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Transcriptomic analysis of World Trade Center particulate Matter-induced pulmonary inflammation and drug treatments

Chen, Yun-Ti; Li, Jinhui; Chang, Jen-Ning; Luo, Yong-Chun; Yu, Wuyue; Chen, Lung-Chi; Yang, Jinn-Moon
Over 400,000 people are estimated to have been exposed to World Trade Center particulate matter (WTCPM) since the attack on the Twin Towers in Lower Manhattan on September 11, 2001. Epidemiological studies have found that exposure to dust may cause respiratory ailments and cardiovascular diseases. However, limited studies have performed a systematic analysis of transcriptomic data to elucidate the biological responses to WTCPM exposure and the therapeutic options. Here, we developed an in vivo mouse exposure model of WTCPM and administered two drugs (i.e., rosoxacin and dexamethasone) to generate transcriptomic data from lung samples. WTCPM exposure increased the inflammation index, and this index was significantly reduced by both drugs. We analyzed the transcriptomics derived omics data using a hierarchical systems biology model (HiSBiM) with four levels, including system, subsystem, pathway, and gene analyses. Based on the selected differentially expressed genes (DEGs) from each group, WTCPM and the two drugs commonly affected the inflammatory responses, consistent with the inflammation index. Among these DEGs, the expression of 31 genes was affected by WTCPM exposure and consistently reversed by the two drugs, and these genes included Psme2, Cldn18, and Prkcd, which are involved in immune- and endocrine-related subsystems and pathways such as thyroid hormone synthesis, antigen processing and presentation, and leukocyte transendothelial migration. Furthermore, the two drugs reduced the inflammatory effects of WTCPM through distinct pathways, e.g., vascular-associated signaling by rosoxacin, whereas mTOR-dependent inflammatory signaling was found to be regulated by dexamethasone. To the best of our knowledge, this study constitutes the first investigation of transcriptomics data of WTCPM and an exploration of potential therapies. We believe that these findings provide strategies for the development of promising optional interventions and therapies for airborne particle exposure.
PMID: 37321070
ISSN: 1873-6750
CID: 5541002

Exposure to World Trade Center Dust Exacerbates Cognitive Impairment and Evokes a Central and Peripheral Pro-Inflammatory Transcriptional Profile in an Animal Model of Alzheimer's Disease

Iban-Arias, Ruth; Trageser, Kyle J; Yang, Eun-Jeong; Griggs, Elizabeth; Radu, Aurelian; Naughton, Sean; Al Rahim, Md; Tatsunori, Oguchi; Raval, Urdhva; Palmieri, Joshua; Huang, Zerlina; Chen, Lung-Chi; Pasinetti, Giulio Maria
BACKGROUND:The terrorist attacks on September 11, 2001, on the World Trade Center (WTC) led to intense fires and a massive dense cloud of toxic gases and suspended pulverized debris. In the subsequent years, following the attack and cleanup efforts, a cluster of chronic health conditions emerged among First Responders (FR) who were at Ground Zero for prolonged periods and were repeatedly exposed to high levels of WTC particulate matter (WTCPM). Among those are neurological complications which may increase the risk for the development of Alzheimer's disease (AD) later in life. OBJECTIVE:We hypothesize that WTCPM dust exposure affects the immune cross-talking between the periphery and central nervous systems that may induce brain permeability ultimately promoting AD-type phenotype. METHODS:5XFAD and wild-type mice were intranasally administered with WTCPM dust collected at Ground Zero within 72 h after the attacks. Y-maze assay and novel object recognition behavioral tests were performed for working memory deficits and learning and recognition memory, respectively. Transcriptomic analysis in the blood and hippocampus was performed and confirmed by RT qPCR. RESULTS:Mice exposed to WTCPM dust exhibited a significant impairment in spatial and recognition short and long-term memory. Furthermore, the transcriptomic analysis in the hippocampal formation and blood revealed significant changes in genes related to immune-inflammatory responses, and blood-brain barrier disruption. CONCLUSION/CONCLUSIONS:These studies suggest a putative peripheral-brain immune inflammatory cross-talking that may potentiate cognitive decline, identifying for the first time key steps which may be therapeutically targetable in future studies in WTC FR.
PMID: 36502334
ISSN: 1875-8908
CID: 5378982

