Cadmium adaptation in the lung – a double-edged sword?
Introduction
Cadmium (Cd) is a widespread environmental pollutant that has been classified as a type I carcinogen by the International Agency for Cancer Research (IARC, 1993). This assessment is based primarily upon epidemiological data and experimentation documenting lung tumor formation in animals after long-term, low level, Cd inhalation exposures (Takenaka et al., 1983). However, mechanisms responsible for Cd-induced carcinogenesis have not been clearly defined.
One of the more intriguing phenomena associated with repeated low dose exposure to Cd is the development of adaptive survival responses that have enabled many cells to become more tolerant to a subsequent high dose Cd exposure and to also exhibit cross-resistance to other rather diverse agents, including oxidants and radiation (Beyersmann and Hechtenberg, 1997). Such adaptive responses are not unique to Cd exposure. They have been documented for many toxic agents and in many cell types, both normal and neoplastic. Whether adaptive phenomena contribute to carcinogenesis remains to be established.
In the short run, the Cd-adaptive response would appear to be protective for the lung. However, it is equally possible that the emergence of a resistant phenotype, particularly in a stem cell that can be stimulated to proliferate, may ultimately contribute to the carcinogenic process. It could provide a selective advantage for an initiated cell that would allow it to survive, undergo clonal expansion, and ultimately develop into a tumor. Moreover, tumors with elevated resistance factor levels clearly could render conventional cancer therapies ineffective. As toxicologists, we are thus faced with a biological conundrum – is adaptation good or is it bad? The research undertaken by our laboratory, particularly within the last several years, has led us to the unavoidable conclusion that pulmonary adaptation to Cd most likely represents a double-edged sword. This review attempts to summarize some of the evidence that we have garnered, to date, that supports this proposition.
Section snippets
In vivo model of pulmonary Cd adaptation
A pulmonary rat model of Cd adaptation has been developed in our laboratory by periodically exposing animals by inhalation (3 h/day; 5 days/week) to an atmosphere containing 1.6 mg Cd/m3, a concentration well within the carcinogenic range. The first two weeks of the adaptive process are characterized by the release of cellular enzymes (lactic dehydrogenase, acid and alkaline phosphatase, lysoszyme) into the alveolar space and by an intense inflammatory response caused by an influx of activated
Development of an in vitro model of Cd adaptation
We have also sought to establish and characterize an in vitro model of pulmonary Cd adaptation in order to address more mechanistic questions related to the role adaptive processes might conceivably play in Cd-induced lung carcinogenesis. An alveolar epithelial cell line, originally isolated from lungs of adult rats at the Lovelace Inhalation Toxicology Institute, was selected for this purpose. These cells are morphologically and biochemically similar to type II pneumocytes (Li et al., 1983)
Suppression of apoptosisis as a contributing factor in Cd-induced carcinogenesis
Apoptotis, or programmed cell death, serves an important physiological function in protecting the lung, as well as other organs, from cancer development by eliminating cells that have incurred oncogenic mutations. Numerous studies have documented that reactive oxygen species (ROS), generated either endogenously or exogenously, participate in the initiation of the apoptotic process (Buttke and Sandstrom, 1994). Moreover, it has also been shown that cellular redox balance, as determined by a
Modulation of DNA repair capabilities by Cd-adaptive processes
It is well accepted that oxidative DNA damage induced by ROS is involved in the process of carcinogenesis. Oxidative damage to DNA is believed to cause mutations that activate oncogenes or inactive tumor suppressor genes. Although more than 50 different oxidative DNA modifications have been identified, 8-oxoguanine (8-oxoG) is a particularly abundant one. The 8-oxoG lesion is highly mutagenic, yielding GC to TA transversions upon its replication by DNA polymerase. To prevent this from
Conclusions
Results summarized in this review suggest that Cd adaptation, while seemingly protective and therefore beneficial, may actually predispose the stem cell of the alveolar epithelium to cancer development. One way by which this could occur involves inhibition of the BER process and the resultant accumulation of 8-oxoG in DNA of Cd-adapted cells following oxidant exposure. The 8-oxoG lesion is highly mutagenic and could cause the inactivation of tumor suppressor proteins. Another deleterious
Acknowledgements
The authors gratefully acknowledge the support from National Institute of Health grants ES-03098, ES-08991, and T-32-ES-07122.
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