Environmental Factor – February 2020: Leaves of the Month Outside the Walls

outside the walls
Written by Sarah Amuligbe

Ozone exposure, worse respiratory outcomes in smokers

A NIEHS funded study showed that long-term exposure to ozone is associated with decreased lung function and increased emphysema in current and former smokers. The study suggested that exposure to higher concentrations of ozone may also contribute to worse respiratory outcomes in adults already at higher risk of developing chronic lung disease due to smoking status.

The researchers analyzed lung function data from 1,874 current and former smokers from seven cities across the United States and also estimated 10-year historical exposure to ambient ozone for each study participant based on their place of residence. The researchers found that historically higher 10-year exposure to ambient ozone was associated with poorer lung function, worse patient-reported respiratory outcomes, increased respiratory symptoms, and higher levels of emphysema and gas traps, an abnormal retention of air in the lungs. Looking at quality-of-life data from the cohort study, the researchers also linked living in areas of the United States with 10-year historical high ozone to poorer quality of life and health status of study participants.

Negative results were consistent across subjects with different levels of smoking history, suggesting that the effects of ozone exposure may be independent of smoking intensity. According to the authors, these findings support the ongoing re-examination of ambient pollution standards designed to protect the most vulnerable members of the US population.

the quote: Paulin LM, Gassett AJ, Alexis NE, Kirwa K, Kanner RE, Peters S, Krishnan JA, Paine R, Dransfield M, Woodruff PG, Cooper CB, Barr RG, Comellas AP, Pirozzi CS, Han M, Hoffman EA, Martinez FJ , Woo H, Peng RD, Fawzy A, Putcha N, Breysse PN, Kaufman JD, Hansel NN. 2019. Association of long-term ambient ozone exposure and respiratory impairment in smokers. JAMA Intern Med 180 (1): 106-115.

New fast screen for different types of DNA damage

NIEHS recipients have developed a new screening method that can detect a wide range of DNA damage in cells. According to the authors, this new method fills a gap in DNA damage testing and can make chemical safety testing faster, easier and more accurate.

The researchers previously developed the CometChip test, a modification of the standard comet test method that detects DNA strand breaks, but with higher throughput and better reproducibility. The CometChip test is good at detecting breaks in DNA, but it can’t pick up a common type of damage known as a megalesion. In this study, the research team modified the CometChip assay so that it can identify massive DNA damage. Normally, the cell will attempt to repair the bulky lesion by cutting it off and replacing it with new DNA. To capture this process, the researchers treated cells with two compounds that prevented them from synthesizing new DNA to repair bulky lesions, stopping the repair process and generating unrepaired single-stranded DNA that the CometChip test could detect.

To test their new system, the researchers exposed liver stem cells to ultraviolet light, which is known to produce massive lesions. After checking their ability to detect pests, they tested the system with nine chemicals, seven of which are known to lead to single DNA pieces or bulky pests, and found that the test accurately detected them all.

the quote: Ngo LP, Owiti NA, Swartz C, Winters J, Su Y, Ge J, Xiong A, Han J, Recio L, Samson LD, Engelward BP. 2019. Sensitive CometChip assay to screen for potentially carcinogenic DNA approaches by trapping DNA repair intermediates. nucleic acids precision; doi: 10.1093/nar/gkz1077 [Online 11 Dec 2019].

The role of astrocytes in inflammation and neurodegeneration

NIEHS recipients have identified a novel pathway that controls the metabolic response of astrocytes, which may explain how it is involved in inflammation and neurodegeneration. Astrocytes are the cells of the brain and spinal cord that are essential to maintaining the health of the central nervous system, and they perform functions such as providing nutrients to neurons. However, they have also been linked to promoting inflammation of the central nervous system and contributing to the development of multiple sclerosis (MS).

Using a mouse model of MS, the researchers examined the role of astrocytes and found that during the advanced stage of the disease, astrocytes in the brain switched on metabolic pathways that activate a specific protein found in the mitochondria of cells known as mitochondrial antiviral signaling (MAVS) protein. This activated several pro-inflammatory genes, resulting in inflammation in the brain and spinal cord. At the same time, the astrocytes begin to produce less lactate, which provides metabolic support to the cells, and reduces it to the neurons.

The researchers tested whether these metabolic pathways were blocked by treating mice with mylostat, a drug used to treat two rare metabolic disorders. Miglustat administered to mice before the onset of MS effectively suppressed MAVS activation and subsequent inflammation.

According to the authors, the findings identify a new role for MAVS in central nervous system inflammation and a potential therapeutic target for MS. Because MAVS is also activated in response to viruses, the authors note that these findings could provide insights into the ways in which viruses that are potential inducers of MS can contribute to disease.

the quote: Chao CC, Gutierrez-Vazquez C, Rothhammer V, Mayo L, Wheeler MA, Tjon EC, Zandee SEJ, Blain M, de Lima KA, Takenaka MC, Avila-Pacheco J, Hewson P, Liu L, Sanmarco LM, Borucki DM, Lipof GZ, Trauger SA, Clish CB, Antel JP, Prat A, Quintana FJ. 2019. Metabolic control of astrocyte pathogenic activity via cPLA2-MAVS. Cell 179 (7): 1483-1498.E22.

Mouse gene mutation leads to infections and tumors

NIEHS-funded researchers found that a mutation in the ultraviolet radiation resistance-associated gene (UVRAG), a gene involved in cell regulation, can disrupt autophagy in mice, leading to an increased inflammatory response and tumor progression. Autophagy is the process of cleaning up damaged cells so that the body can renew newer, healthier cells. Abnormal autophagy is a major known risk factor for inflammatory diseases and cancer. This study provides the first genetic evidence linking UVRAG suppression to the regulation of autophagy, inflammation, and a predisposition to cancer.

UVRAG knockout mice cannot survive beyond the embryo stage. To provide a new way to study the role of this gene, the researchers created mice expressing UVRAG with a frameshift mutation. This genetic mutation is caused by a deletion or insertion in the DNA sequence that changes the way the sequence is read. These mice are normal in basal autophagy but deficient in autophagy induced by stimuli, such as starvation or immune activation.

The researchers induced sepsis or enteric colitis and found that compared to normal mice, mice with the UVRAG mutation showed increased inflammatory responses in both conditions. The mutant mice also had increased spontaneous tumor growth. Increased tumors have been linked to suppression of autophagy associated with aging, suggesting that UVRAG may be one reason people are more likely to develop cancer as they age.

the quote: Quach C, Song Y, Guo H, Li S, Maazi H, Fung M, Sands N, O’Connell D, Restrepo-Vassalli S, Chai B, Nemecio D, Punj V, Akbari O, Idos GE, Mumenthaler SM, Wu N, Martin SE, Hagiya A, Hicks J, Cui H, Liang C. 2019. A truncated mutation in the UVRAG autophagy gene causes inflammation and tumorigenesis in mice. Nat Common 10 (1): 5681.

(Sarah Amuligbe is a research and communications specialist for MDB Inc., a contractor with the Research and Training Outside the Walls of NIEHS.)

from San Jose News Bulletin https://sjnewsbulletin.com/environmental-factor-february-2020-leaves-of-the-month-outside-the-walls/