Faculty Bibliography

BACKGROUND & AIMS:modulates hepatic lipid metabolism. METHODS:exposure-induced metabolic disorder. RESULTS:-induced metabolic dysfunction. CONCLUSIONS:exposure inhibited HPA axis and demonstrated sex-associated differences in its effects on IR and disorder of hepatic lipid metabolism. These findings provide new mechanistic evidence of hormone regulation in air pollution-mediated metabolic abnormalities of lipids and more personalized care should be considered in terms of sex-specific risk factors.

Background: Studies have revealed the increased incidence of health disorders in First Responders (FR) who were at Ground Zero over the initial 72 hr after the World Trade Center (WTC) collapses. Previous studies in rats exposed to WTC dusts using exposure scenarios that mimicked FR mouthbreathing showed exposure led to altered expression of genes whose products could be involved in lung ailments. Nevertheless, it was uncertain if repeated exposures (as occurred in earliest days post-disaster) might have given rise to long-term changes in the lungs/other organs, in white blood cell (WBC) profiles, and/or systemic expression of select (mostly immune-related) proteins.Methods: To examine this, rats were exposed on 2 consecutive days (2 hr/d, intratracheal inhalation) to WTC dusts and then examined over a 1-yr period thereafter. At select times post-exposure, organ (lung, heart, liver, kidney, spleen) weights, WBC profiles, and blood levels of a variety of proteins were evaluated.Results: The study showed that over the 1-yr period, there were nominal effects on organ weights (absolute, index) as a result of the dust exposures. There were significant changes (relative to in naïve rats) in WBC profiles, with exposed rats having increased monocyte-macrophage and decreased lymphocyte percentages. The study also found that dust exposure led to significant systemic increases in many proteins, including MCP-1, RANTES, MMP-9, RAGE, and Galectin-3.Conclusions: These results provide further support for our longstanding hypothesis that the WTC dusts could potentially have acted as direct inducers of many of the health effects that have been seen in the exposed FR.

Electronic-cigarettes (E-cigs) are marketed as a safe alternative to tobacco to deliver the stimulant nicotine, and their use is gaining in popularity, particularly among the younger population. We recently showed that mice exposed to short-term (12 wk) E-cig smoke (ECS) sustained extensive DNA damage in lungs, heart, and bladder mucosa and diminished DNA repair in lungs. Nicotine and its nitrosation product, nicotine-derived nitrosamine ketone, cause the same deleterious effects in human lung epithelial and bladder urothelial cells. These findings raise the possibility that ECS is a lung and bladder carcinogen in addition to nicotine. Given the fact that E-cig use has become popular in the past decade, epidemiological data on the relationship between ECS and human cancer may not be known for a decade to come. In this study, the carcinogenicity of ECS was tested in mice. We found that mice exposed to ECS for 54 wk developed lung adenocarcinomas (9 of 40 mice, 22.5%) and bladder urothelial hyperplasia (23 of 40 mice, 57.5%). These lesions were extremely rare in mice exposed to vehicle control or filtered air. Current observations that ECS induces lung adenocarcinomas and bladder urothelial hyperplasia, combined with our previous findings that ECS induces DNA damage in the lungs and bladder and inhibits DNA repair in lung tissues, implicate ECS as a lung and potential bladder carcinogen in mice. While it is well established that tobacco smoke poses a huge threat to human health, whether ECS poses any threat to humans is not yet known and warrants careful investigation.

