Abstract Chromated copper arsenate, which is used worldwide as a wood preservative, can adversely affect human health. Accumulating evidence suggests that chromium (Cr) and arsenic (As) can ...potentially disrupt the redox balance and cause respiratory diseases and cancer in humans. The present study was designed to determine the combined toxic effects of these metals in the lungs and to clarify the specific molecules that are stimulated by combined exposure to both metals. Male C57BL/6J mice were intratracheally instilled with arsenate As(V), hexavalent chromium Cr(VI), or a combination of both metals. Mice were sacrificed 2 days after treatment to collect bronchoalveolar lavage fluid and lung tissue samples. Inflammation, cytotoxicity, apoptosis, and oxidative stress markers were measured. Our results indicated that administration of Cr(VI) alone or in combination with As(V) induced neutrophil-dominant inflammation as well as phosphorylation of mitogen-activated protein kinases; effects of treatment with As(V) alone were comparatively less potent. By analyzing the production of interleukin-6 and activity of lactate dehydrogenase and caspase, we confirmed that co-treatment intensified pulmonary injury and that it was accompanied by oxidative stress, as confirmed by marked increases in the production of reactive oxygen species, reduced glutathione content, and thioredoxin reductase (TRXRD) activity. Expressed mRNA levels of heme oxygenase-1, glutamylcysteine ligase, glutathione peroxidase 2, thioredoxin (TRX) 1, and TRXRD1 were also enhanced by co-treatment, whereas treatment with As(V) alone reduced the mRNA expression level of TRX2. Our data suggest that co-treatment with As(V) exacerbated Cr(VI)-induced pulmonary injury and that this effect may be exerted through a disruption in the balance among several antioxidant genes.
Didecyldimethylammonium chloride (DDAC), a representative dialkyl-quaternary ammonium compound (QAC), could contaminate working atmospheres when used in disinfectant operation and adversely affect ...human health. Furthermore, the development of bacteria resistant to DDAC might become public health concern. We postulated that DDAC instillation in the lungs alters pulmonary antioxidant and antimicrobial responses and increases susceptibility to systemic administration of a bacterial component lipopolysaccharide (LPS). Mice were intratracheally instilled with DDAC and sacrificed 1, 3, or 7 days after treatment. Pulmonary cytotoxicity in recovered bronchoalveolar lavage was evident on Days 1 and 7, and inflammatory cell influx and interleukin-6 expression peaked on Day 7, in association with altered antioxidant and antimicrobial responses, as demonstrated by measuring heme oxygenase-1, glutathione peroxidase 2, lactoferrin, and mouse β-defensin-2 and -3 mRNA in the lung samples. The impaired defense system tended to enhance the inflammatory reaction caused by a systemic administration of LPS; the effect was in association with increased expression of toll-like receptor-4 mRNA. The results suggest that DDAC alters pulmonary defense system, which may contribute to susceptibility to an exogenous infectious agent.
Didecyldimethylammonium chloride (DDAC) is used worldwide as a germicide, in antiseptics, and as a wood preservative, and can cause adverse pulmonary disease in humans. However, the pulmonary ...toxicity of DDAC has not yet been thoroughly investigated. Mice were intratracheally instilled with DDAC to the lung and the bronchoalveolar lavage (BAL) fluid and lung tissues were collected to assess dose- and time-related pulmonary injury. Exposure to 1500
μg/kg of DDAC caused severe morbidity with pulmonary congestive oedema. When the BAL fluid from survivors was examined on day 3 after treatment, exposure to 150
μg/kg of DDAC caused weakly induced inflammation, and exposure to 15
μg/kg did not cause any visible effects. Next, we observed pulmonary changes that occurred up to day 20 after 150
μg/kg of DDAC exposure. Pulmonary inflammation peaked on day 7 and was confirmed by expression of interleukin-6, monocyte chemotactic protein-1, macrophage inflammatory protein (MIP)-1α, MIP-1β, and regulated upon activation, normal T-cell expressed and secreted in the BAL fluid; these changes were accompanied by altered gene expression of their chemokine (C–C motif) receptor (Ccr) 1, Ccr2, Ccr3, and Ccr5. Cytotoxicity evoked by DDAC was related to the inflammatory changes and was confirmed by an
in vitro study using isolated mouse lung fibroblasts. The inflammatory phase was accompanied or followed by pulmonary remodeling, i.e., fibrosis, which was evident in the mRNA expression of type I procollagen. These results suggest that administering DDAC by intratracheal instillation causes pulmonary injury in mice, and occupational exposure to DDAC might be a potential hazard to human health.
