Global estimates of mortality associated with long-term exposure to outdoor fine particulate matter.

Exposure to ambient fine particulate matter (PM2.5) is a major global health concern. Quantitative estimates of attributable mortality are based on disease-specific hazard ratio models that incorporate risk information from multiple PM2.5 sources (outdoor and indoor air pollution from use of solid fuels and secondhand and active smoking), requiring assumptions about equivalent exposure and toxicity. We relax these contentious assumptions by constructing a PM2.5-mortality hazard ratio function based only on cohort studies of outdoor air pollution that covers the global exposure range. We modeled the shape of the association between PM2.5 and nonaccidental mortality using data from 41 cohorts from 16 countries-the Global Exposure Mortality Model (GEMM). We then constructed GEMMs for five specific causes of death examined by the global burden of disease (GBD). The GEMM predicts 8.9 million [95% confidence interval (CI): 7.5-10.3] deaths in 2015, a figure 30% larger than that predicted by the sum of deaths among the five specific causes (6.9; 95% CI: 4.9-8.5) and 120% larger than the risk function used in the GBD (4.0; 95% CI: 3.3-4.8). Differences between the GEMM and GBD risk functions are larger for a 20% reduction in concentrations, with the GEMM predicting 220% higher excess deaths. These results suggest that PM2.5 exposure may be related to additional causes of death than the five considered by the GBD and that incorporation of risk information from other, nonoutdoor, particle sources leads to underestimation of disease burden, especially at higher concentrations.

Fine particulate matter exposure and incidence of stroke: A cohort study in Hong Kong.

OBJECTIVE: We aimed to assess the association of long-term residential exposure to fine particulate matter (PM) with aerodynamic diameter less than 2.5 µm (PM2.5) with the incidence of stroke and its major subtypes. METHODS: We ascertained the first occurrence of emergency hospital admission for stroke in a Hong Kong Chinese cohort of 66,820 older people (65+ years) who enrolled during 1998-2001 (baseline) and were followed up to December 31, 2010. High-resolution (1 × 1 km) yearly mean concentrations of PM2.5 were predicted from local monitoring data and US National Aeronautics and Space Administration satellite data using linear regression. Baseline residential PM2.5 exposure was used as a proxy for long-term exposure. We used Cox proportional hazards to evaluate the risk of incident stroke associated with PM2.5 exposure adjusted for potential confounders, including individual and neighborhood factors. RESULTS: Over a mean follow-up of 9.4 years, we ascertained 6,733 cases of incident stroke, of which 3,526 (52.4%) were ischemic and 1,175 (17.5%) were hemorrhagic. The hazard ratio for every 10 µg/m3 higher PM2.5 concentration was statistically significant at 1.21 (95% confidence interval [CI] 1.04-1.41) for ischemic and non-statistically significant at 0.90 (95% CI 0.70-1.17) for hemorrhagic stroke in fully adjusted model 3. The estimates for ischemic stroke were higher in older participants (>70 years), less educated participants, and in men for current smokers. CONCLUSION: Long-term PM2.5 exposure was associated with higher risk of incident ischemic stroke, but the association with incident hemorrhagic stroke was less clear.

Cancer Mortality Risks from Long-term Exposure to Ambient Fine Particle.

BACKGROUND: Few studies have assessed long-term effects of particulate matter (PM) with aerodynamic diameter < 2.5 µm (PM2.5) on mortality for causes of cancer other than the lung; we assessed the effects on multiple causes. In Hong Kong, most people live and work in urban or suburban areas with high-rise buildings. This facilitates the estimation of PM2.5 exposure of individuals, taking into account the height of residence above ground level for assessment of the long-term health effects with sufficient statistical power. METHODS: We recruited 66,820 persons who were ≥65 in 1998 to 2001 and followed up for mortality outcomes until 2011. Annual concentrations of PM at their residential addresses were estimated using PM2.5 concentrations measured at fixed-site monitors, horizontal-vertical locations, and satellite data. We used Cox regression model to assess the HR of mortality for cancer per 10 µg/m(3) increase of PM2.5 RESULTS: PM2.5 was associated with increased risk of mortality for all causes of cancer [HR, 1.22 (95% CI, 1.11-1.34)] and for specific cause of cancer in upper digestive tract [1.42 (1.06-1.89)], digestive accessory organs [1.35 (1.06-1.71)] in all subjects; breast [1.80 (1.26-2.55)] in females; and lung [1.36 (1.05-1.77)] in males. CONCLUSIONS: Long-term exposures to PM2.5 are associated with elevated risks of cancer in various organs. IMPACT: This study is particularly timely in China, where compelling evidence is needed to support the pollution control policy to ameliorate the health damages associated with economic growth. Cancer Epidemiol Biomarkers Prev; 25(5); 839-45. ©2016 AACR.

Aberrant chloride intracellular channel 4 expression contributes to endothelial dysfunction in pulmonary arterial hypertension.

BACKGROUND: Chloride intracellular channel 4 (CLIC4) is highly expressed in the endothelium of remodeled pulmonary vessels and plexiform lesions of patients with pulmonary arterial hypertension. CLIC4 regulates vasculogenesis through endothelial tube formation. Aberrant CLIC4 expression may contribute to the vascular pathology of pulmonary arterial hypertension. METHODS AND RESULTS: CLIC4 protein expression was increased in plasma and blood-derived endothelial cells from patients with idiopathic pulmonary arterial hypertension and in the pulmonary vascular endothelium of 3 rat models of pulmonary hypertension. CLIC4 gene deletion markedly attenuated the development of chronic hypoxia-induced pulmonary hypertension in mice. Adenoviral overexpression of CLIC4 in cultured human pulmonary artery endothelial cells compromised pulmonary endothelial barrier function and enhanced their survival and angiogenic capacity, whereas CLIC4 shRNA had an inhibitory effect. Similarly, inhibition of CLIC4 expression in blood-derived endothelial cells from patients with idiopathic pulmonary arterial hypertension attenuated the abnormal angiogenic behavior that characterizes these cells. The mechanism of CLIC4 effects involves p65-mediated activation of nuclear factor-κB, followed by stabilization of hypoxia-inducible factor-1α and increased downstream production of vascular endothelial growth factor and endothelin-1. CONCLUSION: Increased CLIC4 expression is an early manifestation and mediator of endothelial dysfunction in pulmonary hypertension.

