Research funded by grants
PFAS linked with liver injury in children
Exposure to per- and polyfluoroalkyl substances (PFAS) in the womb may increase liver injury risk in children, according to NIEHS-funded researchers. This study is the first to examine the impact of early life exposures to a PFAS mixture on child liver injury. PFAS, a large group of synthetic chemicals found in a variety of consumer products, have been linked to immune dysfunction, altered metabolism, brain development, and certain cancers.
The study used data from 1,105 mothers and their children enrolled in the Human Early-Life Exposome, or HELIX, study in Europe. Using computational modeling, the scientists found that higher exposures to PFAS during pregnancy were associated with higher levels of liver enzymes in children. High liver enzyme levels may point to nonalcoholic fatty liver disease (NAFLD). The researchers also identified a profile for children at high risk for liver injury, characterized by high prenatal PFAS exposures.
Citation: Stratakis N, Conti DV, Jin R, Margetaki K, Valvi D, Siskos AP, Maitre L, Garcia E, Varo N, Zhao Y, Roumeliotaki T, Vafeiadi M, Urquiza J, Fernandez-Barres S, Heude B, Basagana X, Casas M, Fossati S, Grazuleviciene R, Andrusaityte S, Uppal K, McEachan RRC, Papadopoulou E, Robinson O, Haug LS, Wright J, Vos MB, Keun HC, Vrijheid M, Berhane KT, McConnell R, Chatzi L. 2020. Prenatal exposure to perfluoroalkyl substances associated with increased susceptibility to liver injury in children. Hepatology 72(5):1758–1770. (Synopsis(https://factor.niehs.nih.gov/2020/10/papers/dert/#a1))
New layer of control in gene expression
In an NIEHS-funded study, researchers uncovered a previously unknown way that genes code for proteins. Rather than directions going one way from DNA through messenger RNA (mRNA) to proteins, the study showed that RNA can modify how DNA is transcribed into mRNA and translated to produce proteins.
Using mouse stem cells, the scientists found that mRNA modifies how DNA is transcribed using a reversible chemical reaction called methylation, which can change the activity of a DNA segment without changing the sequence. The researchers identified and characterized several proteins that recognized the methylated mRNA. They also discovered a group of RNAs called chromosome-associated regulatory RNAs (carRNAs) that used the same methylation process and controlled how DNA was stored and transcribed. The team found that a specific methylation modification, N6-methyladenosine, served as a switch to control carRNA levels, which regulated DNA transcription.
Citation: Liu J, Dou X, Chen C, Chen C, Liu C, Xu MM, Zhao S, Shen B, Gao Y, Han D, He C. 2020. N 6-methyladenosine of chromosome-associated regulatory RNA regulates chromatin state and transcription. Science 367(6477):580–586. (Synopsis(https://factor.niehs.nih.gov/2020/4/papers/dert/#a1))
TOP1 is critical for protecting neurons from neurodegeneration
Loss of the enzyme topoisomerase 1 (TOP1) leads to DNA damage in neurons and neurodegeneration, according to an NIEHS-funded study. TOP1 plays an important role in facilitating the expression of long genes that are important for neuronal function. The data suggest that TOP1 maintains proper gene function in the central nervous system.
The researchers deleted TOP1 in mouse neurons and examined behavior, development, and underlying indicators of neurodegeneration, such as inflammation. Mice lacking TOP1 showed signs of early neurodegeneration, with brains 3.5-times smaller at postnatal day 15 compared with controls. Although neurons developed normally, mice without TOP1 showed motor deficits, exhibited lower levels of nicotinamide adenine dinucleotide (NAD-plus) — a compound critical in energy metabolism — and died prematurely. However, when these mice received supplemental NAD-plus, they lived 30% longer, had less inflammation, and showed improved neuronal survival.
