Acute exposure of mice to high-dose ultrafine carbon black decreases susceptibility to pneumococcal pneumonia

<p>Abstract</p> <p>Background</p> <p>Epidemiological studies suggest that inhalation of carbonaceous particulate matter from biomass combustion increases susceptibility to bacterial pneumonia. <it>In vitro </it>studies report that phagocytosis of carbon black by alveolar macrophages (AM) impairs killing of <it>Streptococcus pneumoniae</it>. We have previously reported high levels of black carbon in AM from biomass smoke-exposed children and adults. We therefore aimed to use a mouse model to test the hypothesis that high levels of carbon loading of AM <it>in vivo </it>increases susceptibility to pneumococcal pneumonia.</p> <p>Methods</p> <p>Female outbred mice were treated with either intranasal phosphate buffered saline (PBS) or ultrafine carbon black (UF-CB in PBS; 500 μg on day 1 and day 4), and then infected with <it>S. pneumoniae </it>strain D39 on day 5. Survival was assessed over 72 h. The effect of UF-CB on AM carbon loading, airway inflammation, and a urinary marker of pulmonary oxidative stress was assessed in uninfected animals.</p> <p>Results</p> <p>Instillation of UF-CB in mice resulted a pattern of AM carbon loading similar to that of biomass-smoke exposed humans. In uninfected animals, UF-CB treated animals had increased urinary 8-oxodG (P = 0.055), and an increased airway neutrophil differential count (P < 0.01). All PBS-treated mice died within 72 h after infection with S<it>. pneumoniae</it>, whereas morbidity and mortality after infection was reduced in UF-CB treated animals (median survival 48 h vs. 30 h, P < 0.001). At 24 hr post-infection, UF-CB treated mice had lower lung and the blood S<it>. pneumoniae </it>colony forming unit counts, and lower airway levels of keratinocyte-derived chemokine/growth-related oncogene (KC/GRO), and interferon gamma.</p> <p>Conclusion</p> <p>Acute high level loading of AM with ultrafine carbon black particles <it>per se </it>does not increase the susceptibility of mice to pneumococcal infection <it>in vivo</it>.</p

Metabolic profiling detects early effects of environmental and lifestyle exposure to cadmium in a human population

Background: The ‘exposome’ represents the accumulation of all environmental exposures across a lifetime. Topdown strategies are required to assess something this comprehensive, and could transform our understanding of how environmental factors affect human health. Metabolic profiling (metabonomics/metabolomics) defines an individual’s metabolic phenotype, which is influenced by genotype, diet, lifestyle, health and xenobiotic exposure, and could also reveal intermediate biomarkers for disease risk that reflect adaptive response to exposure. We investigated changes in metabolism in volunteers living near a point source of environmental pollution: a closed zinc smelter with associated elevated levels of environmental cadmium. Methods: High-resolution 1H NMR spectroscopy (metabonomics) was used to acquire urinary metabolic profiles from 178 human volunteers. The spectral data were subjected to multivariate and univariate analysis to identify metabolites that were correlated with lifestyle or biological factors. Urinary levels of 8-oxo-deoxyguanosine were also measured, using mass spectrometry, as a marker of systemic oxidative stress. Results: Six urinary metabolites, either associated with mitochondrial metabolism (citrate, 3-hydroxyisovalerate, 4- deoxy-erythronic acid) or one-carbon metabolism (dimethylglycine, creatinine, creatine), were associated with cadmium exposure. In particular, citrate levels retained a significant correlation to urinary cadmium and smoking status after controlling for age and sex. Oxidative stress (as determined by urinary 8-oxo-deoxyguanosine levels) was elevated in individuals with high cadmium exposure, supporting the hypothesis that heavy metal accumulation was causing mitochondrial dysfunction. Conclusions: This study shows evidence that an NMR-based metabolic profiling study in an uncontrolled human population is capable of identifying intermediate biomarkers of response to toxicants at true environmental concentrations, paving the way for exposome research. Keywords: metabonomics, cadmium, environmental health, exposome, metabolomics, molecular epidemiolog

Approaches to the discovery of biomarkers of prostate carcinogenesis in TRAMP mice and of chemopreventive efficacy of tea polyphenols