We previously demonstrated that rat offspring exposed perinatally to methoxychlor (MXC) still exhibited immunotoxic changes in young adulthood at 10 weeks of age. That result led us to further ...investigate whether the influence of perinatal exposure to MXC on the rat immune system persistently remains in adult life. Sprague-Dawley rat offspring of both sexes from dams receiving MXC at dietary dose levels of 0, 30, 100, 300, and 1000 ppm were used for the present study. The pups exposed to MXC through the placenta, milk, and/or direct intake during the gestation and lactation periods were maintained on a normal diet from weaning up to 52 weeks of age. At the termination, a significant increase in plasma chloride was noted in both sexes at 300 and 1000 ppm MXC exposure. Females at 1000 ppm MXC exposure showed increases in serum IgM and urinary protein and had significantly increased relative weights (ratio to body weight) of the spleen and kidneys. An increased relative kidney weight was also noted in females at 300 ppm MXC exposure. Histopathologically, the incidence and severity of chronic nephropathy tended to be higher in females at 1000 ppm MXC exposure, and their kidneys had enlarged glomeruli with increased IgG and IgM deposits. In the immune system, however, there were neither notable histological changes nor significant alterations in the splenic lymphocyte subsets for any dose group of either sex. These results indicate that the immunotoxic damage caused by pre- and post-natal MXC exposure appears to be repaired during the process of growth, although the effect seems to remain in females even at 52 weeks after birth and consequently may accelerate the progression of chronic nephropathy.
Lipopolysaccharide (LPS) produced by P. gingivalis has been reported as a major factor of periodontitis. Recently, LPS has been found to cause neuroinflammation, leading to neurodegeneration such as ...Alzheimer's disease. Neuroinflammation has also been shown to be involved in developmental disorders, but there are few reports on the relationships between LPS and developmental disorders. On the other hand, we have been shown that the repeated stress such as maternal separation causes behavioral abnormalities like developmental disorders via K＋-Cl- co-transporter 2 (KCC2) downregulation in mouse models. Therefore, we hypothesized that LPS causes neuroinflammation and decreases KCC2 that leads to developmental disorders. So, we analyzed KCC2 expression after LPS treatment using primary rat cerebral cortex cells and PC-12 cells. As a result, LPS treatment (10µg/ml) decreased KCC2 expression both in primary rat cerebral cortex cells and PC-12 cells. Gene expression of toll-like receptor4 (TLR4; LPS ligand), IL1-β (inflammation marker), and REST (KCC2 repressor) were up-regulated in PC-12 cells. Moreover, the expression of pWNK, which negatively regulates KCC2, was up-regulated by LPS treatment. These results indicate that we may propose the developmental disorder drug candidates by inhibiting this pathway in the brain.
Mitochondria have been recognized as ¨Powerhouse of the Cell¨ for a long time. Lately, mitochondria have also been shown as the primary site of reactive oxygen species (ROS) generation and to be ...involved in apoptosis. Mitochondria have its own DNA (mtDNA) and mtDNA encodes 13 mitochondrial structure protein.It has been shown that mtDNA damage by ROS causes various types of diseases such as cancer. Therefore, these damaged cells will provide valuable cell models to study oxidative stress and overcome ROS derived diseases. We established mtDNA depleted ρ0 cells from HeLa and SAS cell lines and investigated the effect of ROS, especially hydrogen peroxide (H2O2) sensitivity. First, we performed H2O2 treatment on HeLa and SAS ρ0 cells at a concentration of 0 to 100 μM. Next, we investigated catalase gene expression and catalase enzyme activity. As a result, ρ0 cells showed high sensitivity to H2O2 compared with its parental cells, even though the catalase activity of ρ0 cells were up-regulated. We investigated cell membrane potential by DiBAC4 (3), lipid peroxidation by HNE immunostaining, endogenous H2O2 amount by HYDROP and uptake of H2O2 by stable isotope-containing H2O2. The result showed that the membrane potential of ρ0 cells was lower than their parental cells, the amount of HNE was elevated in ρ0 cells as compared with their parental cells, internal H2O2 amount was significantly increased only in ρ0 cells after 50 μM H2O2 treatment for 1 h and uptake of H2O2 were increased in ρ0 cells as compared with their parental cells. These changes in the membrane state, particularly lipid peroxidation, occurred in ρ0 cells as compared with their parental cells, leads to increase membrane permeability of H2O2. And the timing of the intracellular H2O2 concentration will be advanced. In conclusion, ρ0 cells are considered to be more susceptible to H2O2 than their parental cells because the membrane statuses change.
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