Papers of the Month
By Sara Amolegbe
E-cigs linked to lung cancer and bladder changes in mice
NIEHS grantees showed that mice exposed to e-cigarette smoke (ECS) were more likely to develop lung adenocarcinomas, a type of lung cancer. They also found that exposed mice had higher levels of bladder urothelial hyperplasia, an abnormal increase in epithelial cells that can precede development of bladder tumors.
The researchers exposed one group of mice to ECS aerosols generated from e-juice containing nicotine and compared them to a second group of mice exposed to a control aerosol without ECS. The mice were subjected to whole-body exposure for four hours per day, five days per week, for 54 weeks. A third group of mice was exposed only to filtered air. Of the mice exposed to ECS, 22.5% developed lung adenocarcinomas and 57.5% developed urothelial hyperplasia. These lesions were extremely rare in mice exposed to the control aerosol without ECS or filtered air.
Interestingly, mice with ECS-induced lung adenocarcinomas were not more prone to developing urothelial hyperplasia, suggesting that the two outcomes are divergent events and may involve different mechanisms.
Previous studies have linked nicotine and nicotine-derived products to effects on lung and bladder cells. According to the authors, the findings of this study show that ECS, including nicotine, may be a lung and bladder carcinogen and warrants further study in humans.
Citation: Tang MS, Wu XR, Lee HW, Xia Y, Deng FM, Moreira AL, Chen LC, Huang WC, Lepor H. 2019. Electronic-cigarette smoke induces lung adenocarcinoma and bladder urothelial hyperplasia in mice. Proc Natl Acad Sci U S A 116(43):21727–21731.
Flame-retardant affects social behaviors in prairie voles
An NIEHS-funded study showed that early life exposure to FireMaster 550 (FM550), a commonly used flame-retardant mixture, increases anxiety and affects social behaviors in prairie voles. Effects were more pronounced with increasing exposure levels, and female voles were more greatly affected.
Researchers exposed pregnant prairie voles to 0, 500, 1,000, or 2,000 micrograms of FM550 by injecting it under the skin throughout gestation. Their pups were directly exposed beginning the day after birth until weaning. When the pups became adults, the researchers performed multiple behavior tests that assessed anxiety, memory, and sociability, including partner preference.
Normally, voles are highly social and prefer to spend time with other animals, particularly their partners. But voles exposed to FM550, particularly the females, were less social. For example, when given an opportunity to spend time with a female stranger or spend time alone, females exposed to FM550 avoided the stranger. Exposed females were also much more anxious and less likely to explore new spaces. Exposed males also had social deficits, including failing to show a partner preference. The effects were evident at the lowest dose and more pronounced at higher doses.
Prairie voles are not commonly used in toxicology studies but are widely used in the behavioral neuroscience field. According to the authors, the study also demonstrates the utility of the prairie vole for investigating the impact of chemical exposures on social behavior.
Citation: Gillera SEA, Marinello WP, Horman BM, Phillips AL, Ruis MT, Stapleton HM, Reif DM, Patisaul HB. 2019. Sex-specific effects of perinatal FireMaster 550 (FM 550) exposure on socioemotional behavior in prairie voles. Neurotoxicol Teratol; doi: 10.1016/j.ntt.2019.106840 [Online 12 Nov 2019].
New DNA tool determines totality of DNA crosslink damage
NIEHS grantees developed a high-resolution accurate mass spectrometry (HRMS) method for determining the totality of DNA crosslinks, a type of DNA damage. They tested the approach on cells exposed to agents known to cause DNA crosslinking and found that the method can detect both expected and unexpected crosslinks in biological samples.
DNA crosslinks, especially interstrand crosslinks (ICLs), can be toxic to cells because they link DNA strands together, blocking replication and transcription. Environmental sources of ICLs, such as formaldehyde, can lead to adverse health effects because they can block essential cellular processes. Because they can interfere with rapidly dividing cells associated with tumors, ICL-forming agents are also used in therapeutic cancer drugs, such as chlorambucil.
The researchers used a combination of three enzymes to break up the DNA sample and to detect the total DNA crosslinks present in the sample using HRMS. They tested their method by screening for crosslinks in DNA treated with formaldehyde and chlorambucil, which are both known to induce DNA crosslinks. The results showed that all expected crosslinks were detected successfully, along with various unexpected crosslinks. Using HRMS, they were able to determine the molecular formulas and chemical structures of these unexpected crosslinks.
According to the authors, this method offered structural insights into ICLs caused by chemical exposures and provided a platform for development of predictive diagnostic tests that might improve the use of clinical crosslinking agents.
Citation: Hu CW, Chang YJ, Cooke MS, Chao MR. 2019. DNA crosslinkomics: a tool for the comprehensive assessment of interstrand crosslinks using high resolution mass spectrometry. Anal Chem 91(23):15193–15203.
Air pollution exposure linked to brain atrophy and memory decline
Women in their 70s and 80s who were exposed to higher levels of air pollution were more likely to experience greater memory decline and more Alzheimer’s-like brain atrophy than women in the same age group exposed to cleaner air, according to an NIEHS-funded study.
Researchers used data from 998 women, aged 73 to 87 years, who had up to two brain scans five years apart and took part in an annual episodic memory assessment between 1999 and 2010 as part of the landmark Women’s Health Initiative. The Women’s Health Initiative was launched in 1993 by the National Institutes of Health and enrolled more than 160,000 women. The brain scans were scored on the basis of their similarity to Alzheimer’s disease patterns by a machine learning tool that was trained with brain scans of people with Alzheimer’s disease. The researchers also collected information about where the women lived and environmental data from those locations to estimate their exposure to fine particle air pollution.
The researchers found that long-term fine particle air pollution was associated with accelerated decline of episodic memory based on memory assessments and predominately affected immediate recall and new learning. They also found that higher Alzheimer’s risk scores, which indicate more Alzheimer’s-like brain atrophy, were also associated with higher air pollution and partially explained the association between air pollution and memory decline.
According to the authors, the study provides new information about how fine particulate air pollution may alter brain structure and contribute to Alzheimer’s disease by identifying some of the brain changes linking air pollution and memory decline.
Citation: Younan D, Petkus AJ, Widaman KF, Wang X, Casanova R, Espeland MA, Gatz M, Henderson VW, Manson JE, Rapp SR, Sachs BC, Serre ML, Gaussoin SA, Barnard R, Saldana S, Vizuete W, Beavers DP, Salinas JA, Chui HC, Resnick SM, Shumaker SA, Chen JC. 2019. Particulate matter and episodic memory decline mediated by early neuroanatomic biomarkers of Alzheimer's disease. Brain; doi: 10.1093/brain/awz348 [Online 20 Nov 2019].