Papers of the Month
Intramural
By Janelle Weaver and Meklit Daniel
Indoor wood-burning may be linked to lung cancer in U.S. women
Indoor wood-burning from stoves and fireplaces is associated with the development of lung cancer among women in the U.S., according to researchers from NIEHS, including the institute’s Division of Translational Toxicology.
Burning wood releases both known and suspected lung carcinogens. Epidemiological studies conducted mostly in low- and middle-income countries have found a positive association between household combustion of wood and lung cancer. However, most studies have been retrospective, and few have been conducted in the U.S.
To fill this knowledge gap, the researchers carried out a prospective analysis of data collected from 50,226 U.S.-based women enrolled in the NIEHS Sister Study cohort who did not have a history of lung cancer at the time they enrolled. The women were followed for an average of 11 years, and there were 347 medically confirmed lung cancer cases diagnosed during this time. Overall, women who reported using their wood-burning fireplace or stove at least 30 days per year had a 68% higher rate of lung cancer, compared with those without a wood-burning fireplace or stove. When limiting to participants who had never smoked, positive associations were observed for wood-burning usage at least 30 days per year and for less frequent users (less than 30 days/year).
These findings are some of the first prospective evidence in the U.S. demonstrating that even occasional exposure to indoor wood smoke is associated with a higher incidence of lung cancer, including among never smokers. (JW)
Citation: Mehta SS, Hodgson ME, Lunn RM, Ashley CE, Arroyave WD, Sandler DP, White AJ. 2023. Indoor wood-burning from stoves and fireplaces and incident lung cancer among Sister Study participants. Environ Int 178:108128.
How a protein and RNA team up to ensure normal fly development
A fruit fly protein called Glo uses interchangeable RNA recognition domains to recognize nanos (nos) mRNA, according to NIEHS researchers and their collaborators. Specific recognition of target RNAs such as nos by RNA-binding proteins is essential for gene control.
During fruit fly development, translational control of nos mRNA is essential for the proper formation of the body axis of the embryo. The fruit fly protein Glo is an RNA-binding protein that represses nos translation and uses its quasi-RNA recognition motifs (qRRMs) to recognize both G-tract and UA-rich motifs within the nos translational control element (TCE). However, it has not been clear whether and how the qRRMs combine to recognize the nos TCE.
To fill this knowledge gap, the researchers determined a high-resolution solution structure of an RNA containing the elements recognized by Glo: nos TCEI and TCEIII, together called TCEI_III. The RNA structure demonstrated that a single qRRM is physically incapable of recognizing both RNA elements simultaneously. Additional experiments showed that any two qRRMs are sufficient to repress nos translation.
Together, the results suggest that tandem Glo qRRMs are multifunctional and interchangeable for the recognition of TCE G-tract or UA-rich motifs. According to the authors, this study illustrates how multiple RNA recognition modules within an RNA-binding protein may combine to diversify the RNAs that are recognized and regulated. (JW)
Citation: Warden MS, DeRose EF, Tamayo JV, Mueller GA, Gavis ER, Hall TMT. 2023. The translational repressor Glorund uses interchangeable RNA recognition domains to recognize Drosophila nanos. Nucleic Acids Res gkad586.
Various DNA-damaging agents may induce the same mutation signature
A mutation pattern affecting yeast single-stranded DNA after exposure to a reactive compound called glycidamide is ubiquitous in human cells, according to NIEHS researchers and their collaborators.
Glycidamide is a metabolite generated from acrylamide, which is currently designated as a probable human carcinogen. Acrylamide can be found in a variety of commonly consumed processed food products and through certain occupational exposures. For example, acrylamide can be formed as a byproduct of roasting coffee and cooking starchy foods, including French fries, potato chips, and bread.
The researchers used a yeast model to explore mutations caused by glycidamide. They found that the chemical causes a high rate of mutations in yeast single-stranded DNA, primarily in adenine and cytosine nucleobases. Mutations in adenines were characterized by a specific pattern, or motif, in which mutated adenines were followed by a +1 thymine.
