Papers of the Month
By Sara Amolegbe
Transposable elements contribute to tumor growth
An NIEHS-funded study revealed that transposable elements, which are sequences of DNA that move around in the genome, are important drivers of tumor growth. The study provides the first comprehensive look at the role transposable elements play in activating cancer genes.
Typical genome sequencing methods that look for genetic mutations that drive cancer do not detect transposable elements. So the researchers used more powerful sequencing techniques to analyze 7,769 tumor samples from 15 different types of cancer. They discovered 129 transposable elements that played a part in tumor growth by influencing 106 different cancer genes. The authors reported that transposable elements switch on cancer-related genes that are usually silent and keep them switched on.
At least one transposable element activated a cancer gene in about half of all the tumors studied. Although transposable elements were widespread, the pattern of transposable elements varied across cancer types. For example, 87% of tumor samples from a type of lung cancer called squamous cell carcinoma had at least one transposable element, but this was only 12% for glioma brain cancers.
According to the authors, a better understanding of transposable elements may provide more information about what leads to accelerated tumor growth in some cancers and new targets to study for future cancer therapies.
Citation: Jang HS, Shah NM, Du AY, Dailey ZZ, Pehrsson EC, Godoy PM, Zhang D, Li D, Xing X, Kim S, O'Donnell D, Gordon JI, Wang T. 2019. Transposable elements drive widespread expression of oncogenes in human cancers. Nat Genet 51(4):611–617.
New algorithm allows faster toxicity testing
NIEHS grantees developed a new algorithm to predict the toxicity of new and untested chemicals by evaluating their similarity to chemicals that have been previously tested for toxicity. The algorithm compares chemical components from tested compounds with those of untested compounds. Using mathematical methods, the algorithm identifies similarities and differences in the chemical structures that may factor into toxicity.
Low-cost, cell-based tools for toxicity testing have potential as alternatives to animal testing. However, incorporating cell-based assays into chemical toxicity evaluations requires significant data curation and analysis. To address this problem, the researchers developed a computational method that extracts useful data from cell-based assays and predicts animal toxicity based on relevant toxicity mechanisms.
To fine-tune the algorithm, the researchers began with 7,385 compounds for which rat acute oral toxicity data are known. They compared the data with other data on the same chemicals in PubChem, a National Institutes of Health database on millions of compounds. They then tested the algorithm on 600 new compounds.
For several groups of chemicals, the algorithm had a 62-100% success rate in predicting levels of oral toxicity. By comparing relationships between sets of chemicals, they also discovered new factors that can determine a chemical’s toxicity. According to the authors, this data-driven model provides a tool to prioritize chemicals that may need more comprehensive testing in animals before use in commerce.
Citation: Russo DP, Strickland J, Karmaus AL, Wang W, Shende S, Hartung T, Aleksunes LM, Zhu H. 2019. Nonanimal models for acute toxicity evaluations: applying data-driven profiling and read-across. Environ Health Perspect 127(4):047001.
Arsenic-containing product is a broad-spectrum antibiotic
NIEHS grantees demonstrated that a recently discovered natural product, called arsinothricin (AST), that contains arsenic and has broad-spectrum antibiotic activity. AST is produced by soil bacteria that live around the roots of rice plants. According to the authors, their findings suggest that this soil bacteria has evolved the ability to use arsenic, a toxic soil contaminant, to its advantage.
The researchers tested AST and found it to be effective against pathogens such as Escherichia coli, which can cause severe intestinal infections, and carbapenem-resistant Enterobacter cloacae, a common cause of infections in neonatal and intensive care units, and a World Health Organization global priority pathogen. It was also effective against Mycobacterium bovis, the causative agent of animal tuberculosis.
They found that resistance to AST arose with the prolonged use of the antibiotic and pinpointed that the gene arsN1 was responsible for producing an enzyme that conferred resistance to pathogens. According to the authors, it may be possible to develop arsN1 inhibitors, which block arsN1 activity, for use in combination with AST to prevent resistance.
Researchers tested AST toxicity on human blood cells and found that it had low cell toxicity and was much less toxic to human cells than a more common form of arsenic. According to the authors, these compounds have potential for future clinical use, but further testing is necessary to better determine effectiveness and toxicity.
Citation: Nadar VS, Chen J, Dheeman DS, Galvan AE, Yoshinaga-Sakurai K, Kandavelu P, Sankaran B, Kuramata M, Ishikawa S, Rosen BP, Yoshinaga M. 2019. Arsinothricin, an arsenic-containing non-proteinogenic amino acid analog of glutamate, is a broad-spectrum antibiotic. Commun Biol 2:131.
Endocrine disrupting chemicals linked to inflammatory changes in pregnancy
Exposure to different endocrine-disrupting chemical (EDC) mixtures in early pregnancy is associated with distinct inflammatory changes in mother and child, according to an NIEHS-funded study. According to the authors, unique EDC mixtures may explain changes to immune cells during pregnancy, and those changes may be linked to lower infant birth weight and gestational age at delivery.
Previous studies, which often focused on single EDCs, observed associations between EDC exposure and fetal growth restriction or lower infant birth weight, but the results were mixed. So the team studied associations between individual EDCs and different EDC mixtures on markers of inflammation during pregnancy. In a Michigan-based birth cohort, they tested first trimester urine samples for 12 phthalates, 12 phenols, and 17 metals in 56 women. In the mother’s blood during the first trimester and at term, and in the placental cord blood after delivery, they also measured 12 cytokines that promote inflammation and are important cells in the immune system.
The researchers demonstrated differences in the association between individual EDCs and EDC mixtures and inflammatory markers, indicating that the combination of exposures was an important contributor to the outcome. They also measured several individual cytokines that were associated with gestational age and birth weight. According to the authors, these observed associations between EDC mixtures and inflammation during pregnancy may have clinical and public health implications for women of childbearing age.
Citation: Kelley AS, Banker M, Goodrich JM, Dolinoy DC, Burant C, Domino SE, Smith YR, Song PXK, Padmanabhan V. 2019. Early pregnancy exposure to endocrine disrupting chemical mixtures are associated with inflammatory changes in maternal and neonatal circulation. Sci Rep 9(1):5422.