World Trade Center (WTC) dust exposure in mice is associated with inflammation, oxidative stress and epigenetic changes in the lung

Sunil, Vasanthi R.; Vayas, Kinal N.; Fang, Mingzhu; Zarbl, Helmut; Massa, Christopher B.; Gow, Andrew J.; Cervelli, Jessica A.; Kipen, Howard M.; Laumbach, Robert; Lioy, Paul J.; Laskin, Jeffrey D.; Laskin, Debra L.

doi:10.1016/j.yexmp.2016.12.005

Cited by 27 publications

(17 citation statements)

References 71 publications

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“…Previous studies showed that WTC dust induces oxidative stress [5,6]. Consistent with these reports, tissue samples from all patients examined were found to stain positively for the oxidative stress markers, HO-1 and Lcn-2.…”

Section: Discussionsupporting

confidence: 85%

“…Although WTC dust has been extensively characterized [ 4 ], little is known about the pathophysiologic mechanisms underlying the development of SGD and other lung pathologies. Studies in rodents have reported increased expression of genes associated with inflammation and oxidative stress in the lung following WTC dust exposure [ 5 , 6 ]. However, in these studies, granulomatous inflammation was not observed, making determination of the pathogenesis of WTC dust-induced SGD in humans, problematic.…”

Section: Introductionmentioning

confidence: 99%

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Sarcoid-Like Granulomatous Disease: Pathologic Case Series in World Trade Center Dust Exposed Rescue and Recovery Workers

Sunil

Radbel

Hussain

et al. 2019

IJERPH

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Sarcoid-like granulomatous diseases (SGD) have been previously identified in cohorts of World Trade Center (WTC) dust-exposed individuals. In the present studies, we analyzed lung and/or lymph node biopsies from patients referred to our clinic with suspected WTC dust-induced lung disease to evaluate potential pathophysiologic mechanisms. Histologic sections of lung and/or lymph node samples were analyzed for markers of injury, oxidative stress, inflammation, fibrosis, and epigenetic modifications. Out of seven patients examined, we diagnosed four with SGD and two with pulmonary fibrosis; one was diagnosed later with SGD at another medical facility. Patients with SGD were predominantly white, obese men, who were less than 50 years old and never smoked. Cytochrome b5, cytokeratin 17, heme oxygenase-1, lipocalin-2, inducible nitric oxide synthase, cyclooxygenase 2, tumor necrosis factor α, ADP-ribosylation factor-like GTPase 11, mannose receptor-1, galectin-3, transforming growth factor β, histone-3 and methylated histone-3 were identified in lung and lymph nodes at varying levels in all samples examined. Three of the biopsy samples with granulomas displayed peri-granulomatous fibrosis. These findings are important and suggest the potential of WTC dust-induced fibrotic sarcoid. It is likely that patient demographics and/or genetic factors influence the response to WTC dust injury and that these contribute to different pathological outcomes.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Sarcoid-Like Granulomatous Disease: Pathologic Case Series in World Trade Center Dust Exposed Rescue and Recovery Workers

Sunil

Radbel

Hussain

et al. 2019

IJERPH

Self Cite

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“…In vitro and in vivo studies suggest that macrophages exposed to WTC dust can induce the secretion of cytokines and other inflammatory factors (7). WTC dust exposure in mice is associated with inflammation, oxidative stress, and epigenetic changes in the lung (8). In an effort to understand the underlying causes of the excess incidence of prostate cancer in WTC responders, we hypothesized that inhalation of WTC dust not only exposed prostate cells to genotoxic substances, but also might have facilitated prostate cancer progression through longer-term mechanisms such as fostering chronic inflammation.…”

Section: Introductionmentioning

confidence: 99%

Prostate Cancer in World Trade Center Responders Demonstrates Evidence of an Inflammatory Cascade