Citation: Fragola G, Mabb AM, Taylor-Blake B, Niehaus JK, Chronister WD, Mao H, Simon JM, Yuan H, Li Z, McConnell MJ, Zylka MJ. 2020. Deletion of topoisomerase 1 in excitatory neurons causes genomic instability and early onset neurodegeneration. Nat Commun 11(1):1962. (Synopsis(https://factor.niehs.nih.gov/2020/6/papers/dert/#a4))
XPA protein bends DNA and locates DNA damage
NIEHS grantees found that a protein known as XPA bends DNA and pauses in response to DNA damage, revealing the location of damaged DNA and potentially promoting the recruitment of DNA repair proteins. Using single molecule experiments and imaging techniques, the researchers observed the biochemistry of a living cell.
The researchers used a new method to calculate the molecular weight of small proteins bound to DNA and tracked proteins involved in DNA repair in 3D using real-time single molecule imaging. XPA cycled through three distinct states on DNA: rapidly hopping over long distances of the DNA strand; slowly sliding over short ranges of DNA while bending local DNA regions; and pausing and forming complexes with bent DNA. XPA paused more frequently in the presence of more DNA damage. The work provided insight into a new damage sensor role for XPA.
Citation: Beckwitt EC, Jang S, Detweiler IC, Kuper J, Sauer F, Simon N, Bretzler J, Watkins SC, Carell T, Kisker C, Van Houten B. 2020. Single molecule analysis reveals monomeric XPA bends DNA and undergoes episodic linear diffusion during damage search. Nat Commun 11(1):1356. (Synopsis(https://factor.niehs.nih.gov/2020/5/papers/dert/#a2))
Unanticipated response to estrogen at the single cell level
NIEHS grantees found that individual cells in a population respond differently to estrogen stimulation at both the level of single cells and alleles, which are other possible forms of a gene. These differences were not explained by estrogen receptor levels in the cells or receptor activation status.
The researchers treated human breast cancer cells with estrogen and examined two genes, GREB1 and MYC, whose activities are regulated by estrogen. Unexpectedly, individual cells exhibited large differences in the level of gene activation, even between alleles within the same cell. The scientists used automated high-throughput technologies to test small molecule inhibitors of the estrogen receptor regulators. One inhibitor, called MS049, markedly increased the response of individual alleles to estrogen. The researchers altered estrogenic response by inhibiting estrogen receptor regulators, establishing a previously unrecognized regulation path for estrogen to activate genes at the single cell level.
Citation: Stossi F, Dandekar RD, Mancini MG, Gu G, Fuqua SAW, Nardone A, De Angelis C, Fu X, Schiff R, Bedford MT, Xu W, Johansson HE, Stephan CC, Mancini MA. 2020. Estrogen-induced transcription at individual alleles is independent of receptor level and active conformation but can be modulated by coactivators activity. Nucleic Acids Res 48(4):1800–1810. (Synopsis(https://factor.niehs.nih.gov/2020/4/papers/dert/#a3))
E-cigs linked to lung cancer and bladder changes in mice
NIEHS grantees showed that mice exposed to e-cigarette smoke (ECS) were more likely to develop lung adenocarcinomas, a type of lung cancer. They also found that exposed mice had higher levels of bladder urothelial hyperplasia, an abnormal increase in epithelial cells that can precede development of bladder tumors.
The researchers exposed one group of mice to ECS aerosols generated from e-juice containing nicotine and compared them to a second group of mice exposed to a control aerosol without ECS. A third group of mice was exposed only to filtered air. Of the ECS mice, 22.5% developed lung adenocarcinomas and 57.5% developed urothelial hyperplasia. Mice with ECS-induced lung adenocarcinomas were not more prone to developing urothelial hyperplasia, which suggested that the two outcomes were divergent events and might involve different mechanisms.
Citation: Tang MS, Wu XR, Lee HW, Xia Y, Deng FM, Moreira AL, Chen LC, Huang WC, Lepor H. 2019. 2019. Electronic-cigarette smoke induces lung adenocarcinoma and bladder urothelial hyperplasia in mice. Proc Natl Acad Sci U S A 116(43):21727–21731. (Synopsis(https://factor.niehs.nih.gov/2020/1/papers/dert/#a1))
Astrocytes' role in inflammation and neurodegeneration
NIEHS grantees identified a novel pathway that controls the metabolic response of astrocytes, which are brain and spinal cord cells essential to maintaining central nervous system (CNS) health. Although astrocytes perform various functions, such as providing nerve cells with nutrients, they have been linked to CNS inflammation and multiple sclerosis (MS).
