Air Pollution, Epigenetics and Cardiovascular Health: A Human Intervention Trial

NCT01864824 | Completed Phase 1 DMC

• 1 other identifier: 1R21ES021895-01
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

In this study, the pills formulated are being used to try to ameliorate the effect of air pollution on epigenetic changes, specifically DNA methylation, potentially linked with particulate matter air pollution inhalation and cardiovascular health effects. The way in which this is achieved is that the vitamins, which act as methyl donors, add a methyl group to the DNA to reverse the loss observed on exposure to air pollution. Specifically for this study, the methyl donor supplement has been made by Jamieson Laboratories, and consists of 50mg Vitamin B6 and 1 mg Vitamin B12, (both within Health Canada approved limits) and 2.5 mg folic acid. The non-vitamin ingredients are those commonly used in pill formation. However, the folic acid concentration is 2.5mg, which is above the 1.0mg limit set by Health Canada for a natural health product. This concentration, however, has been used in previous academic studies safely and effectively, and was also formulated by Jamieson Laboratories. (ClinicalTrials.gov number, NCT00106886; Current Controlled Trials number, ISRCTN14017017. HOPE2 study).

Conditions

Heart Rate; Heart Rate Variability; Inflammation

Keywords

air pollution; particulate matter 2.5 (PM2.5); methyl donor; DNA methylation; mRNA; epigenetics; controlled human exposures; cardiovascular responses

Outcome Measures

Primary Outcomes (1)

• DNA methylation in circulating T-helper lymphocytes of six candidate genes (TNFa, TGFb, IFNg, IL17, IL2, IL6)

  Blood will be collected from venous phlebotomy and processed for Th-cell isolation within 4hrs. DNA extraction will be performed manually on fresh unfrozen cells. DNA methylation analyses will be conducted using bisulfite-polymerase chain reaction-pyrosequencing. To select target sequences within each gene, we will rely both on assays from previous investigations and bioinformatic analysis using information from the genome browser on transcription factor binding sites conserved in the human/mouse/rat alignment, histone marks associated with active regulatory sequences and gene accessibility, and nucleosome occupancy. We will validate all assays using a titration curve of 0%-100% methylated DNA. Batch effect will be controlled by: a) using 0%, 50%, 100% methylation and universal DNA in each plate; b) running all samples from the same volunteer in one plate. We will intersperse 5% blind duplicates to test reproducibility. All samples will be assayed in duplicate runs.

  2 years

Secondary Outcomes (1)

• Blood pressure (BP) , brachial artery diameter (BAD), endothelium-dependent flow-mediated dilation (ED-FMD) and heart rate variability (HRV).

  2 years

Other Outcomes (1)

• mRNA expression of inflammatory genes (TNFa, TGFb, IFNg, IL17, IL2, IL6) in circulating T-helper lymphocytes; plasma cytokines.

  2 years

Study Arms (2)

methyl donor

EXPERIMENTAL

Methyl donor is made up of: 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12 The design will include a 2 week placebo run-in followed by a baseline blank study (2-hrs exposure to medical air) to provide benchmarks for all assessed variables. Participants will then receive a 4-week placebo treatment before the first PM2.5 exposure study. A 4-week methyl-donor treatment (Dose: 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12 once a day) will precede the 2nd PM2.5 exposure.

Drug: methyl donor

placebo

PLACEBO COMPARATOR

placebo: The design will include a 2 week placebo run-in followed by a baseline blank study (2-hrs exposure to medical air) to provide benchmarks for all assessed variables. Participants will then receive a 4-week placebo treatment before the first PM2.5 exposure study. A 4-week methyl-donor treatment (Dose: 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12 once a day) will precede the 2nd PM2.5 exposure.

Drug: Placebo

Interventions

methyl donor DRUG

The design will include a 2 week placebo run-in followed by a baseline blank study (2-hrs exposure to medical air) to provide benchmarks for all assessed variables. Participants will then receive a 4-week placebo treatment before the first PM2.5 exposure study. A 4-week methyl-donor treatment (Dose: 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12 once a day) will precede the 2nd PM2.5 exposure.

Also known as: Vitamin B6, Vitamin B12, Folic Acid, Placebo

methyl donor

Placebo DRUG

Placebo

placebo

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy volunteer
• Age 18-60 years old
• Non-smoker
• must be able to fast 8 hours prior to exposure visits and for a further 4 hours during the exposure

You may not qualify if:

• Subjects must not be regularly taking multivitamins, vitamins C \& E, folate, medications, fish oil or aspirin, oral or inhaled steroids, for 4 weeks before and during the trial.
• Lipid abnormalities
• Asthma or respiratory disease
• Hypertension (Bp\> 140/90) or taking any blood pressure drug
• Known cardiac disease
• abnormal homocysteine or glucose levels

Sponsors & Collaborators

• Harvard School of Public Health (HSPH): lead
• University of Toronto: collaborator
• Unity Health Toronto: collaborator

Study Sites (1)

Gage Occupational and Environmental Health St. Michael's Hospital/University of Toronto

Toronto, Ontario, M5T 1R4, Canada

Location

Related Publications (12)

• Brook RD, Rajagopalan S, Pope CA 3rd, Brook JR, Bhatnagar A, Diez-Roux AV, Holguin F, Hong Y, Luepker RV, Mittleman MA, Peters A, Siscovick D, Smith SC Jr, Whitsel L, Kaufman JD; American Heart Association Council on Epidemiology and Prevention, Council on the Kidney in Cardiovascular Disease, and Council on Nutrition, Physical Activity and Metabolism. Particulate matter air pollution and cardiovascular disease: An update to the scientific statement from the American Heart Association. Circulation. 2010 Jun 1;121(21):2331-78. doi: 10.1161/CIR.0b013e3181dbece1. Epub 2010 May 10.

