Epigenetic Effects of Diesel Exhaust and Ozone Exposure

NCT01492517 | Completed

• 1 other identifier: E10-025CS
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 1

Brief Summary

Purpose: The purpose of this protocol is to compare the genetic and epigenetic effects between diesel exhaust and ozone exposure in healthy individuals and in mild/moderate asthmatics. Participants: The investigators will recruit up to 30 mild to moderate asthmatics and up to 50 healthy adults to participate in this study. Procedures (methods): Subjects will be exposed to clean air, to 300 µg/m3 of diesel exhaust for 2 hours and to 0.3 ppm of ozone for 2 hours with intermittent exercise in a controlled environment chamber. Primary endpoints will include spirometry and lung cell changes post-exposure. Secondary endpoints will include analysis of blood clotting/coagulation factors, Holter monitoring of cardiac parameters, analysis of soluble factors present in plasma and bronchial lavage and analysis of intracellular factors present in lung tissue obtained from a brush biopsy.

Conditions

Exposure to Pollution; Inhalation of Ozone

Keywords

Controlled Human exposure study; Air Pollution; Gene expression; Epigenetic; Cardiovascular

Outcome Measures

Primary Outcomes (1)

• Airway responses

  Airway responses include spirometry and lung cell changes following exposure to either clean air, ozone or diesel exhaust Lung cell changes include change in number and type of cells, changes in genetic (gene expression) and epigenetic responses (primarily changes in DNA methylation, microRNA expression and chromatin modification.

  Pre exposure to 24hours post exposure

Secondary Outcomes (2)

• Cardiovascular responses

  Pre exposure to 24hours post exposure

• Soluble factors

  Pre exposure to 24hours post exposure

Study Arms (4)

Clean air exposure

SHAM COMPARATOR

Exposure to clean air will be conducted in an exposure chamber at the EPA Human Studies Facility on the UNC campus. Each subject will be exposed to clean air for 2 hours. Subjects will begin exercising on an exercise bike. Each exercise session will consist of a 15 minute exercise interval at a level of up to 25 L/m2/BSA followed by a 15 minute rest period. The exposure atmosphere will be at approximately 40 + 10% RH and approximately 22 + 2 oC.

Other: Clean Air

Ozone exposure

OTHER

Exposure to 0.3ppm ozone will be conducted in an exposure chamber at the EPA Human Studies Facility on the UNC campus. Each subject will be exposed for 2 hours. Subjects will begin exercising on an exercise bike. Each exercise session will consist of a 15 minute exercise interval at a level of up to 25 L/m2/BSA followed by a 15 minute rest period. The exposure atmosphere will be at approximately 40 + 10% RH and approximately 22 + 2 oC. Ozone exposures will be conducted in a (6 ft x 6 ft x 8 ft) stainless steel chamber with a continuous supply of exposure medium. Ozone will be monitored continuously.

Other: Ozone exposure

Diesel exhaust exposure

OTHER

Exposure to diesel exhaust will be conducted in an exposure chamber at the EPA Human Studies Facility on the UNC campus. Each subject will be exposed to diesel exhaust (up to 300 ug/m3). Subjects will begin exercising on an exercise bike. Each exercise session will consist of a 15 minute exercise interval at a level of up to 25 L/m2/BSA followed by a 15 minute rest period. The exposure atmosphere will be at approximately 40 + 10% RH and approximately 22 + 2 oC. The DE will be generated from a diesel generator used to power a load bank that is located outside the Human Studies Facility, and subsequently introduced into the exposure chamber after different dilutions with clean HEPA and charcoal filtered and humidified air to give a chamber concentration of up to 300 μg/m3.

Other: Diesel exhaust

18Ozone

OTHER

Exposure to ozone generated using the heavy non-radioactive isotope of oxygen (18O). Exposure to 0.3ppm 18O will be conducted in an exposure chamber at the EPA Human Studies Facility on the UNC campus. Each subject will be exposed for 2 hours. Subjects will begin exercising on an exercise bike. Each exercise session will consist of a 15 minute exercise interval at a level of up to 25 L/m2/BSA followed by a 15 minute rest period. The exposure atmosphere will be at approximately 40 + 10% RH and approximately 22 + 2 oC. Ozone exposures will be conducted in a (6 ft x 6 ft x 8 ft) stainless steel chamber with a continuous supply of exposure medium. Ozone will be monitored continuously.