Using a mouse model of MS, researchers found that during the progressive phase of the disease, brain astrocytes switched on metabolic pathways that activated a protein called the mitochondrial antiviral signaling (MAVS) protein. It led to activation of several proinflammatory genes, triggering inflammation in the brain and spinal cord. If the scientists gave the mice the drug miglustat before the onset of MS, they were able to suppress MAVS activation and subsequent inflammation. The findings suggest a new role for MAVS in CNS inflammation and a potential therapeutic target for MS.
Citation: Chao CC, Gutierrez-Vazquez C, Rothhammer V, Mayo L, Wheeler MA, Tjon EC, Zandee SEJ, Blain M, de Lima KA, Takenaka MC, Avila-Pacheco J, Hewson P, Liu L, Sanmarco LM, Borucki DM, Lipof GZ, Trauger SA, Clish CB, Antel JP, Prat A, Quintana FJ. 2019. Metabolic control of astrocyte pathogenic activity via cPLA2-MAVS. Cell 179(7):1483–1498.e22. (Synopsis(https://factor.niehs.nih.gov/2020/2/papers/dert/#a3))
Mouse gene mutation drives inflammation and tumors
NIEHS-funded researchers found that a mutation in the ultraviolet irradiation resistance−associated gene (UVRAG), which is involved in cell regulation, can disrupt autophagy in mice. Autophagy is the process of removing damaged cells so the body can regenerate newer cells. The scientists say the UVRAG mutation causes increased inflammatory response and tumor development. The study provides the first genetic evidence connecting UVRAG suppression to autophagy regulation, inflammation, and cancer predisposition.
The researchers generated mice that expressed UVRAG with a frameshift mutation, which is a deletion or insertion in DNA that shifts the way the sequence is read. After inducing sepsis or intestinal colitis, they found that mice with the UVRAG mutation displayed increased inflammatory responses in both conditions and increased spontaneous tumor development compared with wild-type mice. The results indicate UVRAG could be one reason people are more susceptible to cancers as they age.
Citation: Quach C, Song Y, Guo H, Li S, Maazi H, Fung M, Sands N, O'Connell D, Restrepo-Vassalli S, Chai B, Nemecio D, Punj V, Akbari O, Idos GE, Mumenthaler SM, Wu N, Martin SE, Hagiya A, Hicks J, Cui H, Liang C. 2019. A truncating mutation in the autophagy gene UVRAG drives inflammation and tumorigenesis in mice. Nat Commun 10(1):5681. (Synopsis(https://factor.niehs.nih.gov/2020/2/papers/dert/#a4))
Flame retardant alters sperm, may affect future generations
Exposure to polybrominated biphenyl (PBB) 153, a type of brominated flame retardant, alters DNA methylation in sperm, according to NIEHS grantees. DNA methylation refers to heritable changes in gene expression that occur with no alteration in the DNA sequence. Because PBB153 is toxic to living organisms following direct exposure, the study suggests it may also harm future generations.
The results of a Michigan PBB study showed that PBB153 was associated with gene methylation events in men’s sperm. Based on this information, the research team conducted sperm studies and determined that exposure to PBB153 decreased methylation at regions of DNA that control imprinted genes, which are essential for fetal growth and play an important role in other aspects of development. These effects could explain some of the endocrine-related health effects that have been observed among children of PBB-exposed parents.
Citation: Greeson KW, Fowler KL, Estave PM, Thompson SK, Wagner C, Edenfield RC, Symosko KM, Steves AN, Marder EM, Terrell ML, Barton H, Koval M, Marcus M, Easley CA 4th. 2020. Detrimental effects of flame retardant, PBB153, exposure on sperm and future generations. Sci Rep 10(1):8567. (Synopsis(https://factor.niehs.nih.gov/2020/7/papers/dert/#a4))
Air pollution linked to cardiometabolic disease, effects reversible
NIEHS grantees determined that in mice, air pollution may play a role in the development of cardiometabolic diseases, such as diabetes, with effects comparable to eating a high-fat diet (HFD). They also established that effects were reversed when exposure to air pollution stopped.
