Environmental Factor – August 2019: Inside Papers of the Month

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Written by Aiden Alejo Abdullah, Melissa Lee, Victoria Placentra, Jesse Saffron and King Show

NTP evaluates botanical supplements with a high-throughput screening

Researchers from the National Toxicology Program (NTP) have determined that high-throughput quantitative screening assays (qHTS) are a useful tool for assessing the toxicological effects of plant supplements. Developed by 21st Century Toxicology (Tox 21), a federal collaboration that tests the toxicity of different chemicals, qHTS offers a cell-based approach that can be used to evaluate nutritional supplements.

The consumption and sale of botanical supplements for health benefits is increasing in the United States Although these plant-derived supplements are considered natural and non-toxic, many have been associated with adverse effects in multiple reports. They are also challenging to assess risks due to their chemical complexity and diversity. In this study, researchers investigated whether Tox21 qHTS methods can effectively characterize the biological activities of plant supplements without animal testing.

The researchers used 20 Tox21 qHTS cellular assays to measure the effects of 90 plant substances across multiple biological responses, including cytotoxicity, genotoxicity, nuclear receptor signaling, and endocrine activity. Most of the substances caused measurable activities comparable to those exhibited by the compounds in the Tox21 chemical library. The results support the use of qHTS as a tool in assessing the biological activity of botanical supplements. (QX)

the quote: Hubbard TD, Hsieh JH, Rider CV, Sipes NS, Sedykh A, Collins BJ, Auerbach SS, Xia M, Huang R, Walker NJ, DeVito MJ. 2019. Use of Tox21 High-throughput Screening Assays to Evaluate Dietary and Botanical Supplements. Applet in Vitrotoxicol 5 (1): 10-25.

Air pollutants are associated with an increased risk of breast cancer

Using data from National Air Toxics Assessment (NATA) and Sister study, NIEHS scientists have established that certain toxic substances in the air, especially methylene chloride, were linked to an increased risk of breast cancer. The study also suggested that the association between certain air toxins and breast cancer appears to be stronger in women who are overweight or obese.

In this study, researchers examined 29 air toxicants previously identified as mammary gland carcinogens in animal studies. NATA census tract-level air toxic concentrations were linked to the residential addresses of participants in the sister study. The scientists then estimated the relationship between each air toxicant and the risk of breast cancer. This study used a unique approach to identify combinations of multiple aerobic toxins, as well as personal characteristics such as age and body mass index, that worked together to influence breast cancer risk in the US population. Further study is required to understand the complex relationships between air toxins observed in this multipollutant analysis. (vice president)

the quote: Niehoff NM, Gammon MD, Keil AP, Nichols HB, Engel LS, Sandler DP, White AJ. 2019. Airborne breast cancer etiology and risk of breast cancer in a sister study. Environ Int 130: 10489.

IGF1 is important for maintaining fertility in female mice

Scientists at NIEHS have identified a super-distant enhancer that stimulates the expression of insulin-like growth factor 1 (IGF1) in utero after estrogen therapy. A super enhancer is a region of DNA consisting of multiple specifically active enhancers that can increase gene transcription. Although IGF1 is primarily produced and secreted in the liver, the presence of estrogen increases IGF1 levels specifically in the womb. IGF1 is not required for pregnancy but is essential for maintaining fertility.

The authors identified a set of five enhancers upstream of the IGF1 transcriptional start site (TSS) and confirmed its function as a super enhancer after observing classic properties of enhancers, such as increased enhancer RNA transcription, interaction between enhancer region and TSS, and DNA. forming a ring structure. Redundancy allows the distal enhancers, far from the gene promoter, to align closely with and interact with the TSS. In support of these findings, CRISPR-Cas9 deletion of one enhancer reversed previous observations and abolished estrogen-induced IGF1 transcription in the rat uterus. Although this disorder does not appear to affect fertility or the epithelial development of the uterus, additional experiments completely deleted the uterine IGF1 gene and showed that it is important for fertility preservation. (ML)

the quote: Hewitt SC, Lierz SL, Garcia M, Hamilton KJ, Gruzdev A, Grimm SA, Lydon JP, DeMayo FJ, Korach KS. 2019. The super-distant enhancer mediates the estrogen-dependent uterine gene transcription of Igf1 (insulin-like growth factor 1). J Biol Chem 294 (25): 9746-9759.

Artificial light during sleep may lead to obesity in women

According to NIEHS researchers, exposure to artificial light at night while sleeping is associated with weight gain and the development of obesity in women. Previous studies in mice showed that ALAN affects melatonin signaling, perturbing the sleep-wake cycle and leading to weight gain. This study is the first to describe the relationship in humans, and may enhance scientists’ understanding of the obesity epidemic.

The researchers used data from 43,722 women who participated in the Sister Study, a national group looking at genetic and environmental risk factors for breast cancer. Participants were asked about their exposure to different types of ALAN during sleep, and the responses were categorized into four groups: no light, small night light in the room, light outside the room, and light or TV in the room. The scientists used measurements of weight, height, waist, hip, and BMI taken at enrollment, as well as self-reported information about weight at enrollment and at follow-up, for an average of 5.7 years.

Women who slept with televisions or other lights on at night were more likely to be overweight or obese at the start of the study and were more likely to be overweight or obese during follow-up. Turning off the lights at night, along with a healthy diet and regular exercise, may help prevent women from becoming obese. (AA)

the quote: Park YM, White AG, Jackson CL, Weinberg CR, Sandler DB. 2019. Association of nighttime artificial light exposure during sleep with obesity risk in women. JAMA Intern Med; doi: 10.1001/jamaintermed.2019.0571 [Online 10 June 2019]. (a 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 cell types. They made this discovery after reducing SMARCB1 levels in hESCs. Since other scientists have found that damage to SMARCB1 during development causes CNS tumors in children, this work may help determine how these tumors form.

The authors provided context by explaining the critical role that SMARCB1 plays in brain development. During fetal development, SMARCB1 ensures that the correct genes are turned on or off at the right time. Using gene activity and DNA accessibility data, the research team showed that the protein does its job by turning off parts of the DNA called stem cell super-promoters. Super-enhancers typically increase transcription of genes that keep stem cells in an undifferentiated state, so when SMARCB1 turns off certain 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 to examine the relationship between early brain development and childhood cancers, particularly when SMARCB1 is mutated, as in atypical rhabdomyomas/teratomas. (youth)

the quote: Langer LF, Ward GM, Archer Tech. 2019. The tumor suppressor SMARCB1 inhibits super-enhancers to control hESC lineage determination. Elvi. doi: 10.7554/eLife.45672 [Online 29 April 2019].

(Aidin Alejo Abdala is an internal research training award [IRTA] Post-baccalaureate fellow in NIEHS Clinical Investigations for the Host Defense Group. Melissa Lee, PhD, is an IRTA Fellow in the NIEHS Biostatistics and Computational Biology Branch. Victoria Placentra is an IRTA Post-Baccalaureate Fellow in the NIEHS Mutagenesis and DNA Repair Group. Jesse Saffron, JD, is a writer and technical editor at the NIEHS Office of Communications and Public Liaison. Cheng Shu is a biologist at the NIEHS Metabolism, Genetics, and Ecology group.)

from San Jose News Bulletin https://sjnewsbulletin.com/environmental-factor-august-2019-inside-papers-of-the-month/