Ozone exposure, worse respiratory outcomes in smokers

Higher long-term ozone exposure was associated with lower lung function and increased emphysema in current and former smokers, according to an NIEHS-funded study. The study suggested that exposure to higher concentrations of ozone might also contribute to worse respiratory outcomes in adults already at higher risk for chronic lung disease because of their smoking status.

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

The adverse outcomes were consistent across people with different levels of smoking history, which suggested that the effects of ozone exposure might be independent of smoking intensity. According to the authors, these findings support continued re-examination of ambient pollution standards designed to protect the most vulnerable members of the U.S. population.

Citation: 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 with respiratory morbidity in smokers. JAMA Intern Med 180(1):106–115.

New quick screen for different types of DNA damage

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

The researchers previously developed the CometChip assay, an adaptation of the standard laboratory comet assay method that detects DNA strand breaks, but with higher throughput and better reproducibility. The CometChip assay is good at detecting breaks in DNA, but it cannot pick up a common type of damage known as a bulky lesion. In this study, the research team adapted the CometChip assay so that it could identify bulky lesion DNA damage. Normally, a cell will try to repair a bulky lesion by cutting it out and replacing it with a new DNA. To capture this process, the researchers treated cells with two compounds that prevented them from synthesizing the new DNA to repair bulky lesions, which halted the repair process and generated unrepaired single-stranded DNA that the CometChip assay could detect.

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

Citation: 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 for screening potentially carcinogenic DNA adducts by trapping DNA repair intermediates. Nucleic Acids Res; doi: 10.1093/nar/gkz1077 [Online 11 Dec 2019].

Astrocytes' role in inflammation and neurodegeneration

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

Using a mouse model of MS, researchers examined the role of astrocytes and found that during the progressive phase of the disease, astrocytes in the brain switched on metabolic pathways that activated a specific protein found in the mitochondria of cells known as mitochondrial antiviral signaling (MAVS) protein. This led to activation of several pro-inflammatory genes, triggering inflammation in the brain and spinal cord. At the same time, astrocytes began to produce less lactate, which provides metabolic support to cells, and provided less of it to the nerve cells.

Researchers tested if these metabolic pathways were blocked by treating mice with miglustat, a drug used to treat two rare metabolic disorders. Miglustat given to mice before the onset of MS effectively suppressed MAVS activation and subsequent inflammation.

According to the authors, the findings outline a new role for MAVS in CNS inflammation and a potential therapeutic target for MS. Because MAVS is also activated in response to viruses, the authors noted that these findings could offer insights into the ways in which viruses that are considered possible triggers of MS might contribute to the disease.

Citation: 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 drives inflammation and tumors

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

UVRAG knockout mice cannot survive beyond the embryo stage. To provide a new way to study the role of this gene, the researchers generated mice that expressed UVRAG with a frameshift mutation. This genetic mutation is caused by a deletion or insertion in a DNA sequence that shifts 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 intestinal colitis and found that compared with normal mice, mice with the UVRAG mutation displayed increased inflammatory responses in both conditions. The mutated mice also had increased spontaneous tumor development. Increased tumors were linked to suppression of autophagy associated with aging, indicating that UVRAG could be one reason people are more susceptible to cancers as they get older.

Citation: 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 truncating mutation in the autophagy gene UVRAG drives inflammation and tumorigenesis in mice. Nat Commun 10(1):5681.