The scientists divided male mice into three categories: those that received clean filtered air; those exposed to concentrated particulate matter 2.5 air pollution; and those that received clean filtered air and were fed an HFD. After 14 weeks, team members measured insulin resistance and glucose levels and assessed epigenetic changes, or chemical tags, that attach to DNA and affect gene expression.
Air pollution exposure was comparable to eating an HFD. Mice in the air pollution and HFD groups had impaired insulin resistance, high glucose, and reduced metabolism. After removing air pollution from the environment, health and epigenetic changes reversed within eight weeks.
Citation: Rajagopalan S, Park B, Palanivel R, Vinayachandran V, Deiuliis JA, Gangwar RS, Das LM, Yin J, Choi Y, Al-Kindi S, Jain MK, Hansen KD, Biswal S. 2020. Metabolic effects of air pollution exposure and reversibility. J Clin Invest 130(11):6034–6040. (Synopsis(https://factor.niehs.nih.gov/2020/10/papers/dert/#a3))
Mineralocorticoid receptors determine CA2 neuron cell fate
NIEHS researchers learned that mineralocorticoid receptors (MRs) control the gene profiles of neurons within the CA2 brain region, which is associated with learning and memory. MRs are a type of steroid receptor activated by corticosteroid hormones. The findings revealed the essential roles of MRs in the development and maintenance of CA2 neurons, as well as CA2-related behaviors.
In response to environmental stress, the body secretes corticosteroids that bind to MRs or glucocorticoid receptors and that induce gene expression changes in the brain. The CA2 region of the mouse and human hippocampus is enriched with MRs. Neuronal deletion of MRs at embryonic, early postnatal development, or adulthood stages in mice led to significantly reduced expression of CA2 molecular markers. Mice with CA2-targeted deletion of MRs showed disrupted social behavior and altered responses to novel objects. Therefore, MRs control both the identity and function of CA2 neurons.
Citation: McCann KE, Lustberg DJ, Shaughnessy EK, Carstens KE, Farris S, Alexander GM, Radzicki D, Zhao M, Dudek SM. 2019. Novel role for mineralocorticoid receptors in control of a neuronal phenotype. Mol Psychiatry; doi: 10.1038/s41380-019-0598-7 [Online 19 November 2019]. (Synopsis(https://factor.niehs.nih.gov/2020/1/papers/dir/#a2))
Gut bacteria, human cells together make key energy molecule
NIEHS researchers discovered a novel symbiotic interaction between mammalian cells and bacteria that boosts nicotinamide adenine dinucleotide biosynthesis in host cells. NAD is a cofactor that exists in all cell types and is necessary for life. Decreased levels of NAD are associated with aging, and elevated levels of its biosynthesis are important to sustain the higher metabolic needs of tumors.
The researchers showed that cancer cell lines infected with Mycoplasma hyorhinis were protected against toxicity by nicotinamide phosphoribosyl transferase (NAMPT) inhibitors, which halt NAD biosynthesis. This same effect was observed in vivo, when infected versus noninfected cancer cells were injected in mice. Using a variety of screens and techniques, they showed that this resistance was the result of bacteria providing alternative NAD precursors to mammalian cells through the bacterial nicotinamidase PncA, bypassing the NAMPT-dependent pathway.
Citation: Shats I, Williams JG, Liu J, Makarov MV, Wu X, Lih FB, Deterding LJ, Lim C, Xu X, Randall TA, Lee E, Li W, Fan W, Li J-L, Sokolsky M, Kabanov AV, Li L, Migaud ME, Locasale JW, Li X. 2020. Bacteria boost mammalian host NAD metabolism by engaging the deamidated biosynthesis pathway. Cell Metab 31(3):564−579.e7. (Synopsis(https://factor.niehs.nih.gov/2020/5/papers/dir/#a3)) (Story)
How high-fat diet may lead to liver disease
New insights into how the liver adapts to an HFD may lead to novel treatments for obesity-related diseases such as NAFLD, according to a study by NIEHS researchers. They found that long-term consumption of a diet high in saturated fat led to dramatic reprogramming of gene regulation in the mouse liver.
