Epigenetic Effect Modifications With Ozone Exposure on Healthy Volunteers

NCT02469428 | Completed

• 1 other identifier: 13-3697
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this protocol is to assess whether epigenetic factors in healthy individuals make a person more or less responsive to lung inflammation following ozone exposures.

Conditions

Exposure to Environmental Pollution, Non-occupational

Keywords

Controlled human exposure study; Ozone; Inflammation

Outcome Measures

Primary Outcomes (1)

• Pulmonary inflammation

  18 hrs following exposures the subjects will undergo a research bronchoscopy where lavage fluid and epithelial cells via brush biopsy will be collected. Protein content will be assessed in lavage fluid. Changes in inflammatory genes will be measured in epithelial cells. DNA will be extracted from epithelial cells and DNA methylation arrays will be run.

  pre-exposure to 18 hrs post exposure

Secondary Outcomes (5)

• Changes in heart rate variability

  pre-exposure to 18 hrs post-exposure

• Forced expiratory volume in 1 second (FEV1)

  pre-exposure to 18 hrs post-exposure

• Forced vital capacity (FVC)

  pre-exposure to 18 hrs post-exposure

• Index of clotting/coagulation factors

  pre-exposure to 18 hrs post-exposure

• Index of inflammatory factors from blood

  pre-exposure to 18 hrs post-exposure

Study Arms (2)

Clean air

SHAM COMPARATOR

Exposure to clean air will be conducted in an exposure chamber at the EPA Human Studies Facility on the UNC campus.

Other: Clean air

Ozone

EXPERIMENTAL

Exposure to ozone will be conducted in an exposure chamber at the EPA Human Studies Facility on the UNC campus.

Other: Ozone

Interventions

Clean air OTHER

Each subject will be exposed to clean air for 2 hours. Subjects will exercise on a bike. Each exercise session will consist of a 15 minute exercise interval at a level of up to 20 L/min/m2 BSA followed by a 15 minute rest period, repeated 4 times.

Clean air

Ozone OTHER

Each subject will be exposed to 0.3 ppb ozone for 2 hours. Subjects will exercise on a bike. Each exercise session will consist of a 15 minute exercise interval at a level of up to 20 L/min/m2 BSA followed by a 15 minute rest period, repeated 4 times.

Ozone

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Normal baseline 12-lead resting EKG.
• Normal lung function, defined by NHANES III as:
• FVC of \> 80 %.
• FEV1 of \> 80 %.
• FEV1/FVC ratio of \> 80 %.
• Oxygen saturation of \> 96 %.
• Ability to complete the exposure exercise regimen without reaching 80% of predicted maximal heart rate.

You may not qualify if:

• A history of acute and/or chronic illnesses such as diabetes, rheumatological diseases, immunodeficiency state, neurological disease, renal disease, liver disease, endocrinological disease, malignancy, cardiovascular disease, chronic respiratory diseases, and lung cancer.
• Asthma or a history of asthma.
• A Framingham risk score ≥10.
• Women who are pregnant, attempting to become pregnant, or breastfeeding.
• An allergy to any medications which may be used or prescribed in the course of this study.
• Cannot refrain from taking vitamins C or E (or multivitamins which contain Vitamins C or E) for 7 days prior to all visits.
• Untreated hypertension (≥ 150 systolic or ≥ 90 diastolic blood pressure).
• Dementia.
• Unspecified illnesses, which in the judgment of the investigator or medical staff might increase the risk associated ozone inhalation challenge or exercise.
• A history of skin allergies to adhesives used in securing EKG electrodes.
• Do not understand or speak English.
• Chronic and continuous allergic rhinitis.
• Unable to perform the moderate exercise required for the study.
• Those that are unwilling or unable to refrain from the following medications for the week prior to each exposure: anti-inflammatory agents such as ibuprofen, naproxen, or aspirin.
• Those currently taking or have taken anti-coagulant medication in the week prior to each exposure.

Sponsors & Collaborators

• Environmental Protection Agency (EPA): lead

Study Sites (1)

EPA Human Studies Facility

Chapel Hill, North Carolina, 27514, United States

Location

Related Publications (24)

• Baccarelli A, Wright RO, Bollati V, Tarantini L, Litonjua AA, Suh HH, Zanobetti A, Sparrow D, Vokonas PS, Schwartz J. Rapid DNA methylation changes after exposure to traffic particles. Am J Respir Crit Care Med. 2009 Apr 1;179(7):572-8. doi: 10.1164/rccm.200807-1097OC. Epub 2009 Jan 8.

  PMID: 19136372 BACKGROUND

• Bellavia A, Urch B, Speck M, Brook RD, Scott JA, Albetti B, Behbod B, North M, Valeri L, Bertazzi PA, Silverman F, Gold D, Baccarelli AA. DNA hypomethylation, ambient particulate matter, and increased blood pressure: findings from controlled human exposure experiments. J Am Heart Assoc. 2013 Jun 19;2(3):e000212. doi: 10.1161/JAHA.113.000212.

