ABSTRACT
The cellular responses to carcinogen exposure influence cellular fate, which in turn modulates the neoplastic response. Certain hexavalent chromium [Cr(VI)] compounds are implicated as occupational respiratory carcinogens at doses that are both genotoxic and cytotoxic. We examined the mechanism of Cr(VI)-induced apoptosis in normal human fibroblasts (BJ) immortalized by human telomerase gene transfection (BJ-hTERT), and we assessed the spectrum of cumulative cellular fates [(a) regaining of replicative potential; (b) terminal growth arrest; or (c) apoptosis] for a narrow range of increasingly genotoxic doses of Cr(VI). Exposure of BJ-hTERT cells to Cr(VI) resulted in a dose-dependent increase in apoptosis that involved mitochondrial disruption as evidenced by mitochondrial membrane depolarization and cytochrome c release. The initial response to Cr(VI) exposure was inhibition of cell cycle progression. At the lowest dose tested (1 microM; 32% clonogenic survival), the cell cycle inhibition led to terminal growth arrest but no apoptosis. The fraction of terminally growth arrested cells increased as the dose was increased to 3 microM but then decreased at 4, 5, and 6 microM as apoptosis became the predominant cell fate. Our results suggest that cell populations exposed to Cr(VI) have a different spectrum of responses, depending on the extent of DNA damage, and that the regaining of replicative potential after relatively higher genotoxic exposures may be attributable to either escape from, or resistance to, terminal growth arrest or apoptosis.
Subject(s)
Apoptosis , Chromates/pharmacology , Fibroblasts/drug effects , Fibroblasts/pathology , Sodium Compounds/pharmacology , Telomerase/metabolism , Caspase 3 , Caspases/metabolism , Cell Cycle , Cell Division/drug effects , Cell Lineage , Cells, Cultured , DNA-Binding Proteins , Dose-Response Relationship, Drug , Humans , Immunohistochemistry , Intracellular Membranes , Microscopy, Fluorescence , Mitochondria/metabolism , Phenotype , Stress, Physiological , Telomerase/genetics , Time Factors , TransfectionABSTRACT
Because exposure to microwave fields at the resonant frequency may generate heat deep in the body, hyperthermia may result. This problem has been examined in an animal model to determine both the thresholds for response change and the steady-state thermoregulatory compensation for body heating during exposure at resonant (450 MHz) and supra-resonant (2,450 MHz) frequencies. Adult male squirrel monkeys, held in the far field of an antenna within an anechoic chamber, were exposed (10 min or 90 min) to either 450-MHz or 2,450-MHz CW fields (E polarization) in cool environments. Whole-body SARs ranged from 0-6 W/kg (450 MHz) and 0-9 W/kg (2,450 MHz). Colonic and several skin temperatures, metabolic heat production, and evaporative heat loss were monitored continuously. During brief RF exposures in the cold, the reduction of metabolic heat production was directly proportional to the SAR, but 2,450-MHz energy was a more efficient stimulus than was the resonant frequency. In the steady state, a regulated increase in deep body temperature accompanied exposure at resonance, not unlike that which occurs during exercise. Detailed analyses of the data indicate that temperature changes in the skin are the primary source of the neural signal for a change in physiological interaction processes during RF exposure in the cold.