NAFLD involves the buildup of excessive fat in the liver of an individual who is not a heavy user of alcohol, increasing the risk of liver damage. When the scientists fed mice an HFD, the mice became obese and showed other changes similar to metabolic syndrome in humans. Moreover, their livers became fatty and showed wide-ranging abnormalities at both molecular and cellular levels. The liver’s adaptation to the fat-rich diet was mediated by a protein called hepatocyte nuclear factor 4 alpha.
Citation: Qin Y, Grimm SA, Roberts JD, Chrysovergis K, Wade PA. 2020. Alterations in promoter interaction landscape and transcriptional network underlying metabolic adaptation to diet. Nat Commun 11(1):962. (Synopsis(https://factor.niehs.nih.gov/2020/4/papers/dir/#a3)) (Story)
Prevalence of autoimmunity marker is on the rise in the U.S.
An NIEHS study reported a concerning rise in the prevalence of antinuclear antibodies (ANAs), which are commonly used biomarkers for autoimmunity. ANAs, which are produced by a person’s own immune system, bind to and sometimes attack healthy cells. This study is the first to evaluate ANA changes over time in a representative sampling of the U.S. population. The findings may indicate an increase in autoimmune diseases.
Team members used the National Health and Nutrition Examination Survey to analyze serum ANAs in 14,211 participants aged 12 years and older from three time periods. ANA prevalence increased as follows.
- 11% from 1988 to 1991.
- 11.5% from 1999 to 2004.
- 15.9% from 2011 to 2012.
The researchers found the largest ANA increases in adolescents, males, non-Hispanic whites, and adults older than 50 years compared with other subgroups.
Citation: Dinse GE, Parks CG, Weinberg CR, Co CA, Wilkerson J, Zeldin DC, Chan EKL, Miller FW. 2020. Increasing prevalence of antinuclear antibodies in the United States. Arthritis Rheumatol 72(6):1026−1035. (Synopsis(https://factor.niehs.nih.gov/2020/6/papers/dir/#a4)) (Story)
Ubiquitin regulates removal of TOP2 DNA-protein crosslinks via TDP2
Ubiquitin (Ub) stimulates the removal of topoisomerase 2 DNA-protein crosslinks (TOP2-DPCs) by tyrosyl-DNA phosphodiesterase 2 (TDP2) according to NIEHS researchers and their collaborators in Spain. The team also reported that TDP2 single nucleotide polymorphisms can disrupt the TDP2-Ub interface. Because TDP2 works with a protein called ZATT to remove dangerous DNA-protein crosslinks, the work is important for understanding how cells handle this type of DNA damage.
Using X-ray crystallography and small angle X-ray scattering analysis, the scientists examined how Ub-dependent links and TDP2 function as they relate to DNA repair and other cellular pathways. Previous studies hypothesized that TDP2 interacts with K48-Ub chains to promote recruitment to TOP2-DPCs that are repaired using a proteasome-mediated TOP2 degradation pathway. However, the authors showed that TDP2 preferentially binds to K63-linked Ub3 and associates with K27 and K63 poly-Ub chains.
Citation: Schellenberg MJ, Appel CD, Riccio AA, Butler LR, Krahn JM, Liebermann JA, Cortes-Ledesma F, Williams RS. 2020. Ubiquitin stimulated reversal of topoisomerase 2 DNA-protein crosslinks by TDP2. Nucleic Acids Res 48(11):6310–6325. (Synopsis(https://factor.niehs.nih.gov/2020/7/papers/dir/#a4))
Tankyrase required for normal development of mouse embryo
NIEHS researchers and their collaborators concluded that a protein called tankyrase serves a critical role in mammalian embryonic genome activation (EGA). Using an in vitro culture system, the researchers identified and characterized tankyrase, a factor that allows EGA to occur. The characterization of tankyrase during the oocyte-to-embryo transition fills a gap in knowledge about how factors are activated in mammalian oocytes and early embryos and may lead to improved strategies for treating infertility.
