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Title: Aging Exacerbates Neuroinflammatory Outcomes Induced by Acute Ozone Exposure

Abstract

The role of environmental stressors, particularly exposure to air pollution, in the development of neurodegenerative disease remains underappreciated. We examined the neurological effects of acute ozone (O 3) exposure in aged mice, where increased blood brain barrier (BBB) permeability may confer vulnerability to neuroinflammatory outcomes. C 57BL/6 male mice, aged 8-10 weeks or 12–18 months were exposed to either filtered air (FA) or 1.0 ppm O 3 for 4 hours; animals received a single IP injection of sodium fluorescein (FSCN) 20 hours post-exposure. One-hour post-FSCN injection, animals were transcardially perfused for immunohistochemical analysis of BBB permeability. β-amyloid protein expression was assessed via ELISA. Flow cytometric characterization of infiltrating immune cells, including neutrophils, macrophages, and microglia populations was performed 20 hours post-O 3 exposure. Flow cytometry analysis of brains revealed increased microglia “activation” and presentation of CD11b, F4/80 and MHCII in aged animals relative to younger ones; these age-induced differences were potentiated by acute O 3 exposure. Cortical and limbic regions in aged brains had increased reactive microgliosis and β-amyloid protein expression after O 3 insult. The aged cerebellum was particularly vulnerable to acute O 3 exposure with increased populations of infiltrating neutrophils, peripheral macrophages/monocytes, and Ly6C + inflammatory monocytes aftermore » insult, which were not significantly increased in the young cerebellum. O 3 exposure increased the penetration of FSCN beyond the BBB, the infiltration of peripheral immune cells, and reactive gliosis of microglia. Furthermore, the aged BBB is vulnerable to insult and becomes highly penetrable in response to O 3 exposure, leading to greater neuroinflammatory outcomes.« less

Authors:
 [1];  [2];  [3];  [3];  [3];  [3];  [2];  [2];  [3]
  1. Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Univ. of New Mexico, Albuquerque, NM (United States)
  2. Univ. of New Mexico Health Sciences Center, Albuquerque, NM (United States)
  3. Univ. of New Mexico, Albuquerque, NM (United States)
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
National Institutes of Health (NIH); USDOE
OSTI Identifier:
1419764
Report Number(s):
LA-UR-18-20155
Journal ID: ISSN 1096-6080
Grant/Contract Number:
AC52-06NA25396
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Toxicological Sciences
Additional Journal Information:
Journal Name: Toxicological Sciences; Journal ID: ISSN 1096-6080
Publisher:
Oxford University Press
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; Biological Science; aging; amyloid; enzyme-linked immunosorbent assay; flow cytometry; air pollution; blood-brain barrier; gliosis; injections; intraperitoneal; macrophage-1 antigen; macrophage; mice; inbred c57bl; microglia; monocytes; neurodegenerative disorders; neutrophil; ozone; permeability; brain; cerebellum; stressor; sodium fluorescein; emotional vulnerability; fluid flow