Ambient fine particulate matter exposure disrupts placental autophagy and fetal development in gestational mice

Li, Ran; Peng, Jing; Zhang, Wenhui; Wu, Yunlu; Hu, Renjie; Chen, Rucheng; Gu, Weijia; Zhang, Lu; Qin, Li; Zhong, Mianhua; Chen, Lung-Chi; Sun, Qinghua; Liu, Cuiqing
Recent studies have shown that some adverse pregnancy outcomes, especially intrauterine growth restriction (IUGR), are associated with gestational exposure to ambient fine particulate matter (PM2.5). However, potential mechanism remains to be elucidated. In the present study, pregnant C57BL/6 mice were randomly assigned to be exposed to either filtered air or ambient PM2.5 in the gestation period via a concentrated whole-body exposure system. We found that gestational PM2.5 exposure exerted no effect on implantation, preterm delivery, as well as fetal resorption and death. However, in utero fetal exposure to PM2.5 showed a significant reduction in body weight and crown-rump length on GD13 and GD18. Meanwhile, maternal blood sinusoid in placenta was markedly reduced along with abnormal expression of placental nutrient transporters and growth hormone in dams exposed to PM2.5. Additional tests showed gestational PM2.5 exposure decreased autophagy-related protein levels and inhibited autophagy flux mainly on GD15. Correspondingly, AMPK/mTOR signaling pathway, a critical negative regulator of autophagy, was activated in placenta on GD15 by PM2.5 exposure as well. These findings provide evidences that placental developmental disorder caused by autophagy inhibition might be an important mechanism for the growth restriction caused by PM2.5 exposure.
PMID: 35617897
ISSN: 1090-2414
CID: 5248052

World Trade Center dust induces nasal and neurological tissue injury while propagating reduced olfaction capabilities and increased anxiety behaviors

Hernandez, Michelle; Vaughan, Joshua; Gordon, Terry; Lippmann, Morton; Gandy, Sam; Chen, Lung-Chi
PMID: 35533138
ISSN: 1091-7691
CID: 5214132

Longitudinal Impact of WTC Dust Inhalation on Rat Cardiac Tissue Transcriptomic Profiles

Park, Sung-Hyun; Lu, Yuting; Shao, Yongzhao; Prophete, Colette; Horton, Lori; Sisco, Maureen; Lee, Hyun-Wook; Kluz, Thomas; Sun, Hong; Costa, Max; Zelikoff, Judith; Chen, Lung-Chi; Gorr, Matthew W; Wold, Loren E; Cohen, Mitchell D
First responders (FR) exposed to the World Trade Center (WTC) Ground Zero air over the first week after the 9/11 disaster have an increased heart disease incidence compared to unexposed FR and the general population. To test if WTC dusts were causative agents, rats were exposed to WTC dusts (under isoflurane [ISO] anesthesia) 2 h/day on 2 consecutive days; controls received air/ISO or air only. Hearts were collected 1, 30, 240, and 360 d post-exposure, left ventricle total RNA was extracted, and transcription profiles were obtained. The data showed that differentially expressed genes (DEG) for WTC vs. ISO rats did not reach any significance with a false discovery rate (FDR) < 0.05 at days 1, 30, and 240, indicating that the dusts did not impart effects beyond any from ISO. However, at day 360, 14 DEG with a low FDR were identified, reflecting potential long-term effects from WTC dust alone, and the majority of these DEG have been implicated as having an impact on heart functions. Furthermore, the functional gene set enrichment analysis (GSEA) data at day 360 showed that WTC dust could potentially impact the myocardial energy metabolism via PPAR signaling and heart valve development. This is the first study showing that WTC dust could significantly affect some genes that are associated with the heart/CV system, in the long term. Even > 20 years after the 9/11 disaster, this has potentially important implications for those FR exposed repeatedly at Ground Zero over the first week after the buildings collapsed.
PMID: 35055737
ISSN: 1660-4601
CID: 5131772

