Papers of the Month
Intramural
By Nicholas Alagna, Sanya Mehta, Florencia Pascual, Victoria Placentra, and Saniya Rattan
DNTP finds common mycotoxin decreased body weight in rats
Perinatal exposure to low levels of the fungal toxin deoxynivalenol (DON) leads to mild toxicity in male and female offspring of Sprague Dawley rats, according to a report published by Division of the National Toxicology Program (DNTP) researchers and collaborators. In addition to using environmentally relevant doses, this study examined the potential of perinatal DON exposure to cause DNA damage that could lead to cancer later in life.
DON has been detected globally in grain-based food sources and in human urine, indicating exposure is widespread. Acute exposure to DON is associated with gastrointestinal symptoms, and its toxicity may be due to disruptions in cellular processes that are also crucial for embryonic development.
Pregnant rats were administered DON during gestation; offspring were exposed to the same doses. There were no treatment-related changes in the dams, but at the highest dose, DON exposure resulted in lower body weight in pups. There were no changes in the number of micronucleated, or immature, red blood cells in either the dam or offspring, suggesting DON does not produce genotoxicity via this mechanism. This study sets the stage for further investigation into the mechanistic basis of DON developmental toxicity. (FP)
Citation: Huang MC, Furr JR, Robinson VG, Betz L, Shockley K, Cunny H, Witt K, Waidyanatha S, Germolec D. 2021. Oral deoxynivalenol toxicity in Harlan Sprague Dawley (Hsd:Sprague Dawley® SD®) rat dams and their offspring. Food Chem Toxicol 148:111963.
A tool for visualizing county-level COVID-19 risk factors
The COVID-19 Pandemic Vulnerability Index (PVI) Dashboard, created by NIEHS researchers and collaborators at North Carolina State University and Texas A & M University, addresses knowledge gaps in pandemic risk at the county level. The PVI Dashboard uses the power of bioinformatics, statistics, and computational biology to easily visualize many COVID-19 risk parameters in communities.
The tool synthesizes dynamic, county-level information to track community spread, disease vulnerability, and outcomes. State and local officials can use the PVI Dashboard to guide responses. Twelve COVID-19 risk factors are represented as twelve slices of a pie chart, called the PVI profile. The tool provides a PVI profile for each of the 3,142 U.S. counties.
The data behind the PVI profiles are integrated from multiple sources including the Social Vulnerability Index (SVI) from the Centers for Disease Control and Prevention, and the COVID Tracking Project. This model is highly adaptable and is designed to incorporate new data and analytics as they emerge. The PVI Dashboard is a powerful tool for communities and public health agencies to use in allocating resources for pandemic response and could even inform vaccine distribution plans. (VP)
Citation: Marvel SW, House JS, Wheeler M, Song K, Zhou YH, Wright FA, Chiu WA, Rusyn I, Motsinger-Reif A, Reif DM. 2021. The COVID-19 Pandemic Vulnerability Index (PVI) Dashboard: monitoring county-level vulnerability using visualization, statistical modeling, and machine learning. Environ Health Perspect 129(1):17701.
Crystal structure of SARS-CoV-2 Nsp15 reveals new insights
NIEHS researchers and their colleagues used structural biology to study the endoribonuclease nonstructural protein 15 (Nsp15), an enzyme that cuts single- and double-strand viral RNA. Nsp15 is found in all coronaviruses and, through a complex process, helps the virus evade a host’s immune system. These findings may allow researchers to design therapeutics that bind to the Nsp15 active site of SARS-CoV-2, which could help treat COVID-19 cases.
Researchers used cryogenic electron microscopy, or cryo-EM, to visualize the structure of Nsp15. In addition to creating structural images, they performed molecular dynamics simulations to assess the biological function of the protein. They found that Nsp15 is stable and active when bound with RNA, but when it is not bound with RNA, Nsp15 constantly shifts and creates a wobble effect. Although the significance of the wobble is not completely understood, it may present a previously unexplored function.
