Faculty Bibliography
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258
Inhalation Exposure to PM2.5 Counteracts Hepatic Steatosis in Mice Fed High-fat Diet by Stimulating Hepatic Autophagy
Air pollution is associated with the increased risk of metabolic syndrome. In this study, we performed inhalation exposure of mice fed normal chow or a high-fat diet to airborne fine particulate matters (PM2.5), and then investigated the complex effects and mechanisms of inhalation exposure to PM2.5 on hepatic steatosis, a precursor or manifestation of metabolic syndrome. Our studies demonstrated that inhalation exposure of mice fed normal chow to concentrated ambient PM2.5 repressed hepatic transcriptional regulators involved in fatty acid oxidation and lipolysis, and thus promoted hepatic steatosis. However, PM2.5 exposure relieved hepatic steatosis in high-fat diet-induced obese mice. Further investigation revealed that inhalation exposure to PM2.5 induced hepatic autophagy in mouse livers in a manner depending on the MyD88-mediated inflammatory pathway. The counteractive effect of PM2.5 exposure on high-fat diet-induced hepatic steatosis was mediated through PM2.5-induced hepatic autophagy. The findings from this study not only defined the effects and mechanisms of PM2.5 exposure in metabolic disorders, but also revealed the pleotrophic acts of an environmental stressor in a complex stress system relevant to public health.
PMCID:5701159
PMID: 29176715
ISSN: 2045-2322
CID: 2797242
Genetic determinants of susceptibility to silver nanoparticle-induced acute lung inflammation in mice
Silver nanoparticles (AgNPs) are employed in a variety of consumer products; however, in vivo rodent studies indicate that AgNPs can cause lung inflammation and toxicity in a strain- and particle type-dependent manner, but mechanisms of susceptibility remain unclear. The aim of this study was to assess the variation in AgNP-induced lung inflammation and toxicity across multiple inbred mouse strains and to use genome-wide association (GWA) mapping to identify potential candidate susceptibility genes. Mice received doses of 0.25 mg/kg of either 20-nm citrate-coated AgNPs or citrate buffer using oropharyngeal aspiration. Neutrophils in bronchoalveolar lavage fluid (BALF) served as markers of inflammation. We found significant strain- and treatment-dependent variation in neutrophils in BALF. GWA mapping identified 10 significant single-nucleotide polymorphisms (false discovery rate, 15%) in 4 quantitative trait loci on mouse chromosomes 1, 4, 15, and 18, and Nedd4l (neural precursor cell expressed developmentally downregulated gene 4-like; chromosome 18), Ano6 (anocatmin 6; chromosome 15), and Rnf220 (Ring finger protein 220; chromosome 4) were considered candidate genes. Quantitative RT-PCR revealed significant inverse associations between mRNA levels of these genes and neutrophil influx. Nedd4l, Ano6, and Rnf220 are candidate susceptibility genes for AgNP-induced lung inflammation that warrant additional exploration in future studies.-Scoville, D. K., Botta, D., Galdanes, K., Schmuck, S. C., White, C. C., Stapleton, P. L., Bammler, T. K., MacDonald, J. W., Altemeier, W. A., Hernandez, M., Kleeberger, S. R., Chen, L.-C., Gordon, T., Kavanagh, T. J. Genetic determinants of susceptibility to silver nanoparticle-induced acute lung inflammation in mice.
PMCID:5602892
PMID: 28716969
ISSN: 1530-6860
CID: 5085462
Post-Effect of Air Quality Improvement on Biomarkers for Systemic Inflammation and Microparticles in Asthma Patients After the 2008 Beijing Olympic Games: a Pilot Study
This study's aim was to investigate the post-effect of an air quality improvement on systemic inflammation and circulating microparticles in asthmatic patients during, and 2 months after, the Beijing Olympics 2008. We measured the levels of circulating inflammatory cytokines and microparticles in the peripheral blood from asthma patients and healthy controls during (phase 1), and 2 months after (phase 2) the Beijing 2008 Olympic Games. The concentrations of circulating cytokines (including TNFalpha, IL-6, IL-8, and IL-10) were still seen reduced in phase 2 when compared with those in phase 1. The number of circulating endothelial cell-derived microparticles was significantly lower during the phase 2 than that during phase 1 in asthma patients. The level of plasma lipopolysaccharide-binding protein (LBP) was significantly decreased in asthmatics in phase 2. The level of norepinephrine was significantly higher in phase 2 than that in phase 1 in plasma from both asthma patients and healthy subjects. There were no significant differences in the gene profile for the toll-like receptor (TLR) signaling from peripheral blood mononuclear cells. In vitro, microvesicles from patients with asthma impaired the relaxation to bradykinin and contraction to acetylcholine, whereas microparticles from healthy subjects did not. These data suggested that reduction in systemic pro-inflammatory responses and circulating LBP and increased level of norepinephrine in asthma patients persisted even after 2 months of the air pollution intervention. These changes were independent of the TLR signaling pathway. Circulating microparticles might be associated with airway smooth muscle dysfunction.
