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Environmental Factor, February 2013

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Ho group uses saliva for study on methylation in asthma

By Eddy Ball

Shuk-mei Ho, Ph.D.

Lead researcher Ho is the Jacob A. Schmidlapp Endowed Chair and professor of the UCMC Department of Environmental Health (DEH). She also serves as the director of the Center for Environmental Genetics at UCMC. (Photo courtesy of UC)

Kelly Brunst, Ph.D.

First author Kelly Brunst, Ph.D., who completed her doctoral program last year at UCMC in the DEH division of epidemiology and biostatistics, has worked on several studies (see story) on environmental exposures and asthma. (Photo courtesy of UC)

Grace LeMasters, Ph.D.

Senior author Grace LeMasters, Ph.D., is the lead researcher on CCAAPS. (Photo courtesy of Steve McCaw)

A new study by researchers at the University of Cincinnati Medical Center (UCMC) and the Cincinnati Children’s Hospital Medical Center (CCHMC), led by NIEHS grantee Shuk-mei Ho, Ph.D., has identified epigenetic changes associated with asthma in saliva samples. They report their results in a letter to the editor published online Dec. 20, 2012 in the Journal of Allergy and Clinical Immunology.

According to the authors, the study provides the first evidence that increased methylation of the promoters of the gene that encodes for forkhead box protein 3 (FOXP3) is associated with chronic exposure to diesel exhaust pollution (DEP) during childhood, and increased risk for persistent wheezing and asthma. The findings point to a less invasive and inexpensive procedure for collecting DNA that may become useful in the future for conducting large epidemiologic studies of children.

In addition, the authors conclude, “These findings support future strategies targeting [regulatory T] Treg cell expansion through boosting FOXP3 upregulation for asthma prevention and intervention.”

Downregulation of FOXP3 and a dysregulated immune system

Ho and her colleagues constructed their hypothesis around the role of FOXP3 expression in supporting normal function of Treg cells to suppress immune responses, including the airway inflammation response that becomes chronic in asthma, against such nonspecific stimuli as DEP. In previous studies cited by the authors, researchers found associations between diminished Treg cell function due to downregulation of FOXP3 and increased asthma severity among children exposed to polycyclic aromatic hydrocarbons, a component of DEP.

The team hypothesized that early and consistent exposure to high levels of traffic pollution would cause transcriptional silencing of FOXP3 through hypermethylation. They speculated that this downregulation would be predictive of wheezing and asthma in later life, and could be reliably assessed in DNA from saliva.

Subjects in the study were 92 children, selected from the Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS), with a consistent DEP exposure throughout childhood and no exposure to environmental tobacco smoke, which might have been a confounder. This sample was representative of children in the CCAAPS cohort in regard to sex, race, and prevalence of respiratory outcomes.

Participants were classified as nonwheezers or never-wheezers, if there was no parental report in the previous year; transient wheezers, if there was wheezing at ages 1, 2, 3, or 4 but not at age 7, the point at which asthma can be conclusively diagnosed; and persistent wheezers, whose parents reported wheezing at age 7 and during at least one year in ages 1 through 4.

Increased risk for adverse health effects

Higher levels of FOXP3 methylation showed significant associations with poor respiratory health outcomes, including:

  • Two-fold increase in the mean level of FOXP3 methylation among persistent wheezers, as compared with nonwheezers.
  • Significantly higher mean levels of FOXP3 methylation among early transient wheezers, than among nonwheezers.
  • Three times the risk of persistent wheezing during childhood, for subjects with increased FOXP3 methylation levels.
  • Two times the likelihood of developing asthma for children with increased FOXP3 methylation.

The study represents the most recent set of findings by NIEHS-funded researchers at UCMC and the Columbia Center for Children’s Environmental Health, on biological mechanisms related to the health effects of exposure traffic pollution during windows of susceptibility in fetal and childhood development. Their work has led to the discovery of multiple epigenetic biomarkers of exposure and disease prediction, which may inform innovative public health measures to prevent, reverse, or ameliorate health effects of exposure.

Citation: Brunst KJ, Leung YK, Ryan PH, Khurana Hershey GK, Levin L, Ji H, Lemasters GK, Ho SM. 2012. Forkhead box protein 3 (FOXP3) hypermethylation is associated with diesel exhaust exposure and risk for childhood asthma. J Allergy Clin Immunol; doi: 10.1016/j.jaci.2012.10.042 [Online 20 December 2012].

Tang WY, Levin L, Talaska G, Cheung YY, Herbstman J, Tang D, Miller RL, Perera F, Ho SM. 2012. Maternal exposure to polycyclic aromatic hydrocarbons and 5'-CpG methylation of interferon-gamma in cord white blood cells. Environ Health Perspect 120(8):1195-1200.

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