Induction of DNA damage, alteration of DNA repair and transcriptional activation by stress hormones.

摘要

Stress is associated with increased production of sympathetic and other adrenal hormones. Epinephrine (E), norepinephrine (NE) and cortisol are produced during psychological stress and may affect many cells directly. These effects may be transient (e.g. heart rate, immune cell trafficking) or they can have more long-lasting consequences, such as permanent DNA damage which may result in increased cell transformation and/or tumorigenicity. Here, the molecular effects of short term in vitro exposure of these stress hormones were analyzed on murine 3T3 cells by measuring effects on DNA damage and repair, cell transformation and changes in mRNA expression of genes specifically involved in DNA damage signaling pathways. Short-term exposure (<30 min) to physiological concentrations of either cortisol, NE or E induced at least five-fold increases in DNA damage in treated cells compared to untreated controls. Pre-treatment with blocking agents such as the glucocorticoid receptor antagonist RU486, or the beta-adrenergic receptor antagonist propranolol, eliminated this increase in damage. Both cortisol and NE interfered with repair of DNA damage in cells exposed to UV and resulted in an increase in the transformed phenotype. In contrast, E had none of these effects on 3T3 cells. Stress hormones had no significant effects on cell cycle regulation. Targeted gene arrays showed that cortisol, NE and E modulated the transcription of 21, 14 and 18 genes, respectively. These genes were directly related to DNA damage signaling pathways, and included up-regulation of DNA damage sensors Chk1 and Chk2, and the proto-oncogene CDC25A, which is involved in cell cycle delay following DNA damage. Taken together, these data show that stress hormones can increase DNA damage and transformation and alter transcriptional regulation of the cell cycle.