Using a mouse model, the scientists depleted tankyrase from the embryos and observed that they could not perform EGA and stopped developing. They also found that tankyrase is necessary for gene transcription, protein translation, DNA damage repair, and modulation of beta-catenin in the early embryo. This study found a new role for tankyrase during normal development, revealing an essential function of this protein during the oocyte-to-embryo transition.
Citation: Gambini A, Stein P, Savy V, Grow EJ, Papas BN, Zhang Y, Kenan AC, Padilla-Banks E, Cairns BR, Williams CJ. 2020. Developmentally programmed tankyrase activity upregulates beta-catenin and licenses progression of embryonic genome activation. Dev Cell 53(5):545–560.e7. (Synopsis(https://factor.niehs.nih.gov/2020/7/papers/dir/#a3)) (Story)
CLP1 is a critical negative regulator of tRNA processing
NIEHS researchers showed that an enzyme called CLP1 plays an important role in transfer RNA (tRNA) processing by regulating the ligation of tRNAs. They also demonstrated that mature, functional tRNAs are generated from pre-tRNAs through a process called TSEN, or (tRNA splicing endonuclease)−mediated splicing of introns. Mutations in CLP1 and the TSEN complex often lead to severe neurological disorders.
Using a technique that allowed Escherichia coli to produce several proteins at once, the scientists expressed and reconstituted the TSEN protein complex, which cleaved tRNA. TSEN complex alone was sufficient for removing tRNA introns, but CLP1, a binding partner for TSEN, was needed to correctly regulate the ligation step that generates mature tRNAs and tRNA intronic circular RNAs (tricRNAs). Genetic knockdown of CLP1 led to increases in mature tRNAs and tricRNAs, which suggested that CLP1 acts as a negative modulator of tRNA processing.
Citation: Hayne CK, Schmidt CA, Haque MI, Matera AG, Stanley RE. 2020. Reconstitution of the human tRNA splicing endonuclease complex: insight into the regulation of pre-tRNA cleavage. Nucleic Acids Res 48(14):7609–7622. (Synopsis(https://factor.niehs.nih.gov/2020/8/papers/dir/#a2))
New tool predicts chemical effects on human body
Researchers at NIEHS and the National Toxicology Program developed the Tox21BodyMap to predict which organs in the human body may be affected by a chemical. The tool will help scientists generate novel hypotheses to test, prioritize chemicals for toxicity testing, and identify knowledge gaps.
To identify organs that could potentially be affected by a chemical, Tox21BodyMap used data from 971 high-throughput screening assays that evaluated approximately 10,000 unique chemicals. Specifically, it combined information about which gene an assay targets, how highly expressed that gene is in a human organ, and at what tested concentrations a chemical generated a positive assay result. The result was an overall picture of chemical bioactivity. The Tox21BodyMap provided multiple visualizations of the data, highlighting target organs on a map of the body, as well as showing a web of network connections and providing downloadable data.
Citation: Borrel A, Auerbach SS, Houck KA, Kleinstreuer NC. 2020. Tox21BodyMap: a webtool to map chemical effects on the human body. Nucleic Acids Res 48(W1):W472–W476. (Synopsis(https://factor.niehs.nih.gov/2020/8/papers/dir/#a4))
Maternal fatty acids level associated with newborn size
In pregnant women, polyunsaturated fatty acids and their metabolic derivatives called eicosanoids are associated with infant size at delivery, according to NIEHS scientists and their collaborators. This work also provides novel longitudinal characterization of eicosanoids in blood plasma during different gestational ages of pregnancy. The results link inflammatory eicosanoids with adverse fetal growth outcomes.