  PMID: 20458016 BACKGROUND

• O'Toole TE, Conklin DJ, Bhatnagar A. Environmental risk factors for heart disease. Rev Environ Health. 2008 Jul-Sep;23(3):167-202. doi: 10.1515/reveh.2008.23.3.167.

  PMID: 19119685 BACKGROUND

• Zanobetti A, Canner MJ, Stone PH, Schwartz J, Sher D, Eagan-Bengston E, Gates KA, Hartley LH, Suh H, Gold DR. Ambient pollution and blood pressure in cardiac rehabilitation patients. Circulation. 2004 Oct 12;110(15):2184-9. doi: 10.1161/01.CIR.0000143831.33243.D8. Epub 2004 Oct 4.

  PMID: 15466639 BACKGROUND

• Brook RD, Rajagopalan S. Particulate matter, air pollution, and blood pressure. J Am Soc Hypertens. 2009 Sep-Oct;3(5):332-50. doi: 10.1016/j.jash.2009.08.005.

  PMID: 20409976 BACKGROUND

• Brook RD, Bard RL, Burnett RT, Shin HH, Vette A, Croghan C, Phillips M, Rodes C, Thornburg J, Williams R. Differences in blood pressure and vascular responses associated with ambient fine particulate matter exposures measured at the personal versus community level. Occup Environ Med. 2011 Mar;68(3):224-30. doi: 10.1136/oem.2009.053991. Epub 2010 Oct 8.

  PMID: 20935292 BACKGROUND

• Liu L, Ruddy T, Dalipaj M, Poon R, Szyszkowicz M, You H, Dales RE, Wheeler AJ. Effects of indoor, outdoor, and personal exposure to particulate air pollution on cardiovascular physiology and systemic mediators in seniors. J Occup Environ Med. 2009 Sep;51(9):1088-98. doi: 10.1097/JOM.0b013e3181b35144.

  PMID: 19701101 BACKGROUND

• O'Neill MS, Veves A, Zanobetti A, Sarnat JA, Gold DR, Economides PA, Horton ES, Schwartz J. Diabetes enhances vulnerability to particulate air pollution-associated impairment in vascular reactivity and endothelial function. Circulation. 2005 Jun 7;111(22):2913-20. doi: 10.1161/CIRCULATIONAHA.104.517110. Epub 2005 May 31.

  PMID: 15927967 BACKGROUND

• Baccarelli A, Cassano PA, Litonjua A, Park SK, Suh H, Sparrow D, Vokonas P, Schwartz J. Cardiac autonomic dysfunction: effects from particulate air pollution and protection by dietary methyl nutrients and metabolic polymorphisms. Circulation. 2008 Apr 8;117(14):1802-9. doi: 10.1161/CIRCULATIONAHA.107.726067. Epub 2008 Mar 31.

  PMID: 18378616 BACKGROUND

• Adar SD, Gold DR, Coull BA, Schwartz J, Stone PH, Suh H. Focused exposures to airborne traffic particles and heart rate variability in the elderly. Epidemiology. 2007 Jan;18(1):95-103. doi: 10.1097/01.ede.0000249409.81050.46.

  PMID: 17149139 BACKGROUND

• Zhong J, Trevisi L, Urch B, Lin X, Speck M, Coull BA, Liss G, Thompson A, Wu S, Wilson A, Koutrakis P, Silverman F, Gold DR, Baccarelli AA. B-vitamin Supplementation Mitigates Effects of Fine Particles on Cardiac Autonomic Dysfunction and Inflammation: A Pilot Human Intervention Trial. Sci Rep. 2017 Apr 3;7:45322. doi: 10.1038/srep45322.

  PMID: 28367952 RESULT

• Zhong J, Karlsson O, Wang G, Li J, Guo Y, Lin X, Zemplenyi M, Sanchez-Guerra M, Trevisi L, Urch B, Speck M, Liang L, Coull BA, Koutrakis P, Silverman F, Gold DR, Wu T, Baccarelli AA. B vitamins attenuate the epigenetic effects of ambient fine particles in a pilot human intervention trial. Proc Natl Acad Sci U S A. 2017 Mar 28;114(13):3503-3508. doi: 10.1073/pnas.1618545114. Epub 2017 Mar 13.

  PMID: 28289216 RESULT

• Zhong J, Urch B, Speck M, Coull BA, Koutrakis P, Thorne PS, Scott J, Liu L, Brook RD, Behbod B, Gibson H, Silverman F, Mittleman MA, Baccarelli AA, Gold DR. Endotoxin and beta-1,3-d-Glucan in Concentrated Ambient Particles Induce Rapid Increase in Blood Pressure in Controlled Human Exposures. Hypertension. 2015 Sep;66(3):509-16. doi: 10.1161/HYPERTENSIONAHA.115.05342. Epub 2015 Jun 29.

  PMID: 26123683 RESULT

MeSH Terms

Conditions

Inflammation

Interventions

Vitamin B 6; Vitamin B 12; Folic Acid

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Picolines; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Corrinoids; Tetrapyrroles; Pyrroles; Azoles; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Macrocyclic Compounds; Polycyclic Compounds; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring

Study Officials

• Andrea Baccarelli, MD PHD MPH

  HSPH

  PRINCIPAL INVESTIGATOR

• Frances Silverman, PHD

  Unity Health Toronto

  STUDY DIRECTOR

• Diane R. Gold, MD

  HSPH

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PHD, MPH

Study Record Dates

• First Submitted: May 8, 2013
• First Posted: May 30, 2013
• Study Start: June 1, 2013
• Primary Completion: July 1, 2014
• Study Completion: July 1, 2014
• Last Updated: May 11, 2017

Record last verified: 2017-05

Locations

CA (1)