Cadmium adaptation in the lung – a double-edged sword?

Abstract

This review article discusses the major cellular and molecular responses characterizing pulmonary adaptation to cadmium (Cd) that may ultimately contribute to Cd carcinogenesis. Hallmarks of Cd adaptation include hyperplasia and hypertrophy of type II alveolar epithelial stem cells, an inflammatory response involving polymorphonuclear leukocytes, and the increased gene and protein expression of several resistance factors. The most prominent biochemical change is associated with Cd-induced up-regulation of metallothionein, a cysteine-rich, metal-binding protein that sequesters Cd and also possesses considerable free radical scavenging ability. Increased levels of glutathione (GSH) and induction of enzymes involved with both the synthesis of GSH (γ-glutamylcysteine synthetase regulatory and catalytic subunits) and its metabolism (GSH S-transferases) also constitute important components of the pulmonary adaptive response. Enhancement of several important cellular defense systems in response to Cd exposure may, at first, appear to be beneficial. However, recent evidence suggests that the Cd-adaptive phenotype could have deleterious consequences and may represent a double-edged sword. It has been discovered that Cd-adapted alveolar epithelial cells have a reduced ability to repair DNA damage due, in part, to the inhibition of two base excision repair enzymes (8-oxoguanine-DNA glycosylase and endonuclease III). Cells with genetic aberrations resulting from unrepaired DNA lesions would normally be removed from the lung by apoptosis. However, another study has demonstrated that apoptotic cell death, following an oxidant challenge, is significantly attenuated in Cd-adapted cells compared to non-adapted counterparts. Suppressed apoptosis could leave pre-neoplastic or neoplastic cells alive, favor their clonal expansion, and ultimately promote tumor development. The presence of superior antioxidant defenses would also be expected to increase the resistance of these tumors to chemotherapeutic agents.

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.