E-Cigarette Toxicology

Gordon, Terry; Karey, Emma; Rebuli, Meghan E; Escobar, Yael; Jaspers, Ilona; Chi Chen, Lung
Since the spread of tobacco from the Americas hundreds of years ago, tobacco cigarettes and, more recently, alternative tobacco products have become global products of nicotine addiction. Within the evolving alternative tobacco product space, electronic cigarette (e-cigarette) vaping has surpassed conventional cigarette smoking among adolescents and young adults in the United States and beyond. This review describes the experimental and clinical evidence of e-cigarette toxicity and deleterious health effects. Adverse health effects related to e-cigarette aerosols are influenced by several factors, including e-liquid components, physical device factors, chemical changes related to heating, and health of the e-cigarette user (e.g., asthmatic). Federal, state, and local regulations have attempted to govern e-cigarette flavors, manufacturing, distribution, and availability, particularly to underaged youths. However, the evolving e-cigarette landscape continues to impede timely toxicological studies and hinder progress made toward our understanding of the long-term health consequence of e-cigarettes. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see for revised estimates.
PMID: 34555289
ISSN: 1545-4304
CID: 5085472

DNA damage, DNA repair and carcinogenicity: Tobacco smoke versus electronic cigarette aerosol

Tang, Moon-Shong; Lee, Hyun-Wook; Weng, Mao-Wen; Wang, Hsiang-Tsui; Hu, Yu; Chen, Lung-Chi; Park, Sung-Hyun; Chan, Huei-Wei; Xu, Jiheng; Wu, Xue-Ru; Wang, He; Yang, Rui; Galdane, Karen; Jackson, Kathryn; Chu, Annie; Halzack, Elizabeth
The allure of tobacco smoking is linked to the instant gratification provided by inhaled nicotine. Unfortunately, tobacco curing and burning generates many mutagens including more than 70 carcinogens. There are two types of mutagens and carcinogens in tobacco smoke (TS): direct DNA damaging carcinogens and procarcinogens, which require metabolic activation to become DNA damaging. Recent studies provide three new insights on TS-induced DNA damage. First, two major types of TS DNA damage are induced by direct carcinogen aldehydes, cyclic-1,N2-hydroxy-deoxyguanosine (γ-OH-PdG) and α-methyl-1, N2-γ-OH-PdG, rather than by the procarcinogens, polycyclic aromatic hydrocarbons and aromatic amines. Second, TS reduces DNA repair proteins and activity levels. TS aldehydes also prevent procarcinogen activation. Based on these findings, we propose that aldehydes are major sources of TS induce DNA damage and a driving force for carcinogenesis. E-cigarettes (E-cigs) are designed to deliver nicotine in an aerosol state, without burning tobacco. E-cigarette aerosols (ECAs) contain nicotine, propylene glycol and vegetable glycerin. ECAs induce O6-methyl-deoxyguanosines (O6-medG) and cyclic γ-hydroxy-1,N2--propano-dG (γ-OH-PdG) in mouse lung, heart and bladder tissues and causes a reduction of DNA repair proteins and activity in lungs. Nicotine and nicotine-derived nitrosamine ketone (NNK) induce the same types of DNA adducts and cause DNA repair inhibition in human cells. After long-term exposure, ECAs induce lung adenocarcinoma and bladder urothelial hyperplasia in mice. We propose that E-cig nicotine can be nitrosated in mouse and human cells becoming nitrosamines, thereby causing two carcinogenic effects, induction of DNA damage and inhibition of DNA repair, and that ECA is carcinogenic in mice. Thus, this article reviews the newest literature on DNA adducts and DNA repair inhibition induced by nicotine and ECAs in mice and cultured human cells, and provides insights into ECA carcinogenicity in mice.
PMID: 35690412
ISSN: 1388-2139
CID: 5248622

A Regulatory Role of Chemokine Receptor CXCR3 in the Pathogenesis of Chronic Obstructive Pulmonary Disease and Emphysema