The blood plasma concentration of polyunsaturated fatty acids, including omega-3 and omega-6, in study participants was found to be higher in cases of low birth weight and lower in cases of higher birth weight. Lower and higher birth weights were defined as equal to or less than the 10th percentile and equal to or greater than the 90th percentile for gestational age, respectively. In addition, certain eicosanoids, which are known to derive from inflammatory processes from these fatty acids, were found to be exclusively higher in pregnancy cases, which resulted in low birth weight.
Citation: Welch BM, Keil AP, van't Erve TJ, Deterding LJ, Williams JG, Lih FB, Cantonwine DE, McElrath TF, Ferguson KK. 2020. Longitudinal profiles of plasma eicosanoids during pregnancy and size for gestational age at delivery: a nested case-control study. PLoS Med 17(8):e1003271. (Synopsis(https://factor.niehs.nih.gov/2020/10/papers/dir/#a2))
High-fat diet rewires brain, encourages fatty food consumption
Researchers at NIEHS and collaborators at the National Institute of Diabetes and Digestive and Kidney Diseases uncovered the neural basis behind the drive to select calorie-rich foods over nutritionally balanced diets. The findings partly explain the difficulty of dieting.
One group of mice received a standard diet (SD) consisting of regular chow, and another group ate an HFD. When the HFD mice were switched to a SD, they refused to eat. Even after fasting to stimulate their appetites, HFD mice preferred fatty food, rather than regular chow.
However, when HFD mice were switched to a SD, regular chow no longer fully alleviated the response. The authors also saw that dopamine signaling, which is responsible for the pleasurable feelings from eating, were significantly diminished in the SD mice following HFD exposure.
Citation: Mazzone CM, Liang-Guallpa J, Li C, Wolcott NS, Boone MH, Southern M, Kobzar NP, Salgado IA, Reddy DM, Sun F, Zhang Y, Li Y, Cui G, Krashes MJ. 2020. High-fat food biases hypothalamic and mesolimbic expression of consummatory drives. Nat Neurosci 23(10):1253–1266. (Synopsis(https://factor.niehs.nih.gov/2020/10/papers/dir/#a4))
New tool links faulty mtDNA replication to aging and disease
To uncover novel deletion patterns in mitochondrial DNA (mtDNA), NIEHS researchers and their collaborators developed LostArc, an ultrasensitive method for quantifying deletions in circular mtDNA molecules. The team used the technique to reveal links between mitochondrial DNA replication, aging, and mitochondrial disease.
A mutation in POLG, a nuclear gene responsible for maintaining the mitochondrial genome, is known to be the most common cause of mitochondrial disease, a condition in which the mitochondria fail to produce enough energy for the body to function properly.
The scientists analyzed mtDNA from skeletal muscle biopsies of 41 patients with mitochondrial disease with wild-type and mutated POLG. They used LostArc to detect loss of mtDNA segments by mapping split-reads in the samples to a normal mtDNA reference. Thirty-five million deletion segments were detected in the biopsies. They spanned more than 470,000 unique segments, 99% of which were novel.
Citation: Lujan SA, Longley MJ, Humble MH, Lavender CA, Burkholder A, Blakely EL, Alston CL, Gorman GS, Turnbull DM, McFarland R, Taylor RW, Kunkel TA, Copeland WC. 2020. Ultrasensitive deletion detection links mitochondrial DNA replication, disease, and aging. Genome Biol 21(1):248. (Synopsis(https://factor.niehs.nih.gov/2020/11/papers/dir/#a3))
Ancestry affects reprogramming of fibroblasts to iPSCs
Individual heterogeneity, or genetic variability among samples, can substantially affect reprogramming of somatic cells into induced pluripotent stem cells (iPSCs), according to NIEHS scientists and their collaborators. iPSCs are stem cells that are derived from differentiated cells, such as fibroblasts, and they can both self-renew and are pluripotent, meaning they can be differentiated into other cell types. In a previous publication, the research team obtained fibroblasts from healthy diverse donors and observed that each person’s fibroblasts had consistent differences in the ability to be reprogrammed to iPSCs. Ancestry was identified as a large contributing factor.