Citation Formats

Tyler, Christina R., Noor, Shahani, Young, Tamara, Rivero, Valeria, Sanchez, Bethany, Lucas, Selita, Caldwell, Kevin K., Milligan, Erin D., and Campen, Matthew J.. Aging Exacerbates Neuroinflammatory Outcomes Induced by Acute Ozone Exposure. United States: N. p., 2018. Web. doi:10.1093/toxsci/kfy014.
Tyler, Christina R., Noor, Shahani, Young, Tamara, Rivero, Valeria, Sanchez, Bethany, Lucas, Selita, Caldwell, Kevin K., Milligan, Erin D., & Campen, Matthew J.. Aging Exacerbates Neuroinflammatory Outcomes Induced by Acute Ozone Exposure. United States. doi:10.1093/toxsci/kfy014.
Tyler, Christina R., Noor, Shahani, Young, Tamara, Rivero, Valeria, Sanchez, Bethany, Lucas, Selita, Caldwell, Kevin K., Milligan, Erin D., and Campen, Matthew J.. 2018. "Aging Exacerbates Neuroinflammatory Outcomes Induced by Acute Ozone Exposure". United States. doi:10.1093/toxsci/kfy014.
@article{osti_1419764,
title = {Aging Exacerbates Neuroinflammatory Outcomes Induced by Acute Ozone Exposure},
author = {Tyler, Christina R. and Noor, Shahani and Young, Tamara and Rivero, Valeria and Sanchez, Bethany and Lucas, Selita and Caldwell, Kevin K. and Milligan, Erin D. and Campen, Matthew J.},
abstractNote = {The role of environmental stressors, particularly exposure to air pollution, in the development of neurodegenerative disease remains underappreciated. We examined the neurological effects of acute ozone (O3) exposure in aged mice, where increased blood brain barrier (BBB) permeability may confer vulnerability to neuroinflammatory outcomes. C57BL/6 male mice, aged 8-10 weeks or 12–18 months were exposed to either filtered air (FA) or 1.0 ppm O3 for 4 hours; animals received a single IP injection of sodium fluorescein (FSCN) 20 hours post-exposure. One-hour post-FSCN injection, animals were transcardially perfused for immunohistochemical analysis of BBB permeability. β-amyloid protein expression was assessed via ELISA. Flow cytometric characterization of infiltrating immune cells, including neutrophils, macrophages, and microglia populations was performed 20 hours post-O3 exposure. Flow cytometry analysis of brains revealed increased microglia “activation” and presentation of CD11b, F4/80 and MHCII in aged animals relative to younger ones; these age-induced differences were potentiated by acute O3 exposure. Cortical and limbic regions in aged brains had increased reactive microgliosis and β-amyloid protein expression after O3 insult. The aged cerebellum was particularly vulnerable to acute O3 exposure with increased populations of infiltrating neutrophils, peripheral macrophages/monocytes, and Ly6C+ inflammatory monocytes after insult, which were not significantly increased in the young cerebellum. O3 exposure increased the penetration of FSCN beyond the BBB, the infiltration of peripheral immune cells, and reactive gliosis of microglia. Furthermore, the aged BBB is vulnerable to insult and becomes highly penetrable in response to O3 exposure, leading to greater neuroinflammatory outcomes.},
doi = {10.1093/toxsci/kfy014},
journal = {Toxicological Sciences},
number = ,
volume = ,
place = {United States},
year = 2018,
month = 1
}

