suppressed by pS3-radS1 interaction, which is also a route for initiating intracellular pS3-dependent signal transduction pathways. Broken double stranded DNA indicated by a,b; recipient intact strands by c,d; strands created by strand extension c', d'.
|
From page 112... ...
Persistent genetic changes caused by radiation must then be caused by repair that Disassembles broken termini from distant regions of the genome and triggers a lasting genetic instability. Homologous rejoining involves matching of a broken fragment with the corresponding region on the undamaged homologous chromosome followed by strand invasion and reconstruction of the damaged region by replication of the sequence information in the intact homologue (figure 6.2~.
|
From page 113... ...
The nonhomologous recombination pathway for repair of radiation-induced DNA breakage in somatic cells involves an end-to-end rejoining reaction in which broken ends of DNA are braced by a set of supporting proteins. The gap between DNA ends is bridged by overlapping single-strand termini that are usually less than 10 nucleotides long (more commonly one to five long)
|
From page 114... ...
DNA breaks and other base damage therefore are the assembly points for complex, multifunctional, multipurpose structures that signal their presence to many other cellular processes and within which repair and genetic changes occur. The combined actions of these cellular caretakers produces surviving cells that bear the permanent marks of alpha particle exposure, including deletions, insertions, amplifications, point mutations, and altered cellular regulation (Kronenberg and others 1995; Kronenberg 1994~.
|
From page 115... ...
The size of deletions that persist in surviving cells is determined by the initial spacing of DNA double-strand breaks and by the presence of vital genes in the intervening sequences. Deletion sizes associated with loss of function of the adenine phosphoribosyl transferase (APRT)
|
From page 116... ...
or in initiating apoptosis. Several of the protein complexes involved in DNA breakage and repair interact with p53, including the homologous and nonhomologous recombination complexes, and the transcription-factor component of nucleotide-excision repair, so the action of repair systems leads into the signal-transduction pathways regulated by p53.
|
From page 117... ...
and others 1995; Kumar 1995; Leonard and others 1995; Caelles and others 1994; Canman and others 1994; Jacobson and Evan 1994; Meyn and others 1994; Lowe and others 1993; Waddick and others 1993; Uckun and others 1992~. Fluctuating oxygen levels leading to oxidative bursts and the production of reactive oxygen intermediates can trigger apoptosis through their activation of p53.
|
From page 118... ...
In colon carcinogenesis, APC mutation seems to be required early, before ras mutation; when ras mutations are observed first in colon polyps, the growths are usually benign and regress; when APC mutations occur before ras mutations the tissue usually progresses to other changes that result in malignancy (den and others 1994~. It is unlikely that such an ordered sequence of mutations or gene loss will be as clear and precise in most tissues, but the principle of an approximate sequential order to the earlier genetic changes involved in carcinogenesis seems reasonable.
|
From page 119... ...
Tissue-specific genes might be similarly involved in the initiation of cancers of lung, stomach, and other tissues by exposure to radon and radon progeny alpha particles. Some of the initial genetic changes resulting from alpha-particle irradiation, such as deletions and rearrangements, are distinctive and might leave characteristic genetic changes, or "fingerprints," on gatekeeper genes and on others activated early by exposures, thus aiding in their identification.
|
From page 120... ...
Rather, the genomes of cancer cells are unstable, and this results in a cascade of mutations that cumulatively enable cancer cells to bypass the host regulatory processes (Loeb 1994~. The development of genetic instability, especially the capacity for gene amplification, is acquired in stages through preneoplastic to fully neoplastic cells, and this capacity appears to depend on the progressive loss of p53 function (Tlsty 1996; Tlsty and others 1995~.
|
From page 121... ...
MUTATIONS IN oc-PARTICLE-INDUCED TUMORSTHE FINGERPRINTS It would be expected on the basis of in vitro work, that radon alpha-particleinduced cancers of the lung and other tissues would contain characteristic mutations, fingerprints, in critical gatekeeper genes that initiate carcinogenesis (Dogliotti 1996~. Genetic changes that occur during tumor progression are likely to involve many genes but would lack characteristic fingerprints.
|
From page 122... ...
Most often, this approach has been used to explain such phenomena as the inverse dose-rate effects relevant at doses higher than those that would arise from domestic exposures (Brenner 1994; Elkind 1994~. The approach still does not pay specific attention to the particular genetic changes involved in cancers, and a more detailed attempt to interpret carcinogenesis on a quantitative basis has incorporated changes in cell cycles, proliferation kinetics, cell-killing (Luebeck and others 1994)
|
From page 123... ...
MOLECULAR AND CELLULAR MECHANISMS OF RADON-INDUCED CARCINOGENESIS 123 Instead, the biologic approach gives a mechanistic underpinning to the epidemiology and biophysical interpretations of risk. Together, they lead to a more comprehensive understanding of cancer risks posed by low ambient radiation exposures and provide a rational basis for quantitative exposure risk assessment and mitigation by multimedia approaches to risk reduction.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.