Environmental Factor, August 2010, National Institute of Environmental Health Sciences
Extramural Papers of the Month
By Jerry Phelps
- Link Discovered Between Particulate Matter Air Pollution and Sleep-Disordered Breathing
- Living, Breathing Lung-on-a-Chip
- Transcription Termination Flips Out
- Fetal Leydig Cell Protein Regulates Sertoli Cell Proliferation
Link Discovered Between Particulate Matter Air Pollution and Sleep-Disordered Breathing
In a study co-funded by NIEHS, the National Heart, Lung, and Blood Institute, and the U.S. Environmental Protection Agency, researchers at the Harvard School of Public Health report for the first time a link between particulate matter air pollution and sleep-disordered breathing (SDB), a known contributor to cardiovascular diseases.
SDB includes conditions such as apnea and hypopnea and affects approximately 17 percent of U.S. adults, many of whom are not aware that they have a problem. The current studies included more than 3,000 subjects and found novel evidence for temperature and pollution effects on SDB. Increases in apnea and hypopnea were associated with short-term temperature increases in all seasons and with increases in particulate matter air pollution in the summer months.
Specifically, increases in particulate matter of less than ten micrometers in size were associated with about a 13 percent increase in the Respiratory Disturbance Index and with a 20 percent increase in the amount of time the blood oxygen saturation fell below 90 percent.
Air pollution and SDB are independently associated with increased risk for cardiovascular diseases, strokes, and other major health conditions. Further research is necessary to determine whether particulate matter air pollution produces its negative effects, at least in part, by promoting sleep-disordered breathing.
Citation: Zanobetti A, Redline S, Schwartz J, Rosen D, Patel S, O'Connor GT, et al (https://www.ncbi.nlm.nih.gov/pubmed/20508218). 2010. Associations of PM10 with Sleep and Sleep-disordered Breathing in Adults from Seven U.S. Urban Areas. Am J Respir Crit Care Med. Epub ahead of print. doi:10.1164/rccm.200912-1797OC (See story (https://factor.niehs.nih.gov/2010/july/science-pollution.cfm))
Living, Breathing Lung-on-a-Chip
In response to the NIH Nanoscience and Nanotechnology in Biology and Medicine Program, NIEHS-supported researchers have developed a device that mimics a living and breathing human lung on a microchip roughly the size of a quarter.
The device has the potential to be a valuable research tool for testing the effects of environmental agents, as well as the absorption, safety, and efficacy of drug candidates. The device may help accelerate and reduce the expense of drug development, which can cost more than $2 million per substance.
The lung-on-a-chip device uses a new approach to tissue engineering that places tissue from the lining of the alveoli and blood vessels that surround them across a porous membrane. Air flows across the lung cells while culture medium, mimicking blood, is pumped through the capillaries. Mechanical stretching of the device mimics the expansion and contraction of the lungs during breathing.
The researchers tested the device by introducing E. coli bacteria on the lung cell side of the device while allowing white blood cells to flow through the capillaries. The lung cells detected the bacteria, and, through the porous membrane, activated the blood vessel cells, which caused an immune response resulting in the movement of white blood cells to the air chamber where they killed the bacteria.
The team is also working to build other model systems to mimic the intestinal system, bone marrow, and cancer models.
Citation: Huh D, Matthews BD, Mammoto A, Montoya-Zavala M, Hsin HY, Ingber DE (https://www.ncbi.nlm.nih.gov/pubmed/20576885). 2010. Reconstituting organ-level lung functions on a chip. Science 328(5986):1662-1668.
Transcription Termination Flips Out
Miguel Garcia-Diaz, Ph.D., recipient of an NIEHS Pathway to Independence Award (K99/R00), reports the determination of the structure of a mitochondrial termination factor called MTERF1. Mitochondrial termination factors are a family of proteins implicated in mitochondrial transcription - the coordination between transcription and replication and the regulation of mitochondrial protein synthesis. Human MTERF1 is responsible for transcription termination in the mitochondria.
Combined with functional studies, the structure reveals that upon binding MTERF1 unwinds the DNA double helix and promotes base flipping, the rotation of a single base to the outside of the helix, and that this reorganization is essential for termination. The analyses show how MTERF1 recognizes specific DNA sequences and provides a context for understanding the mechanistic consequences of two pathogenic mitochondrial DNA mutations.
Further experiments are planned to address whether the two mutations, G3249A and G3242A, result in transcriptional differences and if these alterations fully explain the clinical phenotype.
Citation: Yakubovskaya E, Mejia E, Byrnes J, Hambardjieva E, Garcia-Diaz M (https://www.ncbi.nlm.nih.gov/pubmed/20550934). 2010. Helix unwinding and base flipping enable human MTERF1 to terminate mitochondrial transcription. Cell 141(6):982-993.
Fetal Leydig Cell Protein Regulates Sertoli Cell Proliferation
NIEHS-supported trainee Denise Archambeault reports a newly discovered function for a fetal Leydig cell-produced protein called Activin A.
The protein, which is a member of the transforming growth factor beta (TGF-beta) protein superfamily, acts directly on Sertoli cells to promote proliferation during late embryogenesis. Prior to this discovery, it was thought that fetal Leydig cells, which produce testosterone, served only to masculinize the embryo and did not function in testis morphogenesis.
In the research team's experiments, which genetically disrupted the gene that encodes for Activin A specifically in fetal Leydig cells, testis cord elongation and expansion due to decreased Sertoili cell proliferation failed to occur. Disruption of TGF-beta signaling in Sertoli cells led to testis cord dysgenesis and proliferative deficits similar to those in the Leydig cell-specific Activin A knockout mice.
These results indicated that Activin A is the major TGF-beta protein that acts directly on Sertoli cells. The effects last into adulthood, resulting in low sperm production and abnormal testicular development. These findings challenge the existing paradigm that fetal testis development is solely under the control of the Sertoli cells.
Citation: Archambeault DR, Yao HH (https://www.ncbi.nlm.nih.gov/pubmed/20498064). 2010. Activin A, a product of fetal Leydig cells, is a unique paracrine regulator of Sertoli cell proliferation and fetal testis cord expansion. Proc Natl Acad Sci U S A 107(23):10526-10531.
(Jerry Phelps is a program analyst in the NIEHS Division of Extramural Research and Training.)