Perfluorooctanoate suppresses spheroid attachment on endometrial epithelial cells through peroxisome proliferator-activated receptor alpha and down-regulation of Wnt signaling.

Exposure of animals to perfluorooctanoic acid (PFOA), a surfactant used in emulsion polymerization processes causes early pregnancy loss, delayed growth and development of fetuses. The mechanisms of action are largely unknown. We studied the effect of PFOA on implantation using an in vitro spheroid-endometrial cell co-culture model. PFOA (10-100µM) significantly reduced Jeg-3 spheroid attachment on RL95-2 endometrial cells. PFOA also suppressed ß-catenin expression in Jeg-3 cells. The Wnt agonist Wnt3a stimulated ß-catenin expression in Jeg-3 cells and reversed the PFOA suppression of the spheroid attachment. The putative PFOA receptors (PPARα, ß, γ) present in both cell lines were not affected by PFOA (0.01-100µM). The PPARα antagonist MK886 restored the ß-catenin and E-cadherin expression levels in Jeg-3 cells and reversed the suppression of the spheroid attachment caused by PFOA. Taken together, PFOA suppresses spheroid attachment through PPARα and Wnt signaling pathways via down-regulation of ß-catenin and E-cadherin expression.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) suppresses spheroids attachment on endometrial epithelial cells through the down-regulation of the Wnt-signaling pathway.

The environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) affects embryo development, implantation and fertility in humans. The underlying molecular mechanism by which TCDD suppresses implantation remains largely unknown. We used the trophoblastic spheroids (embryo surrogate)-endometrial cells co-culture assay to study the attachment of trophoblastic spheroids (BeWo and Jeg-3) onto the endometrial epithelial (RL95-2 and Ishikawa) cells. TCDD dose-dependently induced cytochrome P450 1A1 (Cyp1A1) expression in trophoblastic and endometrial epithelial cells. Moreover, TCDD at 1 and 10 nM suppressed ß-catenin (a Wnt-signaling molecule) and E-cadherin expression, as well as spheroids attachment onto endometrial cells. Interestingly, activation of the canonical Wnt-signaling pathway via Wnt3a or lithium chloride reverted the suppressive effect of TCDD on ß-catenin and E-cadherin expressions in the BeWo and RL95-2 cells, and restored the spheroids attachment rate to be comparable to the untreated controls. Taken together, TCDD induces Cyp1A1 expression, modulates the Wnt-signaling pathway and suppresses spheroids attachment onto endometrial cells.

The hereditary spastic paraplegia proteins NIPA1, spastin and spartin are inhibitors of mammalian BMP signalling.

The hereditary spastic paraplegias (HSPs) are genetic conditions characterized by distal axonopathy of the longest corticospinal tract axons, and so their study provides an important opportunity to understand mechanisms involved in axonal maintenance and degeneration. A group of HSP genes encode proteins that localize to endosomes. One of these is NIPA1 (non-imprinted in Prader-Willi/Angelman syndrome 1) and we have shown recently that its Drosophila homologue spichthyin inhibits bone morphogenic protein (BMP) signalling, although the relevance of this finding to the mammalian protein was not known. We show here that mammalian NIPA1 is also an inhibitor of BMP signalling. NIPA1 physically interacts with the type II BMP receptor (BMPRII) and we demonstrate that this interaction does not require the cytoplasmic tail of BMPRII. We show that the mechanism by which NIPA1 inhibits BMP signalling involves downregulation of BMP receptors by promoting their endocytosis and lysosomal degradation. Disease-associated mutant versions of NIPA1 alter the trafficking of BMPRII and are less efficient at promoting BMPRII degradation than wild-type NIPA1. In addition, we demonstrate that two other members of the endosomal group of HSP proteins, spastin and spartin, are inhibitors of BMP signalling. Since BMP signalling is important for distal axonal function, we propose that dysregulation of BMP signalling could be a unifying pathological component in this endosomal group of HSPs, and perhaps of importance in other conditions in which distal axonal degeneration is found.

Endogenous spartin (SPG20) is recruited to endosomes and lipid droplets and interacts with the ubiquitin E3 ligases AIP4 and AIP5.

The HSPs (hereditary spastic paraplegias) are genetic conditions in which there is distal degeneration of the longest axons of the corticospinal tract, resulting in spastic paralysis of the legs. The gene encoding spartin is mutated in Troyer syndrome, an HSP in which paralysis is accompanied by additional clinical features. There has been controversy over the subcellular distribution of spartin. We show here that, at steady state, endogenous spartin exists in a cytosolic pool that can be recruited to endosomes and to lipid droplets. Cytosolic endogenous spartin is mono-ubiquitinated and we demonstrate that it interacts via a PPXY motif with the ubiquitin E3 ligases AIP4 [atrophin-interacting protein 4; ITCH (itchy E3 ubiquitin protein ligase homologue] [corrected] and AIP5 (WWP1). Surprisingly, the PPXY motif, AIP4 and AIP5 are not required for spartin's ubiquitination, and so we propose that spartin acts as an adaptor for these proteins. Our results suggest that spartin is involved in diverse cellular functions, which may be of relevance to the complex phenotype seen in Troyer syndrome.