Environmental Factor - March 2020: Intramural Papers of the Month

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Environmental Factor - March 2020: Intramural Papers of the Month

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Intramural By Aidin Alejo Abdala, Robin Arnette, Nicholas Alagna, Saniya Rattan, and Dahea You

Researchers at the Division of the National Toxicology Program (NTP) at NIEHS have comprehensively characterized an Echinacea purpurea root extract for safety testing. Using DNA and chemistry-based techniques, they authenticated an E. purpurea extract and identified numerous constituents. The proposed approach could be adapted to other botanical dietary supplements.

Supplement use is widespread and increasing. However, there is a significant knowledge gap in the safe use of these products. Due to the popularity of E. purpurea, the team selected it for safety testing using rodent models. To select an authentic material that is representative of what humans are exposed to, the scientists procured multiple lots of Echinacea. They screened the products using nontargeted chemical fingerprinting techniques and chemometric analysis of data to select an extract that is similar to standard reference material. The candidate lot was subsequently authenticated using chromatographic and DNA barcoding methods and characterized to confirm the absence of contaminants and presence of Echinacea-specific constituents. Among many constituents found, the key components were caftaric acid, chicoric acid, chlorogenic acid, and dodeca-2(E),4(E),8(E),10 (E/Z)-tetraenoic acid isobutylamide. (SR)

Citation : Waidyanatha S, Pierfelice J, Cristy T, Mutlu E, Burback B, Rider CV, Ryan K . 2020. A strategy for test article selection and phytochemical characterization of Echinacea purpurea extract for safety testing. Food Chem Toxicol 137:111125.

NIEHS researchers developed a groundbreaking software to estimate cell population and cell-specific gene expression profiles (GEPs) from heterogenous tissue samples. Known as Complete Deconvolution for Sequencing Data (CDseq), the software only requires bulk RNAseq data as an input. Current deconvolution methods are partial, meaning they require either cell type proportions or GEPs to provide the other as output. Furthermore, obtaining the necessary input using partial deconvolution methods requires single cell RNAseq or flow cytometry, both of which can be technically challenging and expensive.

To assess the accuracy of CDseq, the new method was compared with current partial deconvolution methods using a variety of datasets, from GEPs of synthetic and pure cell lines, to samples of peripheral blood mononuclear cells. CDseq performed at the same level or better than all other methods to which it was compared. It is an innovative alternative to current heterogenous sample analysis methods. Its application is an important step toward better and more practical genomic analysis of tissue samples. (AAA)

Citation : Kang K, Meng Q, Shats I, Umbach DM, Li M, Li Y, Li X, Li L . 2019. CDSeq: A novel complete deconvolution method for dissecting heterogeneous samples using gene expression data. PLoS Comput Biol 15(12):e1007510.

Epithelial membrane protein 2 (EMP2) plays a critical role in controlling neutrophil traffic into the airway by regulating adhesion molecules on the surface of alveolar epithelial type 1 (AT1) cells according to NIEHS scientists and their collaborators. AT1 cells are sites of solute transport and gas exchange. Neutrophils, which are immune cells critical for host defense in the lung, are also known to cause bystander tissue damage when they enter the lung. Neutrophils may affect survival in diseases such as bacterial pneumonia.

Mice lacking the EMP2 gene displayed reduced migration of neutrophils from lung tissue into the airspace after inhalational exposure to various types of bacteria. Consequently, mice that were deficient in the EMP2 gene had less systemic inflammation and lung injury and better overall survival compared with mice having a normal EMP2 gene. Mechanistic studies in AT1 cells revealed that EMP2 deficiency alters migration of neutrophils across the epithelium by dysregulating AT1 expression of proteins called caveolins, which are important for cell membrane organization and function. Taken together, this study improved scientists’ understanding of immune-mediated lung damage by defining the function of EMP2 in the lung and by identifying a novel role for AT1 cells as gatekeepers of lung immune responses. (DY)

Citation : Lin WC, Gowdy KM, Madenspacher JH, Zemans RL, Yamamoto K, Lyons-Cohen M, Nakano H, Janardhan K, Williams CJ, Cook DN, Mizgerd JP, Fessler MB . 2020. Epithelial membrane protein 2 governs transepithelial migration of neutrophils into the airspace. J Clin Invest 130(1):157–170.

NIEHS researchers determined that inhibiting an organelle called the proteasome, which breaks down damaged proteins, creates a distinct chromatin environment marked by the spreading of trimethyl histone H3 lysine 4 (H3K4me3) into the gene body. This chromatin environment allows RNA polymerase II (RNA Pol II) transcription, primarily of genes that inhibit cancer cell proliferation. The research demonstrated the crucial function that protein degradation has in cancer cell survival.

The scientists performed gene expression analysis and chromatin immunoprecipitation (ChIP) followed by sequencing (ChIP-seq) in MCF-7 breast cancer cells treated with MG132, a proteasome inhibitor. They observed a distinct distribution of multiple epigenetic marks ― in this case, histone modifications ― in proteasome-inhibited cells. By modulating the chromatin environment, these epigenetic modifications facilitated RNA Pol II transcription of genes that inhibited the cancer phenotype. These fundamental studies have important implications for the mechanism(s) of action by proteasome inhibitors and their use as anticancer therapies. The findings also provide a more comprehensive understanding of cancer biology and an expanded database of probable therapeutic targets. (NA)

Citation : Kinyamu HK, Bennett BD, Bushel PR, Archer TK . 2020. Proteasome inhibition creates a chromatin landscape favorable to RNA Poll II processivity. J Biol Chem 295(5):1271–1287.

Scientists at NIEHS and the National Cancer Institute found a small positive, but not statistically significant, association between genital powder use and ovarian cancer. The increase in risk may be limited to women who have not had a hysterectomy or tubal ligation. The study used data from 252,745 women in a pooled analysis of four large cohorts.

Previous studies of the association between use of talcum powder and ovarian cancer were retrospective and may have been biased if women with cancer were more likely than those without cancer to report their exposure. The current prospective study avoided this bias because the data on powder use was collected before any participants developed ovarian cancer. The study did not evaluate talc specifically because some of the studies asked about powders more generically. The authors stressed that while they accounted for many factors related to exposure and ovarian cancer, there might be other factors that influenced the observed associations.

Ovarian cancer is rare, so even this large study may not have been big enough to detect a small change in risk. Participants in these studies will continue to be followed to track ovarian cancer development. (RA)

Citation : O’Brien KM, Tworoger SS, Harris HR, Anderson GL, Weinberg CR, Trabert B, Kaunitz AM, D’Aloisio AA, Sandler DP, Wentzensen N . 2020. Association of powder use in the genital area with risk of ovarian cancer. JAMA 323(1):49–59.

(Aidin Alejo Abdala is an Intramural Research Training Award [IRTA] postbaccalaureate fellow in the NIEHS Clinical Investigation of Host Defense Group. Nicholas Alagna is an IRTA fellow in the NIEHS Mechanisms of Mutation Group. Saniya Rattan, Ph.D., is an IRTA fellow in the NIEHS Reproductive Developmental Biology Group. Dahea You, Pharm.D., Ph.D., is an IRTA postdoctoral fellow in the NTP Biomolecular Screening Branch.)

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