Other: Ozone18

Interventions

Ozone exposure OTHER

Exposure to 0.3ppm ozone for 2 hours

Also known as: O3

Ozone exposure

Diesel exhaust OTHER

Diesel exhaust generated from a diesel generator delivered to the exposure at a target concentration of 300 μg/m3

Also known as: DE, DEP

Diesel exhaust exposure

Ozone18 OTHER

Exposure to ozone generated using the heavy non-radioactive isotope of oxygen (18O).

Also known as: O18

18Ozone

Clean Air OTHER

Exposure to air which has been scrubbed to remove air pollutants including ozone and particles.

Also known as: CA

Clean air exposure

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Physical exams will be performed by study physicians during the screening visit (IRB approved EPA protocol 95-EPA-66).
• Normal lung function (pre or post albuterol), defined by Knudson 1976/1984 as:
• \- FVC of \> 75 % of that predicted for gender, ethnicity, age and height.
• \- FEV1 of \> 75 % of that predicted for gender, ethnicity, age and height.
• \- FEV1/FVC ratio of \> 75 % of predicted values.
• Oxygen saturation of \> 96 %.
• Ability to tolerate intervals of moderate exercise
• Mild to Moderate Asthmatics
• Physical exams will be performed by study physicians during the screening visit (IRB approved EPA protocol 95-EPA-66) where diagnosis will be judged by EPA physicians.
• Mild/Moderate asthmatics as defined by NHLBI guidelines.
• Positive history of asthma (wheezing, chest tightness, and reversible airway obstruction);
• Baseline FEV1/FVC ≥ 60%;
• Oxygen saturation of ≥ 94%
• Ability to tolerate moderate exercise

You may not qualify if:

• Healthy Individuals
• A history of chronic illnesses such as diabetes, rheumatological diseases, immunodeficiency state, known clinically significant cardiac disease (including myocardial infarction, congestive heart failure and angina), chronic respiratory diseases such as chronic obstructive pulmonary disease, and lung cancer.
• If the subject is pregnant, attempting to become pregnant or breastfeeding.
• Allergy to any medications which may be used or prescribed in the course of this study.
• Smoking history within 2 years of the study.
• Use of inhaled steroids, cromolyn, or leukotriene inhibitors (Montelukast, Zafirkulast, etc) initiated within the past month (except for use of cromolyn exclusively prior to exercise). Patients must be on a stable regimen of therapy.
• Untreated hypertension (\> 150 systolic, \> 90 diastolic)
• Dementia.
• History of skin allergy to tape or electrodes.
• Subjects who do not understand or speak English
• Subjects who are unable to perform moderate exercise
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• Any food or fluids after midnight prior to bronchoscopy
• FEV1/FVC ratio less than 60% predicted on AM of bronchoscopy.
• Regular use of aspirin or other nonsteroidal anti-inflammatory drugs (which inhibit platelet function).

Sponsors & Collaborators

• Environmental Protection Agency (EPA): lead

Study Sites (1)

U.S. EPA Human Studies Facility

Chapel Hill, North Carolina, 27514, United States

Location

Related Publications (3)

• Sommer AJ, Okonkwo J, Monteiro J, Bind MC. A permutation-based approach using a rank-based statistic to identify sex differences in epigenetics. Sci Rep. 2023 Sep 8;13(1):14838. doi: 10.1038/s41598-023-41360-6.

  PMID: 37684282 DERIVED

• Miller DB, Ghio AJ, Karoly ED, Bell LN, Snow SJ, Madden MC, Soukup J, Cascio WE, Gilmour MI, Kodavanti UP. Ozone Exposure Increases Circulating Stress Hormones and Lipid Metabolites in Humans. Am J Respir Crit Care Med. 2016 Jun 15;193(12):1382-91. doi: 10.1164/rccm.201508-1599OC.

  PMID: 26745856 DERIVED

• 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 DERIVED

MeSH Terms

Interventions

Vehicle Emissions; 1-(2-(dodecyloxy)ethyl)pyrrolidine hydrochloride; Environment, Controlled

Intervention Hierarchy (Ancestors)

Complex Mixtures; Environment; Environment and Public Health

Study Officials

• David Diaz-Sanchez, Ph.D.

  U.S. Environmental Protection Agency

  STUDY DIRECTOR

• Kelly Duncan, PhD

  University of North Carolina, Chapel Hill

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Intervention Model: CROSSOVER
• Sponsor Type: FED
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Chief, Clinical Research Branch

Study Record Dates

• First Submitted: December 13, 2011
• First Posted: December 15, 2011
• Study Start: May 1, 2010
• Primary Completion: June 1, 2013
• Study Completion: May 1, 2015
• Last Updated: January 18, 2016

Record last verified: 2015-02

Locations

US (1)