World Trade Center (WTC) responders were exposed to mixture of dust, smoke, chemicals and carcinogens. New York University (NYU) and Mount Sinai have recreated WTC exposure in rodents to observe the resulting systemic and local biological responses. These experiments aid in the interpretation of epidemiological observations and are useful for understanding the carcinogenesis process in the exposed human WTC cohort. Here we describe the implementation of a tissue bank system for the rodents experimentally exposed to WTC dust. NYU samples were experimentally exposed to WTC dust via intratracheal inhalation that mimicked conditions in the immediate aftermath of the disaster. Tissue from Mount Sinai was derived from genetically modified mice exposed to WTC dust via nasal instillation. All processed tissues include annotations of the experimental design, WTC dust concentration/dose, exposure route and duration, genetic background of the rodent, and method of tissue isolation/storage. A biobank of tissue from rodents exposed to WTC dust has been compiled representing an important resource for the scientific community. The biobank remains available as a scientific resource for future research through established mechanisms for samples request and utilization. Studies using the WTC tissue bank would benefit from confirming their findings in corresponding tissues from organs of animals experimentally exposed to WTC dust. Studies on rodent tissues will advance the understanding of the biology of the tumors developed by WTC responders and ultimately impact the modalities of treatment, and the probability of success and survival of WTC cancer patients.

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 G₂-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.Visual Overview: http://mcr.aacrjournals.org/content/early/2019/06/18/1541-7786.MCR-19-0115/F1.large.jpg.

Recent studies have demonstrated that mobile sampling can improve the spatial granularity of land use regression (LUR) models. Mobile sampling campaigns deploying low-cost (<$300) air quality sensors could potentially offer an inexpensive and practical approach to measure and model air pollution concentration levels. In this study, we developed LUR models for street-level fine particulate matter (PM_2.5) concentration levels in Seoul, South Korea. 169 h of data were collected from an approximately three week long campaign across five routes by ten volunteers sharing seven AirBeams, a low-cost ($250 per unit), smartphone-based particle counter, while geospatial data were extracted from OpenStreetMap, an open-source and crowd-generated geographical dataset. We applied and compared three statistical approaches in constructing the LUR models - linear regression (LR), random forest (RF), and stacked ensemble (SE) combining multiple machine learning algorithms - which resulted in cross-validation R² values of 0.63, 0.73, and 0.80, respectively, and identification of several pollution 'hotspots.' The high R² values suggest that study designs employing mobile sampling in conjunction with multiple low-cost air quality monitors could be applied to characterize urban street-level air quality with high spatial resolution, and that machine learning models could further improve model performance. Given this study design's cost-effectiveness and ease of implementation, similar approaches may be especially suitable for citizen science and community-based endeavors, or in regions bereft of air quality data and preexisting air monitoring networks, such as developing countries.

BACKGROUND:With the number of annual global travelers reaching 1.2 billion, many individuals encounter greater levels of air pollution when they travel abroad to megacities around the world. This study's objective was to determine if visits to cities abroad with greater levels of air pollution adversely impacts cardiopulmonary health. METHODS:Thirty-four non-smoking, adult, healthy participants who traveled abroad to selected cities from the NYC metropolitan area were pre-trained to measure lung function, blood pressure, heart rate/variability, and record symptoms before, during, and after traveling abroad. Outdoor PM2.5 concentrations were obtained from central monitors in each city. Associations between PM exposure concentrations and cardiopulmonary health endpoints were analyzed using a mixed effects statistical design. RESULTS:East and South Asian cities had significantly higher PM2.5 concentrations compared to pre-travel NYC PM2.5 levels, with maximum concentrations reaching 503 μg/m3. PM exposure-related associations for lung function were statistically significant and strongest between evening FEV1 and same day morning PM2.5 concentrations: a 10 μg/m3 increase in outdoor PM2.5 was associated with a mean decrease of 7 ml. Travel to a highly polluted city (PM2.5 > 100 μg/m3) was associated with a 209 ml reduction in evening FEV1 compared to a low polluted city (PM2.5 < 35 μg/m3). In general, participants who traveled to East and South Asian cities experienced increased respiratory symptoms/scores and changes in heart rate and heart rate variability. CONCLUSIONS:Exposure to increased levels of PM2.5 in cities abroad caused small but statistically significant acute changes in cardiopulmonary function and respiratory symptoms in healthy young adults. These data suggest that travel-related exposure to increased PM2.5 adversely impacts cardiopulmonary health, which may be particularly important for travelers with pre-existing respiratory or cardiac disease.