PMID: 28444548
ISSN: 1573-2576
CID: 2544162
Exposure to Ambient Particulate Matter during Specific Gestational Periods Produces Adverse Obstetric Consequences in Mice
BACKGROUND: Epidemiological studies associate inhalation of fine-sized particulate matter (PM2.5) during pregnancy with preterm birth (PTB) and low birth weight (LBW) but disagree over which time frames are most sensitive, or if effects are cumulative. OBJECTIVES: Our objective was to provide experimental plausibility for epidemiological observations by testing the hypothesis that exposure to PM2.5 during discrete periods of pregnancy results in PTB and LBW. METHODS: For the first study, timed-pregnant B6C3F1 mice were exposed to concentrated ambient PM2.5 (CAPs) or filtered air (FA) throughout pregnancy [6 h/d from gestational day (GD) 0.5 through GD16.5]. A follow-up study examined the effects of CAPs exposure during discrete gestational periods (1: GD0.5-5.5; 2: GD6.5-14.5; 3: GD14.5-16.5; 4: GD0.5-16.5) aligning to milestones during human development. RESULTS: In the first experiment, exposure to 160 mug CAPs/m3 throughout pregnancy decreased gestational term by 0.5 d ( approximately 1.1 wk decrease for humans) and birth weight by 11.4% compared with FA. The follow-up experiment investigated timing of CAPs exposure (mean concentrations at 178, 193, 171, and 173 mug/m3 for periods 1-4, respectively). Pregnancy was significantly shortened (vs. FA) by approximately 0.4d when exposure occurred during gestational periods 2 and 4, and by approximately 0.5d if exposure occurred during period 3. Exposure during periods 1, 2, and 4 reduced birth weight by approximately 10% compared with FA, and placental weight was reduced ( approximately 8%) on GD17.5 if exposure occurred only during period 3. CONCLUSIONS: Adverse PM2.5-induced outcomes such as PTB and LBW are dependent upon the periods of maternal exposure. The results of these experimental studies could contribute significantly to air pollution policy decisions in the future. https://doi.org/10.1289/EHP1029.
PMCID:5744697
PMID: 28893721
ISSN: 1552-9924
CID: 2701572
Exposure to Concentrated Ambient PM2.5 Shortens Lifespan and Induces Inflammation-Associated Signaling and Oxidative Stress in Drosophila
Exposure to ambient PM2.5 is associated with human premature mortality. However, it has not yet been toxicologically replicated, likely due to the lack of suitable animal models. Drosophila is frequently used in longevity research due to many incomparable merits. The present study aims to validate Drosophila models for PM2.5 toxicity study through characterizing their biological responses to exposure to concentrated ambient PM2.5 (CAP). The survivorship curve demonstrated that exposure to CAP markedly reduced lifespan of Drosophila. This antilongevity effect of CAP exposure was observed in both male and female Drosophila, and by comparison, the male was more sensitive [50% survivals: 20 and 48 days, CAP- and filtered air (FA)-exposed males, respectively; 21 and 40 days, CAP- and FA-exposed females, respectively]. Similar to its putative pathogenesis in humans, CAP exposure-induced premature mortality in Drosophila was also coincided with activation of pro-inflammatory signaling pathways including Jak, Jnk, and Nf-kappab and increased systemic oxidative stress. Furthermore, like in humans and mammals, exposure to CAP significantly increased whole-body and circulating glucose levels and increased mRNA expression of Ilp2 and Ilp5, indicating that CAP exposure induces dysregulated insulin signaling in Drosophila. Similar to effects on humans ,: exposure to CAP leads to premature mortality likely through induction of inflammation-associated signaling, oxidative stress, and metabolic abnormality in Drosophila, strongly supporting that it can be a useful model organism for PM2.5 toxicity study.
