Toxicogenomic analysis of susceptibility to inhaled urban particulate matter in mice with chronic lung inflammation

<p>Abstract</p> <p>Background</p> <p>Individuals with chronic lung disease are at increased risk of adverse health effects from airborne particulate matter. Characterization of underlying pollutant-phenotype interactions may require comprehensive strategies. Here, a toxicogenomic approach was used to investigate how inflammation modifies the pulmonary response to urban particulate matter.</p> <p>Results</p> <p>Transgenic mice with constitutive pulmonary overexpression of tumour necrosis factor (TNF)-α under the control of the surfactant protein C promoter and wildtype littermates (C57BL/6 background) were exposed by inhalation for 4 h to particulate matter (0 or 42 mg/m³EHC-6802) and euthanized 0 or 24 h post-exposure. The low alveolar dose of particles (16 μg) did not provoke an inflammatory response in the lungs of wildtype mice, nor exacerbate the chronic inflammation in TNF animals. Real-time PCR confirmed particle-dependent increases of CYP1A1 (30–100%), endothelin-1 (20–40%), and metallothionein-II (20–40%) mRNA in wildtype and TNF mice (p < 0.05), validating delivery of a biologically-effective dose. Despite detection of striking genotype-related differences, including activation of immune and inflammatory pathways consistent with the TNF-induced pathology, and time-related effects attributable to stress from nose-only exposure, microarray analysis failed to identify effects of the inhaled particles. Remarkably, the presence of chronic inflammation did not measurably amplify the transcriptional response to particulate matter.</p> <p>Conclusion</p> <p>Our data support the hypothesis that health effects of acute exposure to urban particles are dominated by activation of specific physiological response cascades rather than widespread changes in gene expression.</p

Examples of individual supported living for adults with intellectual disability

Background: This article provides a qualitative account of four models of support for adults with intellectual disability in individual supported living (ISL) arrangements. Materials and Methods: Completion of the first 50 evaluations of 150 arrangements for the third phase of the ISL project provided the examples. Results: Four approaches are described: living alone, co-residency, relationship and host family. Within each type, wide variations occur particularly based on security of tenure, formal and informal support and management variations. Conclusion: Fifty evaluations so far illustrated a wide range of approaches to ISL, providing evidence of the critical importance of the formal and informal support environment and reinforcing the contention that ISL is appropriate for people with high support needs

Contrasting biological potency of particulate matter collected at sites impacted by distinct industrial sources

Association of biological effects in A549 cells with metal content in size-fractionated particles. Cytotoxic potencies according to lactate dehydrogenase (LDH) release and resazurin reduction were regressed against total, water-soluble, and non-water-soluble metals. Pearson product–moment correlation coefficient r-values are presented. LDH release. A) Total metals. UFP, r = 0.77, p = 0.13; PM0.1–2.5, r = −0.55, p = 0.34; PM2.5–10, r = 0.32, p = 0.60; PM>10, r = −0.68, p = 0.21. B) Water-soluble metals. UFP, r = 0.51, p = 0.38; PM0.1–2.5, r = −0.64, p = 0.25; PM2.5–10, r = −0.35, p = 0.57; PM>10, r = −0.68, p = 0.20. C) Non-water-soluble metals. UFP, r = 0.75, p = 0.14; PM0.1–2.5, r = −0.46, p = 0.43; PM2.5–10, r = 0.36, p = 0.55; PM>10, r = −0.68, p = 0.21. Resazurin reduction. D) UFP, r = −0.19, p = 0.76; PM0.1–2.5, r = −0.63, p = 0.26; PM2.5–10, r = −0.60, p = 0.28; PM>10,r = 0.18, p = 0.78. Water-soluble metals. UFP, r = −0.20, p = 0.74; PM0.1–2.5, r = −0.41, p = 0.49; PM2.5–10, r = −0.09, p = 0.88; PM>10, r = 0.04, p = 0.95. Non-water-soluble metals. UFP, r = −0.12, p = 0.84; PM0.1–2.5, r = −0.65, p = 0.24; PM2.5–10, r = −0.62, p = 0.26; PM>10, r = 0.18, p = 0.77. (PDF 43 kb

Innovations in research ethics governance in humanitarian settings.

CAPRISA, 2015.Abstract available in pdf

Modulation by Ozone of Glucocorticoid-Regulating Factors in the Lungs in Relation to Stress Axis Reactivity

Exposure to air pollutants increases levels of circulating glucocorticoid stress hormones that exert profound effects relevant to health and disease. However, the nature and magnitude of tissue-level effects are modulated by factors that regulate local glucocorticoid activity; accordingly, inter-individual differences could contribute to susceptibility. In the present study, we characterized effects of ozone (O3) inhalation on glucocorticoid-regulating factors in the lungs of rat strains with contrasting hypothalamic–pituitary–adrenal stress axis responses. Hyper-responsive Fischer (F344) and less responsive Lewis (LEW) rats were exposed to air or 0.8 ppm O3 for 4 h by nose-only inhalation. Levels of the high-specificity and -affinity corticosteroid-binding globulin protein increased in the lungs of both strains proportional to the rise in corticosterone levels following O3 exposure. Ozone reduced the ratio of 11β-hydroxysteroid dehydrogenase type 1 (HSDB1)/HSDB2 mRNA in the lungs of F344 but not LEW, indicating strain-specific transcriptional regulation of the major glucocorticoid metabolism factors that control tissue-level action. Intercellular adhesion molecule (ICAM)-1 and total elastase activity were increased by O3 in both strains, consistent with extravasation and tissue remodeling processes following injury. However, mRNA levels of inflammatory markers were significantly higher in the lungs of O3-exposed LEW compared to F344. The data show that strain differences in the glucocorticoid response to O3 are accompanied by corresponding changes in regulatory factors, and that these effects are collectively associated with a differential inflammatory response to O3. Innate differences in glucocorticoid regulatory factors may modulate the pulmonary effects of inhaled pollutants, thereby contributing to differential susceptibility

Ambient air pollution exposure and emergency department visits for substance abuse.

There is growing evidence supporting the notion that exposure to air pollution can contribute to cognitive and psychiatric disorders, including depression and suicide. Given the relationship between exposure to acute stressors and substance abuse, the present study assessed the association between exposure to ambient air pollution and emergency department (ED) visits for alcohol and drug abuse. ED visit data selected according to International Classification of Disease (ICD-9) coding 303 (alcohol dependence syndromes) and 305 (non-dependent abuse of drugs) were collected in five hospitals in Edmonton, Canada. A time-stratified case crossover design was used. Conditional logistic regression was applied to calculate odds ratios (OR) and 95% confidence intervals (95% CI). Season, temperature, and relative humidity were adjusted for using natural splines. Results are reported for an increase in pollutant concentrations equivalent to one interquartile range (IQR). Statistically significant positive associations with substance abuse were observed for CO, NO2 and particulate matter with an aerodynamic diameter less than 10 μm (PM10) and 2.5 μm (PM2.5). The strongest results were obtained in the cold period (October-March) for 1-day lagged CO (OR = 1.03, 95% CI: 1.01, 1.05, IQR = 0.4 ppm) and NO2 (OR = 1.04, 95% CI: 1.01, 1.07, IQR = 12.8 ppb); ORs were also significant for CO and NO2 with lags of 2 to 6 days and 2 to 7 days, respectively. The study suggests that, even at low levels, increases in ambient CO, NO2, and PMs are associated with increased hospital admissions for substance abuse, possibly as a result of impacts of air quality on mental health or depression