  PMID: 23782920 BACKGROUND

• Bergamaschi E, De Palma G, Mozzoni P, Vanni S, Vettori MV, Broeckaert F, Bernard A, Mutti A. Polymorphism of quinone-metabolizing enzymes and susceptibility to ozone-induced acute effects. Am J Respir Crit Care Med. 2001 May;163(6):1426-31. doi: 10.1164/ajrccm.163.6.2006056.

  PMID: 11371413 BACKGROUND

• Bind MA, Baccarelli A, Zanobetti A, Tarantini L, Suh H, Vokonas P, Schwartz J. Air pollution and markers of coagulation, inflammation, and endothelial function: associations and epigene-environment interactions in an elderly cohort. Epidemiology. 2012 Mar;23(2):332-40. doi: 10.1097/EDE.0b013e31824523f0.

  PMID: 22237295 BACKGROUND

• Bollati V, Marinelli B, Apostoli P, Bonzini M, Nordio F, Hoxha M, Pegoraro V, Motta V, Tarantini L, Cantone L, Schwartz J, Bertazzi PA, Baccarelli A. Exposure to metal-rich particulate matter modifies the expression of candidate microRNAs in peripheral blood leukocytes. Environ Health Perspect. 2010 Jun;118(6):763-8. doi: 10.1289/ehp.0901300. Epub 2010 Jan 8.

  PMID: 20061215 BACKGROUND

• Bonsch D, Wunschel M, Lenz B, Janssen G, Weisbrod M, Sauer H. Methylation matters? Decreased methylation status of genomic DNA in the blood of schizophrenic twins. Psychiatry Res. 2012 Aug 15;198(3):533-7. doi: 10.1016/j.psychres.2011.09.004. Epub 2012 Oct 25.

  PMID: 23102571 BACKGROUND

• Corradi M, Alinovi R, Goldoni M, Vettori M, Folesani G, Mozzoni P, Cavazzini S, Bergamaschi E, Rossi L, Mutti A. Biomarkers of oxidative stress after controlled human exposure to ozone. Toxicol Lett. 2002 Aug 5;134(1-3):219-25. doi: 10.1016/s0378-4274(02)00169-8.

  PMID: 12191881 BACKGROUND

• Cortessis VK, Thomas DC, Levine AJ, Breton CV, Mack TM, Siegmund KD, Haile RW, Laird PW. Environmental epigenetics: prospects for studying epigenetic mediation of exposure-response relationships. Hum Genet. 2012 Oct;131(10):1565-89. doi: 10.1007/s00439-012-1189-8. Epub 2012 Jun 28.

  PMID: 22740325 BACKGROUND

• De Prins S, Koppen G, Jacobs G, Dons E, Van de Mieroop E, Nelen V, Fierens F, Int Panis L, De Boever P, Cox B, Nawrot TS, Schoeters G. Influence of ambient air pollution on global DNA methylation in healthy adults: a seasonal follow-up. Environ Int. 2013 Sep;59:418-24. doi: 10.1016/j.envint.2013.07.007. Epub 2013 Aug 3.

  PMID: 23917442 BACKGROUND

• Dempster EL, Pidsley R, Schalkwyk LC, Owens S, Georgiades A, Kane F, Kalidindi S, Picchioni M, Kravariti E, Toulopoulou T, Murray RM, Mill J. Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder. Hum Mol Genet. 2011 Dec 15;20(24):4786-96. doi: 10.1093/hmg/ddr416. Epub 2011 Sep 9.

  PMID: 21908516 BACKGROUND

• Devlin RB, Duncan KE, Jardim M, Schmitt MT, Rappold AG, Diaz-Sanchez D. Controlled exposure of healthy young volunteers to ozone causes cardiovascular effects. Circulation. 2012 Jul 3;126(1):104-11. doi: 10.1161/CIRCULATIONAHA.112.094359. Epub 2012 Jun 25.

  PMID: 22732313 BACKGROUND

• Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suner D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, Esteller M. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A. 2005 Jul 26;102(30):10604-9. doi: 10.1073/pnas.0500398102. Epub 2005 Jul 11.

  PMID: 16009939 BACKGROUND

• Heyn H, Carmona FJ, Gomez A, Ferreira HJ, Bell JT, Sayols S, Ward K, Stefansson OA, Moran S, Sandoval J, Eyfjord JE, Spector TD, Esteller M. DNA methylation profiling in breast cancer discordant identical twins identifies DOK7 as novel epigenetic biomarker. Carcinogenesis. 2013 Jan;34(1):102-8. doi: 10.1093/carcin/bgs321. Epub 2012 Oct 10.