Journal Article:
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  • Current evidence indicates that individuals exposed to short term elevations in ambient ozone may experience both upper and lower respiratory effects. Some respiratory symptoms and spirometric changes are mild and reversible in nature, while others involve more severe outcomes, including hospital admissions and emergency room visits. However, many questions remain about the effects of acute ozone exposure and the implications of this exposure for chronic disease outcomes. For example, the identification of sensitive subgroups, the delineation of the entire spectrum of health effects due to exposure to ozone, the potential synergy between viral infections and ozone exposure, and the naturemore » of adaptation to ozone are not well characterized. In addition, studies that examine the association between acute responses to ozone and potential biological indicators of a chronic disease process would be desirable. This paper serves to provide an overview of the types of epidemiologic studies that may be appropriate and factors to consider in addressing these questions. 23 refs.« less
  • Dimethoate is an organophosphorus insecticide extensively used in horticulture. Previous studies have shown that the administration of dimethoate to male rats, at a very low dose and during a sub-chronic period, increases the oxidation of lipids and proteins, reduces the levels of antioxidants and impairs mitochondrial function in various brain regions. In this study, we have assessed in C57Bl/6 adult male mice, whether sub-chronic (5 weeks) intoxication with a low dose of dimethoate (1.4 mg/kg) affects the expression of inflammatory molecules and the reactivity of microglia in the hippocampus and striatum under basal conditions and after an immune challenge causedmore » by the systemic administration of lipopolysaccharide. Dimethoate increased mRNA levels of tumor necrosis factor α (TNFα) and interleukin (IL) 6 in the hippocampus, and increased the proportion of Iba1 immunoreactive cells with reactive phenotype in dentate gyrus and striatum. Lipopolysaccharide caused a significant increase in the mRNA levels of IL1β, TNFα, IL6 and interferon-γ-inducible protein 10, and a significant increase in the proportion of microglia with reactive phenotype in the hippocampus and the striatum. Some of the effects of lipopolysaccharide (proportion of Iba1 immunoreactive cells with reactive phenotype and IL6 mRNA levels) were amplified in the animals treated with dimethoate, but only in the striatum. These findings indicate that a sub-chronic period of administration of a low dose of dimethoate, comparable to the levels of the pesticide present as residues in food, causes a proinflammatory status in the brain and enhances the neuroinflammatory response to the lipopolysaccharide challenge with regional specificity. - Highlights: • The dose of pesticide used was comparable to the levels of residues found in food. • Dimethoate administration increased cytokine expression and microglia reactivity. • Hippocampus and striatum were differentially affected by the treatment. • Dimethoate impairs the neuroinflammatory response to an inflammatory challenge.« less
  • Air pollution may play some role in the recent increase in severity and prevalence of asthma, but the specific chemical components with the ambient pollutant mix that may be responsible have not been delineated. Since ambient exposures involve mixtures, it is essential to examine airway responses to realistic pollutant mixtures. This study examined the ability of single (3-h) inhalation exposures to ozone and to mixtures of ozone plus sulfuric acid to induce nonspecific airway hyperresponsiveness in healthy rabbits. Airway responsiveness was assessed using an in vitro assay involving administration of increasing doses of acetylcholine to bronchial rings obtained from animalsmore » exposed to 0.1-0.6 ppm ozone or to mixtures of ozone and 50-125 {mu}g/m{sup 3} sulfuric acid aerosol; results were compared to those reported previously for sulfuric acid alone. Bronchial hyperresponsiveness in healthy animals and suggest that interaction with sulfuric acid may reduce the effectiveness of both pollutants. 31 refs., 3 figs., 3 tabs.« less
  • Twenty O/sub 3/-sensitive and /sup 2/O O/sub 3/-nonsensitive subjects participated in a study to investigate the effects of disparate O/sub 3/ sensitivity on plasma prostaglandin F2 alpha responses consequent to exposure to ambient O3 concentrations. Subjects were selected from a pool of 75 normal healthy college-aged males who had been previously exposed to 0.35 ppm O3 for 1 h at an exercising VE of 60 L/min. The selection criterion used was the observed decrement in FEV1 after the O/sub 3/ exposure: O/sub 3/-sensitive, FEV1 decrement greater than 24%; O/sub 3/-nonsensitive, FEV1 decrement less than 11%. Each subject was exposed tomore » filtered air and to 0.20 and 0.35 ppm O/sub 3/ for 80 min while exercising at a VE of 50 L/min. These experimental protocols were divided into two 40-min sessions separated by a period of 4 to 10 min. PGF2 alpha, FVC, FEV1, and FEF25-75 were evaluated before, during, and after each protocol. SGaw and Vtg were measured before and after each protocol. Plasma PGF2 alpha was significantly increased in the O/sub 3/-sensitive group during and after the 0.35-ppm O/sub 3/ exposure.« less
  • Purpose: To assess the magnitude and predictors of patient-reported fatigue among breast cancer patients receiving radiation therapy (RT). Methods and Materials: Patients receiving breast RT completed a survey querying fatigue at each weekly on-treatment visit. Patient-reported fatigue severity and interference was assessed on an ordinal scale of 0 to 4, using a validated scoring system. Baseline anxiety and depression scores were also obtained. The kinetics of mean fatigue scores per week and the maximum fatigue scores over the course of the entire treatment were assessed, and clinical predictors were identified by univariate and multivariate regression. Results: The average fatigue severitymore » and interference scores were 0.6 and 0.46. The average fatigue scores increased to an equivalent extent from week to week, with expected increases of 0.99 in fatigue severity and 0.85 in interference over 7 weeks. Patients treated with hypofractionated RT (HF-RT) versus conventionally fractionated RT (CF-RT) had significantly fewer maximum fatigue severity or interference scores that were >2 (ie, severe or very severe; 29% vs 10% for severity, and 26% vs 8% for interference, P<.01). Age ≤45 years, presence of psychiatric/pain-related comorbidities, and baseline sadness and anxiety severity were predictive of average and maximum fatigue scores (P<.05), but variables related to treatment intensity (eg, mastectomy vs lumpectomy, chemotherapy use, radiation target volumes) and other host factors (working, children, marital status, proximity to RT facility) were not. Conclusion: Patient-reported fatigue modestly increases over RT courses, with less maximum fatigue reported with HF-RT. Younger age and baseline sadness, anxiety, and psychiatric/pain-related comorbidities are powerful predictors of fatigue, whereas other factors, such as treatment intensity, are not. Future studies will investigate interventions for patients at high risk for fatigue.« less