To improve prostate cancer management in humans who have, or are at risk of developing, the disease, biomarkers are required to aid early diagnosis and monitoring of response to chemotherapeutic or chemopreventive intervention. In this project metabonomic and peptidomic approaches were used to study biological changes associated with prostate carcinogenesis in a transgenic mouse model (TRAMP, TRansgenic Adenocarcinoma of the Mouse Prostate). Observed changes were compared with pathological alterations. Metabolome and peptidome analyses were conducted in TRAMP mice exposed to chemopreventive intervention with green tea polyphenols (GTP). Effects of consumption of GTP or black tea theaflavins on the plasma and urine metabonome/peptidome in patients with benign prostatic hyperplasia (BPH) were also investigated. Oxidative stress status reflected by urinary 8-oxo-7,8-dihydro-2’-deoxyguanosine (8-oxodG) was assessed in mice and humans on tea polyphenols. Metabonomic profiling revealed that at early stages of carcinogenesis in mice, alterations of tumour levels of choline metabolites resembled the human disease. In contrast, in advanced stages of TRAMP prostate carcinogenesis, phospholipid metabolism is affected differently by malignancy than in its human counterpart. Disturbed prostate-specific citrate metabolism seems common to both human and TRAMP prostate tumours when compared to normal tissue. These results suggest that the TRAMP mouse may be a better model with respect to humans of early stage carcinogenesis with minor proliferative lesions than of more advanced stages of malignancy. Urinary 8-oxodG levels were not affected by presence of prostate cancer or intervention with tea. Metabolic profiling gave evidence for an effect of GTP on energy metabolism in both mice and humans. Although TRAMP and GTP-groupspecific metabonomic and peptidomic changes were found in plasma and urine, none of these metabolites or peptides could be unambiguously identified as biomarkers of carcinogenesis or GTP exposure. Among possible confounding factors which should be taken into consideration in future metabonomic/peptidomic studies is the host’s gut microflora

Approaches to the discovery of biomarkers of prostate carcinogenesis in TRAMP mice and of chemopreventive efficacy of tea polyphenols

To improve prostate cancer management in humans who have, or are at risk of developing, the disease, biomarkers are required to aid early diagnosis and monitoring of response to chemotherapeutic or chemopreventive intervention. In this project metabonomic and peptidomic approaches were used to study biological changes associated with prostate carcinogenesis in a transgenic mouse model (TRAMP, TRansgenic Adenocarcinoma of the Mouse Prostate). Observed changes were compared with pathological alterations. Metabolome and peptidome analyses were conducted in TRAMP mice exposed to chemopreventive intervention with green tea polyphenols (GTP). Effects of consumption of GTP or black tea theaflavins on the plasma and urine metabonome/peptidome in patients with benign prostatic hyperplasia (BPH) were also investigated. Oxidative stress status reflected by urinary 8-oxo-7,8-dihydro-2’-deoxyguanosine (8-oxodG) was assessed in mice and humans on tea polyphenols. Metabonomic profiling revealed that at early stages of carcinogenesis in mice, alterations of tumour levels of choline metabolites resembled the human disease. In contrast, in advanced stages of TRAMP prostate carcinogenesis, phospholipid metabolism is affected differently by malignancy than in its human counterpart. Disturbed prostate-specific citrate metabolism seems common to both human and TRAMP prostate tumours when compared to normal tissue. These results suggest that the TRAMP mouse may be a better model with respect to humans of early stage carcinogenesis with minor proliferative lesions than of more advanced stages of malignancy. Urinary 8-oxodG levels were not affected by presence of prostate cancer or intervention with tea. Metabolic profiling gave evidence for an effect of GTP on energy metabolism in both mice and humans. Although TRAMP and GTP-groupspecific metabonomic and peptidomic changes were found in plasma and urine, none of these metabolites or peptides could be unambiguously identified as biomarkers of carcinogenesis or GTP exposure. Among possible confounding factors which should be taken into consideration in future metabonomic/peptidomic studies is the host’s gut microflora.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Chronic exposure to cadmium and arsenic strongly influences concentrations of 8-oxo-7,8-dihydro-2'-deoxyguanosine in urine.

