Papers of the Month
By Aidin Alejo Abdala, Melissa Li, Victoria Placentra, Jesse Saffron, and Qing Xu
NTP assesses botanical supplements with high-throughput screening
Researchers from the National Toxicology Program (NTP) have determined that quantitative high-throughput screening (qHTS) assays are a useful tool for assessing toxicological effects of botanical supplements. Developed by the Toxicology in the 21st Century (Tox21) program, a federal collaboration that tests the toxicity of various chemicals, qHTS offers a cell-based approach that can be used to evaluate dietary supplements.
Both consumption and sales of botanical supplements for health benefits are increasing in the U.S. Even though these plant-derived supplements are perceived to be natural and nontoxic, many have been associated with adverse effects in multiple reports. They also pose a challenge for hazard assessment due to their chemical complexity and variability. In this study, researchers investigated if Tox21 qHTS methods could efficiently characterize the biological activities of botanical supplements without animal testing.
The researchers used 20 cell-based Tox21 qHTS assays to measure the effects of 90 botanical substances across multiple biological responses, including cytotoxicity, genotoxicity, nuclear receptor signaling, and endocrine activity. Most substances induced measurable activities that were comparable to those displayed by the compounds in the Tox21 chemical library. The findings support the use of qHTS as a tool in assessing the biological activity of botanical supplements. (QX)
Citation: Hubbard TD, Hsieh JH, Rider CV, Sipes NS, Sedykh A, Collins BJ, Auerbach SS, Xia M, Huang R, Walker NJ, DeVito MJ. 2019. Using Tox21 high-throughput screening assays for the evaluation of botanical and dietary supplements. Appl In Vitro Toxicol 5(1):10–25.
Air pollutants associated with increased breast cancer risk
Using data from the National Air Toxics Assessment (NATA) and the Sister Study, NIEHS scientists demonstrated that some air toxics, especially methylene chloride, were associated with an increased risk of breast cancer. The study also suggested the association between certain air toxics and breast cancer appeared stronger in women who were overweight or obese.
For this study, the researchers examined 29 air toxics that were previously identified as mammary gland carcinogens in animal studies. Census tract-level air toxic concentrations from NATA were linked to Sister Study participants’ residential addresses. The scientists then estimated the association between each air toxic and the risk of developing breast cancer. This study used a unique approach to further identify combinations of multiple air toxics, as well as personal characteristics such as age and body mass index, which acted together to influence the risk of breast cancer in a U.S. population. Further study is required to understand the complex relationships between air toxics observed in this multipollutant analysis. (VP)
Citation: Niehoff NM, Gammon MD, Keil AP, Nichols HB, Engel LS, Sandler DP, White AJ. 2019. Airborne mammary carcinogens and breast cancer risk in the Sister Study. Environ Int 130:10489.
IGF1 important for maintaining fertility in female mice
Scientists at NIEHS identified a distal super enhancer that induces insulin-like growth factor 1 (IGF1) expression in the uterus after estrogen treatment. A super enhancer is a region of DNA consisting of multiple, particularly active enhancers that can increase transcription of a gene. Although IGF1 is primarily made and secreted in the liver, the presence of estrogen increases IGF1 levels specifically in the uterus. IGF1 is not required for pregnancy but is essential for maintaining fertility.
The authors identified a group of five enhancers upstream of the IGF1 transcriptional start site (TSS) and confirmed their function as a super enhancer after observing classic characteristics of enhancers, such as increased enhancer RNA transcription, interaction between the enhancer region and TSS, and DNA loop structure formation. Looping allows distal enhancers, which are far from the gene promoter, to become closely aligned with and interact with the TSS. Supporting these findings, CRISPR-Cas9 deletion of one of the enhancers reversed the previous observations and abolished estrogen-induced IGF1 transcription in the uteri of mice. Although this disruption did not seem to affect fertility or uterine epithelial growth, additional experiments deleted the uterine IGF1 gene completely and showed it is important for maintaining fertility. (ML)
Citation: Hewitt SC, Lierz SL, Garcia M, Hamilton KJ, Gruzdev A, Grimm SA, Lydon JP, DeMayo FJ, Korach KS. 2019. A distal super enhancer mediates estrogen-dependent mouse uterine-specific gene transcription of Igf1 (insulin-like growth factor 1). J Biol Chem 294(25):9746–9759.
Artificial light while sleeping may lead to obesity in women
Exposure to artificial light at night (ALAN) while sleeping is associated with increased weight gain and development of obesity in women, according to NIEHS researchers. Previous mouse studies showed that ALAN affects melatonin signaling, which disturbs the sleep-wake cycle and leads to weight gain. The study is the first to describe the association in humans, perhaps furthering scientists’ understanding of the obesity epidemic.
The researchers used data from 43,722 women participating in the Sister Study, a national cohort that investigates genetic and environmental risk factors for breast cancer. Participants were asked about their exposure to different types of ALAN while sleeping, and responses were categorized into four groups: no light, small nightlight in the room, light outside the room, and light or television on in the room. The scientists used weight, height, waist and hip circumference, and body mass index measurements taken at enrollment, as well as self-reported information on weight at enrollment and at follow-up, an average of 5.7 years.
Women who slept with televisions or other lights at night were more likely to have been overweight or obese at the start of the study and were more likely to gain weight or become obese during follow-up. Turning off lights at night, along with eating a healthy diet and regular exercise, may help women prevent obesity. (AA)
Citation: Park YM, White AJ, Jackson CL, Weinberg CR, Sandler DP. 2019. Association of exposure to artificial light at night while sleeping with risk of obesity in women. JAMA Intern Med; doi: 10.1001/jamaintermed.2019.0571 [Online 10 June 2019]. (Story)
SMARCB1 key to early brain development
NIEHS researchers determined that SMARCB1, an important protein in the SWI/SNF chromatin remodeling complex, allows human embryonic stem cells (hESCs) to differentiate into brain cells, but not other types of cells. They made the discovery after reducing levels of SMARCB1 in hESCs. Because other scientists found having damaged SMARCB1 during development causes central nervous system tumors in children, this work could help determine how these tumors form.
The authors provided context by explaining the crucial role SMARCB1 plays in brain development. During the growth of an embryo, SMARCB1 ensures that the correct genes are turned on or off at the appropriate time. Using genetic activity and DNA accessibility data, the research team demonstrated that the protein does its job by turning off portions of DNA called stem cell super enhancers. Super enhancers usually increase the transcription of genes that keep stem cells in an undifferentiated state, so when SMARCB1 switches off specific super enhancers, the cells can turn into mature brain cells.
This study provides important information about the regulatory functions of SMARCB1. It may help researchers examine the relationship between early brain development and childhood cancers, especially when SMARCB1 is mutated, as is the case in atypical rhabdoid/teratoid tumors. (JS)
Citation: Langer LF, Ward JM, Archer TK. 2019. Tumor suppressor SMARCB1 suppresses super-enhancers to govern hESC lineage determination. Elife; doi: 10.7554/eLife.45672 [Online 29 April 2019].
(Aidin Alejo Abdala is an Intramural Research Training Award [IRTA] postbaccalaureate fellow in the NIEHS Clinical Investigation of Host Defense Group. Melissa Li, Ph.D., is an IRTA fellow in the NIEHS Biostatistics and Computational Biology Branch. Victoria Placentra is an IRTA postbaccalaureate fellow in the NIEHS Mutagenesis and DNA Repair Regulation Group. Jesse Saffron, J.D., is a technical writer and editor in the NIEHS Office of Communications and Public Liaison. Qing Xu is a biologist in the NIEHS Metabolism, Genes, and Environment Group.)