Collectively, the researchers provide critical insight into the structure of SARS-CoV-2 Nsp15, and how it processes viral RNA. These data can aid in the development of effective inhibitors or new therapeutic targets against SARS-CoV-2 and help fight the global pandemic. (SR)
Citation: Pillon MC, Frazier MN, Dillard LB, Williams JG, Kocaman S, Krahn JM, Perera L, Hayne CK, Gordon J, Stewart ZD, Sobhany M, Deterding LJ, Hsu AL, Dandey VP, Borgnia MJ, Stanley RE. 2021. Cryo-EM structures of the SARS-CoV-2 endoribonuclease Nsp15 reveal insight into nuclease specificity and dynamics. Nat Commun 12(1):636.
Scientists link impaired mitochondrial autophagy with autoimmunity
Using a mouse model that lacked the gene IRGM1, a research team led by NIEHS researchers determined that a buildup of defective mitochondria led to an autoimmune condition that resembled Sjogren’s syndrome. In humans, Sjogren’s is characterized by dryness in the mouth, eyes, and other parts of the body. The research suggests a possible mechanism for how autoimmunity develops in people.
IRGM1 is the mouse version of a human gene called IRGM. These genes are responsible for autophagy, a process that removes malfunctioning organelles from the cell. In addition to displaying symptoms of autoimmunity, the scientists determined that IRGM1 knockout mice also had evidence for increased signaling by an inflammatory protein called type 1 interferon. Type 1 interferon has been linked to Sjogren’s syndrome and other autoimmune diseases, so they used molecular genetic techniques to prevent signaling by type 1 interferon in the mice. Doing so abolished the Sjogren’s syndrome-like symptoms.
The scientists also provided evidence that the DNA and RNA that spills out of faulty mitochondria elicit an immune response that causes an overproduction of type 1 interferon. They added that autoimmune damage is tissue-specific, arising from the DNA sensor cGAS in some, but not all tissues. (NA)
Citation: Rai P, Janardhan KS, Meacham J, Madenspacher JH, Lin WC, Karmaus PWF, Martinez J, Li QZ, Yan M, Zeng J, Grinstaff MW, Shirihai OS, Taylor GA, Fessler MB. 2021. IRGM1 links mitochondrial quality control to autoimmunity. Nat Immunol 22(3):312−321. (Article)
Histone crotonylation is crucial for early embryonic development
NIEHS researchers and their collaborators reported that an epigenetic modification known as histone crotonylation (Kcr) is necessary for the differentiation of human embryonic stem cells (hESCs) during early embryonic development. Epigenetics, the study of how genes are read and expressed, is known to be important in regulation of pluripotency and differentiation of hESCs in response to metabolic alterations, but the specific mechanisms are still unclear.
Using immunofluorescence and quantitative proteomic analyses, the authors showed that histone Kcr, a specific epigenetic modification to the proteins that package DNA inside chromosomes, increases during a metabolic switch from glycolysis to oxidative phosphorylation early in the process by which hESCs differentiate into mesoendodermal cells. This increase induces mesoendodermal gene expression and promotes mesoendoderm differentiation in vitro and in vivo. For the first time, this research team’s data directly links metabolic programming to histone Kcr and further demonstrates that Kcr plays a role in promoting mesoendodermal gene expression.
According to the authors, these findings have important translational implications for human diseases affecting organs that arise from the endoderm germ layer, including the liver, lungs, pancreas, and digestive tract. (SM)
Citation: Fang Y, Xu X, Ding J, Yang L, Doan MT, Karmaus PWF, Snyder NW, Zhao Y, Li JL, Li X. 2021. Histone crotonylation promotes mesoendodermal commitment of human embryonic stem cells. Cell Stem Cell; doi: 10.1016/j.stem.2020.12.009 [Online 8 January 2021].
(Nicholas Alagna is an Intramural Research Training Award [IRTA] postbaccalaureate fellow in the NIEHS Mechanisms of Mutation Group. Sanya Mehta is an IRTA postbaccalaureate fellow in the NIEHS Matrix Biology Group. Florencia Pascual, Ph.D., is a scientist in the NIEHS Pediatric Neuroendocrinology Group. Victoria Placentra is an IRTA postbaccalaureate fellow in the NIEHS Mutagenesis and DNA Repair Regulation Group. Saniya Rattan, Ph.D., is an IRTA postdoctoral fellow in the NIEHS Reproductive Developmental Biology Group.)