Gong

Wang

et al. 2019

Molecular Cancer Research

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An excess incidence of prostate cancer has been identified among World Trade Center (WTC) responders. In this study, we hypothesized that WTC dust, which contained carcinogens and tumor-promoting agents, could facilitate prostate cancer development by inducing DNA damage, promoting cell proliferation, and causing chronic inflammation. We compared expression of immunologic and inflammatory genes using a NanoString assay on archived prostate tumors from WTC Health Program (WTCHP) patients and non-WTC patients with prostate cancer. Furthermore, to assess immediate and delayed responses of prostate tissue to acute WTC dust exposure via intratracheal inhalation, we performed RNA-seq on the prostate of normal rats that were exposed to moderate to high doses of WTC dust. WTC prostate cancer cases showed significant upregulation of genes involved in DNA damage and G 2-M arrest. Cell-type enrichment analysis showed that Th17 cells, a subset of proinflammatory Th cells, were specifically upregulated in WTC patients. In rats exposed to WTC dust, we observed upregulation of gene transcripts of cell types involved in both adaptive immune response (dendritic cells and B cells) and inflammatory response (Th17 cells) in the prostate. Unexpectedly, genes in the cholesterol biosynthesis pathway were also significantly upregulated 30 days after acute dust exposure. Our results suggest that respiratory exposure to WTC dust can induce inflammatory and immune responses in prostate tissue. Implications: WTC-related prostate cancer displayed a distinct gene expression pattern that could be the result of exposure to specific carcinogens. Our data warrant further epidemiologic and cellular mechanistic studies to better understand the consequences of WTC dust exposure.

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“…One possible pathway for HNC is that WTC dust exposure could facilitate the HPV infection and persistence initially via direct tissue damage and then by inflammation. In mouse models, WTC dust‐exposure induces inflammation and oxidative stress associated with epigenetic modifications in the lung that result in altered pulmonary mechanics . WTC responders continue to have a high burden of inflammation‐inducing, upper aerodigestive‐tract conditions today …”

Section: Discussionmentioning

confidence: 99%

Excess HPV‐related head and neck cancer in the world trade center health program general responder cohort

Graber

Harris

Black

et al. 2019

Intl Journal of Cancer

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The World Trade Center (WTC) attacks exposed rescue and recovery workers to a complex mix of toxicants, including carcinogens. our study compared site-specific cancer incidence of head and neck cancers (HNC) from 2003 through 2012 among 33,809 consented WTC General Responder Cohort (GRC) members to the New Jersey State Cancer Registry, using standardized incidence ratios (SIRs). HNC grouped using SEER ICD-O-3 codes into HPV-related (oropharyngeal) and non-related (other oral-nasal; laryngeal) tumors based on anatomical site. For the 73 GRC members identified with HNC, proportional hazard regression assessed the relationship between WTC exposure and other socio-demographic characteristics. An overall excess of HNC was not observed (SIR = 1.00, 95% CI: 0.78, 1.25) but excess cancer was seen in the latest observation period (2009-2012: SIR = 1.4; 95% CI: 1.01, 1.89). A similar temporal pattern was seen for HPV-related oropharyngeal cancer and laryngeal cancer, but not for non-HPV-related sites (oral-nasal cancer). HNC was significantly associated with increasing age (8% per year, 95% CI: 5%, 12%), non-Hispanic white ethnic group-ethnicity (hazard ratio (HR) = 3.51, 95 CI: 1.49, 8.27); there was a borderline association with the 9/11 occupation of military/protective services vs. others (HR = 1.83 95% CI: 0.99, 3.38; p = 0.0504). Caution is needed in interpreting these results given the small number of cases, potential for surveillance bias, and long latency for most cancers. Our findings highlight the need to examine the potentially carcinogenic effects of WTC exposure in the context of other strong risk factors, and the need for continued medical monitoring of WTC responders.

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World Trade Center (WTC) dust exposure in mice is associated with inflammation, oxidative stress and epigenetic changes in the lung

Cited by 27 publications

References 71 publications

Sarcoid-Like Granulomatous Disease: Pathologic Case Series in World Trade Center Dust Exposed Rescue and Recovery Workers

Sarcoid-Like Granulomatous Disease: Pathologic Case Series in World Trade Center Dust Exposed Rescue and Recovery Workers

Prostate Cancer in World Trade Center Responders Demonstrates Evidence of an Inflammatory Cascade

Excess HPV‐related head and neck cancer in the world trade center health program general responder cohort

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