PMCID:5837417
PMID: 28069988
ISSN: 1096-0929
CID: 2424822
Receptor for advanced glycation end-products and World Trade Center particulate induced lung function loss: A case-cohort study and murine model of acute particulate exposure
World Trade Center-particulate matter(WTC-PM) exposure and metabolic-risk are associated with WTC-Lung Injury(WTC-LI). The receptor for advanced glycation end-products (RAGE) is most highly expressed in the lung, mediates metabolic risk, and single-nucleotide polymorphisms at the AGER-locus predict forced expiratory volume(FEV). Our objectives were to test the hypotheses that RAGE is a biomarker of WTC-LI in the FDNY-cohort and that loss of RAGE in a murine model would protect against acute PM-induced lung disease. We know from previous work that early intense exposure at the time of the WTC collapse was most predictive of WTC-LI therefore we utilized a murine model of intense acute PM-exposure to determine if loss of RAGE is protective and to identify signaling/cytokine intermediates. This study builds on a continuing effort to identify serum biomarkers that predict the development of WTC-LI. A case-cohort design was used to analyze a focused cohort of male never-smokers with normal pre-9/11 lung function. Odds of developing WTC-LI increased by 1.2, 1.8 and 1.0 in firefighters with soluble RAGE (sRAGE)>/=97pg/mL, CRP>/=2.4mg/L, and MMP-9
PMCID:5604982
PMID: 28926576
ISSN: 1932-6203
CID: 2706992
Upregulation of SQSTM1/p62 contributes to nickel-induced malignant transformation of human bronchial epithelial cells
Chronic lung inflammation is accepted as being associated with the development of lung cancer caused by nickel exposure. Therefore, identifying the molecular mechanisms that lead to anickel-induced sustained inflammatory microenvironment that causes transformation of human bronchial epithelial cells is of high significance. In the current studies, we identified SQSTM1/p62 as a novel nickel-upregulated protein that is important for nickel-induced inflammatory TNF expression, subsequently resulting in transformation of human bronchial epithelial cells. We found that nickel exposure induced SQSTM1 protein upregulation in human lung epithelial cells in vitro and in mouse lung tissues in vivo. The SQSTM1 upregulation was also observed in human lung squamous cell carcinoma. Further studies revealed that the knockdown of SQSTM1 expression dramatically inhibited transformation of human lung epithelial cells upon chronic nickel exposure, whereas ectopic expression of SQSTM1 promoted such transformation. Mechanistic studies showed that the SQSTM1 upregulation by nickel was the compromised result of upregulating SQSTM1 mRNA transcription and promoting SQSTM1 protein degradation. We demonstrated that nickel-initiated SQSTM1 protein degradation is mediated by macroautophagy/autophagy via an MTOR-ULK1-BECN1 axis, whereas RELA is important for SQSTM1 transcriptional upregulation following nickel exposure. Furthermore, SQSTM1 upregulation exhibited its promotion of nickel-induced cell transformation through exerting an impetus for nickel-induced inflammatory TNF mRNA stability. Consistently, the MTOR-ULK1-BECN1 autophagic cascade acted as an inhibitory effect on nickel-induced TNF expression and cell transformation. Collectively, our results demonstrate a novel SQSTM1 regulatory network that promotes a nickel-induced tumorigenic effect in human bronchial epithelial cells, which is negatively controlled by an autophagic cascade following nickel exposure.
