“Hexavalent chromium is a human respiratory carcinogen that undergoes intracellular activation in vivo primarily via reduction with ascorbate. Replication of Cr-adducted DNA triggers mismatch repair that generates toxic DNA double-strand breaks (DSBs) as secondary lesions. Here, we examined the intranuclear distribution of chromate-induced breaks and a central DSB signaling branch targeting histone H2AX. Using ascorbate-restored cells (H460 human lung epithelial
cells, normal human lung and normal mouse embryonic fibroblasts (MEFs)), we found that Cr(VI) produced a typical DSB-associated spectrum of H2AX modifications, including its Ser139-phosphorylated (known as gamma H2AX) and mono- and diubiquitinated forms. However, whereas canonical DSB signaling relies on ATM, the formation of gamma H2AX and its ubiquitinated products by Cr(VI) was dependent on ATR kinase. SC79 Adavosertib mouse Based on the established mode of ATR activation, this suggests that Cr-induced DSB are not blunt-ended and likely contain single-stranded tails. Confocal imaging with markers of active and inactive chromatin revealed a selective formation of Cr-induced DSB in euchromatin of mouse and
human cells. In contrast to DSB, Cr-DNA adducts were produced in both types of chromatin. The euchromatin targeting of Cr-induced DSB makes these lesions particularly dangerous by increasing the probability of deleting active tumor suppressors and producing oncogenic translocations. Accumulation of transcription-inhibiting
CA4P ubiquitinated forms of gamma H2AX in euchromatin is expected to contribute to the ability of Cr(VI) to suppress upregulation of inducible genes.”
“We investigated whether, during maximal exercise, intercostal muscle blood flow is as high as during resting hyperpnoea at the same work of breathing. We hypothesized that during exercise, intercostal muscle blood flow would be limited by competition from the locomotor muscles. Intercostal (probe over the 7th intercostal space) and vastus lateralis muscle perfusion were measured simultaneously in ten trained cyclists by near-infrared spectroscopy using indocyanine green dye. Measurements were made at several exercise intensities up to maximal (WRmax) and subsequently during resting isocapnic hyperpnoea at minute ventilation levels up to those at WRmax. During resting hyperpnoea, intercostal muscle blood flow increased linearly with the work of breathing (R-2 = 0.94) to 73.0 +/- 8.8 ml min(-1) (100 g)(-1) at the ventilation seen at WRmax (work of breathing similar to 550-600 J min(-1)), but during exercise it peaked at 80% WRmax (53.4 +/- 10.3 ml min(-1) (100 g)(-1)), significantly falling to 24.7 +/- 5.3 ml min(-1) (100 g)(-1) at WRmax. At maximal ventilation intercostal muscle vascular conductance was significantly lower during exercise (0.22 +/- 0.