This mutational motif is detectable in large fractions of tumors belonging to multiple cancer types, as well as in non-cancerous human cells. It is also associated with a person’s smoking history and age. Because of its presence in numerous diseased and healthy human cell types, the researchers propose that this motif reflects genome-wide mutations caused by a broad class of DNA-damaging agents. [Read related article.] (JW)
Citation: Hudson KM, Klimczak LJ, Sterling JF, Burkholder AB, Kazanov MD, Saini N, Mieczkowski PA, Gordenin DA. 2023. Glycidamide-induced hypermutation in yeast single-stranded DNA reveals a ubiquitous clock-like mutational motif in humans. Nucleic Acids Res gkad611.
Cellular markers indicate faster aging in women treated for breast cancer
Women diagnosed with and treated for breast cancer may experience faster biological aging than women who remain breast cancer-free, according to NIEHS researchers. Biological age differs from chronological age in that it reflects a person’s cell and tissue health.
Breast cancer survivors have higher rates of age-related illnesses compared with women without breast cancer. DNA methylation (DNAm), which is a biochemical change whereby methyl groups are attached to specific DNA sites, can be used to estimate a person’s biological age and age-related disease risk. Studies have explored DNAm in relation to breast cancer incidence, but metrics to assess such cellular markers of biological aging have not been widely applied in breast cancer survivorship studies.
The researchers used three DNAm-based metrics (called “epigenetic clocks”) to examine whether breast cancer and related treatments are associated with accelerated biological aging. Blood DNAm profiles were generated at two time points about eight years apart for 417 women, half of whom had developed breast cancer in the interim.
Women who were diagnosed and treated for breast cancer had higher biological aging at the second blood draw than women who remained breast cancer-free. Among women with breast cancer, the greatest biological age increase was observed among women who were treated with radiation. According to the authors, these findings indicate that the type of breast cancer treatment may differentially contribute to biological aging, and that the aging effect may not be linked to breast cancer itself. (MD)
Citation: Kresovich JK, O’Brien KM, Xu Z, et al. 2023. Changes in methylation-based aging in women who do and do not develop breast cancer. J Natl Cancer Inst djad117.
How the stability of an mRNA molecule regulates lung biology in mammals
Mice with stabilized Csf2 mRNA develop lethal pneumonia characterized by the accumulation of crystal-containing macrophages in the lungs, according to NIEHS researchers and their collaborators.
Granulocyte–macrophage colony-stimulating factor (GM-CSF) is a small protein that is encoded by the Csf2 gene in mice, and it plays an important role in lung biology. The Csf2 mRNA contains an adenosine–uridine-rich element (ARE) — an element with frequent adenosine and uridine bases and commonly observed AUUUA sequence motifs — which makes this transcript unstable. The GM-CSF ARE was found almost forty years ago and was shown in cell-based studies to increase the instability of the Csf2 mRNA. However, the physiological role of this element in mammals has not been clear.
To add clarity, the NIEHS researchers generated a mouse model in which the ARE instability element was deleted in the Csf2 mRNA, which resulted in elevated GM-CSF levels in the blood and lungs. Mice with this ARE deletion, in all cells and specifically in alveolar type II (AT2) cells in the lungs, developed severe respiratory distress and died within about 12 weeks of age. The lungs of these mice contained large accumulations of white blood cells, called alveolar macrophages, which contained fine crystal-like material.
Taken together, the results demonstrate that Csf2 mRNA decay regulation in lung AT2 cells appears to be essential for controlling GM-CSF secretion and lung alveolar macrophage responses. According to the authors, this mouse model highlights an important and previously uncharacterized aspect of Csf2 mRNA stability in balancing levels of gene expression and influencing physiological responses. (JW)
Citation: Arao Y, Stumpo DJ, Hoenerhoff MJ, Tighe RM, Yu YR, Sutton D, Kashyap A, Beerman I, Blackshear PJ. 2023. Lethal eosinophilic crystalline pneumonia in mice expressing a stabilized Csf2 mRNA. FASEB J 37(8):e23100.
(Janelle Weaver, Ph.D., is a contract writer for the NIEHS Office of Communications and Public Liaison, and Meklit Daniel is a fellow in the NIEHS Environment and Cancer Epidemiology Group.)