PMCID:5079680
PMID: 27467530
ISSN: 1554-8635
CID: 2191672
International journal of environmental research & public health. 2015:13(1).DOI: 10.3390/ijerph13010080
Improving Knowledge about Children's Environmental Health in Northwest China
The main purpose of this study was to identify policy maker opinions and attitudes towards children's environmental health (CEH), potential barriers to child-specific protective legislation and implementation in northwest China, and evaluate knowledge and attitudes about CEH before and after an educational conference. We conducted seventy-two interviews with regional officials, researchers and non-governmental organization representatives from five provinces, and surveyed participants (forty-seven) before and after an educational conference in northwest China about CEH. Interviews identified general consensus among participants of the adverse effects of air pollution on children, yet few participants knew of policies to protect them. Barriers identified included limited funding and enforcement, weak regional governments and absence of child-specific policy-making. After the conference, substantially greater self-efficacy was identified for lead, mercury, air pollution and polychlorinated biphenyls (+0.57-0.72 on a 1-5 Likert scale, p = 0.002-0.013), and the scientific knowledge for the role of environment in children's health (+0.58, p = 0.015), and health care provider control (+0.52, p = 0.025) were rated more strongly. We conclude that policy makers in Northwest China appreciate that children are uniquely vulnerable, though additional regulations are needed to account for that vulnerability. Further research should examine effectiveness of the intervention on a larger scale and scope, and evaluate the usefulness of such interventions in translating research into improved care/reduced exposure to environmental hazards.
PMCID:4730471
PMID: 26712775
ISSN: 1660-4601
CID: 1894472
Cigarette side-stream smoke lung and bladder carcinogenesis: inducing mutagenic acrolein-DNA adducts, inhibiting DNA repair and enhancing anchorage-independent-growth cell transformation
Second-hand smoke (SHS) is associated with 20-30% of cigarette-smoke related diseases, including cancer. Majority of SHS (>80%) originates from side-stream smoke (SSS). Compared to mainstream smoke, SSS contains more tumorigenic polycyclic aromatic hydrocarbons and acrolein (Acr). We assessed SSS-induced benzo(a)pyrene diol epoxide (BPDE)- and cyclic propano-deoxyguanosine (PdG) adducts in bronchoalveolar lavage (BAL), lung, heart, liver, and bladder-mucosa from mice exposed to SSS for 16 weeks. In SSS exposed mice, Acr-dG adducts were the major type of PdG adducts formed in BAL (p < 0.001), lung (p < 0.05), and bladder mucosa (p < 0.001), with no significant accumulation of Acr-dG adducts in heart or liver. SSS exposure did not enhance BPDE-DNA adduct formation in any of these tissues. SSS exposure reduced nucleotide excision repair (p < 0.01) and base excision repair (p < 0.001) in lung tissue. The levels of DNA repair proteins, XPC and hOGG1, in lung tissues of exposed mice were significantly (p < 0.001 and p < 0.05) lower than the levels in lung tissues of control mice. We found that Acr can transform human bronchial epithelial and urothelial cells in vitro. We propose that induction of mutagenic Acr-DNA adducts, inhibition of DNA repair, and induction of cell transformation are three mechanisms by which SHS induces lung and bladder cancers.
PMCID:4741761
PMID: 26431382
ISSN: 1949-2553
CID: 1790072
Malignant human cell transformation of Marcellus Shale gas drilling flow back water
The rapid development of high-volume horizontal hydraulic fracturing for mining natural gas from shale has posed potential impacts on human health and biodiversity. The produced flow back waters after hydraulic stimulation are known to carry high levels of saline and total dissolved solids. To understand the toxicity and potential carcinogenic effects of these wastewaters, flow back waters from five Marcellus hydraulic fracturing oil and gas wells were analyzed. The physicochemical nature of these samples was analyzed by inductively coupled plasma mass spectrometry and scanning electron microscopy/energy dispersive X-ray spectroscopy. A cytotoxicity study using colony formation as the endpoint was carried out to define the LC50 values of test samples using human bronchial epithelial cells (BEAS-2B). The BEAS-2B cell transformation assay was employed to assess the carcinogenic potential of the samples. Barium and strontium were among the most abundant metals in these samples and the same metals were found to be elevated in BEAS-2B cells after long-term treatment. BEAS-2B cells treated for 6weeks with flow back waters produced colony formation in soft agar that was concentration dependent. In addition, flow back water-transformed BEAS-2B cells show better migration capability when compared to control cells. This study provides information needed to assess the potential health impact of post-hydraulic fracturing flow back waters from Marcellus Shale natural gas mining.
PMCID:4698968
PMID: 26210350
ISSN: 1096-0333
CID: 1698402