Li, Lun; Liu, Yi; Chiu, Chin; Jin, Yang; Zhou, Weixun; Peng, Min; Chen, Lung-Chi; Sun, Qinghua; Gao, Jinming
Chronic obstructive pulmonary disease (COPD)/pulmonary emphysema is driven by the dysregulated airway inflammation and primarily influenced by the interaction between cigarette smoking (CS) and the individual's susceptibility. The inflammation in COPD involves both innate and adaptive immunity. By binding to its specific ligands, chemokine receptor CXCR3 plays an important role in regulating tissue inflammation and damage. In acute animal model challenged with either CS or pathogens, CXCR3 knockout (KO) attenuated lung inflammation and pathology. However, the role of CXCR3 in CS-induced chronic airway inflammation and pulmonary emphysema remains unknown. In this present study, we investigated the effect of CXCR3 in CS-induced pulmonary emphysema in an animal model, and the association between CXCR3 single nucleotide polymorphisms (SNPs) and COPD susceptibility in human subjects. We found that after chronic exposure to side stream CS (SSCS) for 24 weeks, CXCR3 KO mice demonstrated significant airspace enlargement expressed by mean linear intercept (Lm) compared with the wild-type (WT) mice. Consistently, CXCR3 KO mice had significantly higher BAL fluid macrophages and neutrophils, TNFα, and lung homogenate MMP-9 and MMP-12. Through genetic analysis of CXCR3 polymorphisms in a cohort of COPD patients with Han Chinese ethnicity, one CXCR3 SNP, rs2280964, was found to be genetically related to COPD susceptibility. Furthermore, CXCR3 SNP rs2280964 was significantly associated with the levels of serum MMP-9 in COPD patients. Our data from both animal and human studies revealed a novel role of CXCR3 possibly via influencing MMP9 production in the pathogenesis and progression of CS-associated COPD/pulmonary emphysema.
PMID: 33415536
ISSN: 1573-2576
CID: 4751392

Longitudinal impact on rat cardiac tissue transcriptomic profiles due to acute intratracheal inhalation exposures to isoflurane

Park, Sung-Hyun; Lu, Yuting; Shao, Yongzhao; Prophete, Colette; Horton, Lori; Sisco, Maureen; Lee, Hyun-Wook; Kluz, Thomas; Sun, Hong; Costa, Max; Zelikoff, Judith; Chen, Lung-Chi; Cohen, Mitchell D
Isoflurane (ISO) is a widely used inhalation anesthetic in experiments with rodents and humans during surgery. Though ISO has not been reported to impart long-lasting side effects, it is unknown if ISO can influence gene regulation in certain tissues, including the heart. Such changes could have important implications for use of this anesthetic in patients susceptible to heart failure/other cardiac abnormalities. To test if ISO could alter gene regulation/expression in heart tissues, and if such changes were reversible, prolonged, or late onset with time, SHR (spontaneously hypertensive) rats were exposed by intratracheal inhalation to a 97.5% air/2.5% ISO mixture on two consecutive days (2 hr/d). Control rats breathed filtered air only. On Days 1, 30, 240, and 360 post-exposure, rat hearts were collected and total RNA was extracted from the left ventricle for global gene expression analysis. The data revealed differentially-expressed genes (DEG) in response to ISO (compared to naïve control) at all post-exposure timepoints. The data showed acute ISO exposures led to DEG associated with wounding, local immune function, inflammation, and circadian rhythm regulation at Days 1 and 30; these effects dissipated by Day 240. There were other significantly-increased DEG induced by ISO at Day 360; these included changes in expression of genes associated with cell signaling, differentiation, and migration, extracellular matrix organization, cell-substrate adhesion, heart development, and blood pressure regulation. Examination of consistent DEG at Days 240 and 360 indicated late onset DEG reflecting potential long-lasting effects from ISO; these included DEG associated with oxidative phosphorylation, ribosome, angiogenesis, mitochondrial translation elongation, and focal adhesion. Together, the data show acute repeated ISO exposures could impart variable effects on gene expression/regulation in the heart. While some alterations self-resolved, others appeared to be long-lasting or late onset. Whether such changes occur in all rat models or in humans remains to be investigated.
PMID: 34648499
ISSN: 1932-6203
CID: 5046652

Sex-dependent effects of ambient PM2.5 pollution on insulin sensitivity and hepatic lipid metabolism in mice

Li, Ran; Sun, Qing; Lam, Sin Man; Chen, Rucheng; Zhu, Junyao; Gu, Weijia; Zhang, Lu; Tian, He; Zhang, Kezhong; Chen, Lung-Chi; Sun, Qinghua; Shui, Guanghou; Liu, Cuiqing
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.
PMID: 32321544
ISSN: 1743-8977
CID: 4464332