Exposure to arsenic (As), cadmium (Cd) and lead (Pb) may generate oxidative stress, which can be assessed by 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in urine, a sensitive marker of oxidatively damaged DNA. We have evaluated oxidative stress induced by mixed chronic exposure to As, Cd, Pb, as well as the influence of As metabolism and nutritional status, i.e. ferritin (Ft), selenium (Se), zinc (Zn), manganese (Mn) and body weight. 8-oxodG was measured in urine from 212 women in early pregnancy from Matlab, rural Bangladesh, using LC-MS/MS. Cd and Pb were analyzed in urine and erythrocytes, while Se, Mn and Zn were analyzed in erythrocytes, all by ICPMS. As and As metabolites were analyzed in urine by HPLC-ICPMS. Ferritin was analyzed in plasma by radioimmunoassay. Median concentration of 8-oxodG was 8.3 nmol/L (adjusted for specific gravity), range 1.2-43, corresponding to a median of 4.7 mug/g creatinine, range 1.8-32. 8-oxodG was positively associated with urinary Cd (ss=0.32, p<0.001), urinary As (ss=0.0007, p=0.001), fraction of the monomethylated arsenic metabolite (MMA) in urine (ss=0.0026, p=0.004) and plasma Ft (ss = 0.20, p<0.001). A joint effect was seen for U-Cd and U-As, but whether this effect was additive or multiplicative was difficult to discern

ERK1/2 Activity Is Critical for the Outcome of Ischemic Stroke

Ischemic disorders are the leading cause of death worldwide. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) are thought to affect the outcome of ischemic stroke. However, it is under debate whether activation or inhibition of ERK1/2 is beneficial. In this study, we report that the ubiquitous overexpression of wild-type ERK2 in mice (ERK2wt) is detrimental after transient occlusion of the middle cerebral artery (tMCAO), as it led to a massive increase in infarct volume and neurological deficits by increasing blood&ndash;brain barrier (BBB) leakiness, inflammation, and the number of apoptotic neurons. To compare ERK1/2 activation and inhibition side-by-side, we also used mice with ubiquitous overexpression of the Raf-kinase inhibitor protein (RKIPwt) and its phosphorylation-deficient mutant RKIPS153A, known inhibitors of the ERK1/2 signaling cascade. RKIPwt and RKIPS153A attenuated ischemia-induced damages, in particular via anti-inflammatory signaling. Taken together, our data suggest that stimulation of the Raf/MEK/ERK1/2-cascade is severely detrimental and its inhibition is rather protective. Thus, a tight control of the ERK1/2 signaling is essential for the outcome in response to ischemic stroke

Low 8-oxo-7,8-dihydro-2'-deoxyguanosine levels and influence of genetic background in an Andean population exposed to high levels of arsenic.

BACKGROUND: Arsenic (As) causes oxidative stress through generation of reactive oxygen species. 8-Oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), a sensitive marker of oxidative DNA damage, has been associated with As exposure in some studies, but not in others, possibly due to population-specific genetic factors. OBJECTIVES: To evaluate the association between As and 8-oxodG in urine in a population with a low urinary monomethylated As (%MMA) and high dimethylated As (%DMA), as well as the genetic impact on (a) 8-oxodG concentrations and (b) the association between As and 8-oxodG. MATERIALS AND METHODS: Women (N=108) in the Argentinean Andes were interviewed and urine was analyzed for arsenic metabolites (ICPMS) and 8-oxodG (LC-MS/MS). Twenty-seven polymorphisms in genes related to oxidative stress and one in As(+III)methyltransferase (AS3MT) were studied. RESULTS: Median concentration of 8-oxodG was 4.7nmol/L (adjusted for specific weight; range 1.6-13, corresponding to 1.7mug/g creatinine, range 0.57-4.8) and of total urinary As metabolites (U-As) 290mug/L (range 94-720; 380mug/g creatinine, range 140-1100). Concentrations of 8-oxodG were positively associated with %MMA (strongest association, p=0.013), and weakly associated with U-As (positively) and %DMA (negatively). These associations were strengthened when taking ethnicity into account, possibly reflecting genetic differences in As metabolism and genes regulating oxidative stress and DNA maintenance. A genetic influence on 8-oxodG concentrations was seen for polymorphisms in apurinic/apyrimidinic endonuclease 1 (APEX1), DNA-methyltransferases 1 and 3b (DNMT1, DNMT3B), thioredoxin reductase 1 (TXNRD1) and 2 (TXNRD2) and glutaredoxin (GLRX). CONCLUSION: Despite high As exposure, the concentrations of 8-oxodG in this population were low compared with other As-exposed populations studied. The strongest association was found for %MMA, stressing that some inconsistencies between As and 8-oxodG partly depend on population variations in As metabolism. We found evidence of genetic impact on 8-oxodG concentrations