  PMID: 23054610 BACKGROUND

• Kim CS, Alexis NE, Rappold AG, Kehrl H, Hazucha MJ, Lay JC, Schmitt MT, Case M, Devlin RB, Peden DB, Diaz-Sanchez D. Lung function and inflammatory responses in healthy young adults exposed to 0.06 ppm ozone for 6.6 hours. Am J Respir Crit Care Med. 2011 May 1;183(9):1215-21. doi: 10.1164/rccm.201011-1813OC. Epub 2011 Jan 7.

  PMID: 21216881 BACKGROUND

• Koren HS, Devlin RB, Becker S, Perez R, McDonnell WF. Time-dependent changes of markers associated with inflammation in the lungs of humans exposed to ambient levels of ozone. Toxicol Pathol. 1991;19(4 Pt 1):406-11. doi: 10.1177/0192623391019004-109.

  PMID: 1813985 BACKGROUND

• Li C, Zhao S, Zhang N, Zhang S, Hou Y. Differences of DNA methylation profiles between monozygotic twins' blood samples. Mol Biol Rep. 2013 Sep;40(9):5275-80. doi: 10.1007/s11033-013-2627-y. Epub 2013 May 7.

  PMID: 23649773 BACKGROUND

• Liu L, Poon R, Chen L, Frescura AM, Montuschi P, Ciabattoni G, Wheeler A, Dales R. Acute effects of air pollution on pulmonary function, airway inflammation, and oxidative stress in asthmatic children. Environ Health Perspect. 2009 Apr;117(4):668-74. doi: 10.1289/ehp11813. Epub 2008 Nov 28.

  PMID: 19440509 BACKGROUND

• Madrigano J, Baccarelli A, Mittleman MA, Wright RO, Sparrow D, Vokonas PS, Tarantini L, Schwartz J. Prolonged exposure to particulate pollution, genes associated with glutathione pathways, and DNA methylation in a cohort of older men. Environ Health Perspect. 2011 Jul;119(7):977-82. doi: 10.1289/ehp.1002773. Epub 2011 Mar 8.

  PMID: 21385671 BACKGROUND

• Romieu I, Barraza-Villarreal A, Escamilla-Nunez C, Almstrand AC, Diaz-Sanchez D, Sly PD, Olin AC. Exhaled breath malondialdehyde as a marker of effect of exposure to air pollution in children with asthma. J Allergy Clin Immunol. 2008 Apr;121(4):903-9.e6. doi: 10.1016/j.jaci.2007.12.004. Epub 2008 Jan 30.

  PMID: 18234317 BACKGROUND

• Runyon RS, Cachola LM, Rajeshuni N, Hunter T, Garcia M, Ahn R, Lurmann F, Krasnow R, Jack LM, Miller RL, Swan GE, Kohli A, Jacobson AC, Nadeau KC. Asthma discordance in twins is linked to epigenetic modifications of T cells. PLoS One. 2012;7(11):e48796. doi: 10.1371/journal.pone.0048796. Epub 2012 Nov 30.

  PMID: 23226205 BACKGROUND

• Salam MT, Byun HM, Lurmann F, Breton CV, Wang X, Eckel SP, Gilliland FD. Genetic and epigenetic variations in inducible nitric oxide synthase promoter, particulate pollution, and exhaled nitric oxide levels in children. J Allergy Clin Immunol. 2012 Jan;129(1):232-9.e1-7. doi: 10.1016/j.jaci.2011.09.037. Epub 2011 Nov 4.

  PMID: 22055874 BACKGROUND

• Szyf M. The dynamic epigenome and its implications in toxicology. Toxicol Sci. 2007 Nov;100(1):7-23. doi: 10.1093/toxsci/kfm177. Epub 2007 Aug 3.

  PMID: 17675334 BACKGROUND

• Tarantini L, Bonzini M, Apostoli P, Pegoraro V, Bollati V, Marinelli B, Cantone L, Rizzo G, Hou L, Schwartz J, Bertazzi PA, Baccarelli A. Effects of particulate matter on genomic DNA methylation content and iNOS promoter methylation. Environ Health Perspect. 2009 Feb;117(2):217-22. doi: 10.1289/ehp.11898. Epub 2008 Sep 26.

  PMID: 19270791 BACKGROUND

• Wong CC, Meaburn EL, Ronald A, Price TS, Jeffries AR, Schalkwyk LC, Plomin R, Mill J. Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits. Mol Psychiatry. 2014 Apr;19(4):495-503. doi: 10.1038/mp.2013.41. Epub 2013 Apr 23.

  PMID: 23608919 BACKGROUND

MeSH Terms

Conditions

Inflammation

Interventions

Environment, Controlled; Ozone

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Environment; Environment and Public Health; Oxygen; Gases; Inorganic Chemicals

Study Officials

• David Diaz-Sanchez, PhD

  Environmental Protection Agency (EPA)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: FED
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: June 5, 2015
• First Posted: June 11, 2015
• Study Start: December 1, 2013
• Primary Completion: July 1, 2017
• Study Completion: November 5, 2018
• Last Updated: July 30, 2019

Record last verified: 2019-07

Locations

US (1)