Using 72 dermal fibroblast-iPSCs from self-identified African Americans and White Americans, the researchers found ancestry-dependent and ancestry-independent genes associated with reprogramming efficiency. They also added 36 new genomic profiles of African American fibroblast-iPSCs pairs to publicly available databases, which will help address the underrepresentation of genomic data from non-European groups.
Citation: Bisogno LS, Yang J, Bennett BD, Ward JM, Mackey LC, Annab LA, Bushel PR, Singhal S, Schurman SH, Byun JS, Napoles AM, Perez-Stable EJ, Fargo DC, Gardner K, Archer TK. 2020. Ancestry-dependent gene expression correlates with reprogramming to pluripotency and multiple dynamic biological processes. Sci Adv 6(47):eabc3851. (Synopsis(https://factor.niehs.nih.gov/2021/1/papers/dir/#a2))
New strategy predicts polycyclic aromatics toxicity
Researchers in the Division of the National Toxicology Program (DNTP) at NIEHS successfully compiled a rich resource to explore data on polycyclic aromatic compound (PACs) toxicity. This data-driven approach to contextualizing PAC hazard characterization allows researchers to predict eight different toxicity profiles of various PACs and other classes of compounds.
PACs are a structurally diverse class of human-made toxicants found widely in the environment. Unfortunately, information about human exposure and health effects of PACs is limited. To facilitate greater understanding of PAC toxicity in a cost-effective manner, DNTP researchers created an automated approach to identify PAC structures using computer workflows, algorithms, and clusters. Using existing data on similar compounds, the scientists categorized PACs based on structure and hazard characterization. The analysis results are available and searchable through an interactive web application.
Citation: Hsieh JH, Sedykh A, Mutlu E, Germolec DR, Auerbach SS, Rider CV. 2020. Harnessing in silico, in vitro, and in vivo data to understand the toxicity landscape of polycyclic aromatic compounds (PACs). Chem Res Toxicol; doi:10.1021/acs.chemrestox.0c00213 [Online 16 October 2020]. (Synopsis(https://factor.niehs.nih.gov/2020/12/papers/dir/#a1))
Computational modeling identifies drug candidates for SARS-CoV-2
DNTP scientists and their collaborators used computational modeling to probe databases and to identify existing drugs that could be repurposed to fight SARS-CoV-2, the virus that causes COVID-19.
Proteases are enzymes that break down proteins. An essential step in the formation of infectious viral particles is the breakdown of precursor viral proteins by viral proteases. A class of antiviral drugs called protease inhibitors block the activity of viral proteases. The main protease (Mpro) of SARS-CoV-2 is a proposed target for COVID-19 drugs. The structure and activity of Mpro is highly conserved across the coronavirus family. In this study, previous data on drug interactions with SARS-CoV Mpro were used to develop quantitative structure-activity relationship models, which the team used to virtually screen all drugs in the DrugBank database. They identified 42 drugs that could be repurposed against SARS-CoV-2 Mpro.
Citation: Alves VM, Bobrowski T, Melo-Filho CC, Korn D, Auerbach S, Schmitt C, Muratov EN, Tropsha A. 2020. QSAR modeling of SARS-CoV Mpro inhibitors identifies sufugolix, cenicriviroc, proglumetacin, and other drugs as candidates for repurposing against SARS-CoV-2. Mol Inform; doi:10.1002/minf.202000113 [Online 28 July 2020]. (Synopsis(https://factor.niehs.nih.gov/2020/10/papers/dir/#a1))
New 5-day assay speeds chemical toxicity screening
DNTP scientists evaluated a high-throughput transcriptomics approach using liver and kidney tissue from 5-day assays in male rats to estimate the toxicological potency of chemicals.
Toxicity and carcinogenicity are typically assessed by the resource intensive two-year cancer bioassay. In the 5-day assays, the authors determined toxicological potency based on the most sensitive sets of genes active in the liver and kidney. For most chemicals, the results approximated the toxicological potency derived from the most sensitive histopathological effects — independent of target tissue or organ — observed in male rats in long-term assays. Notably, these approximations were similar in female rats, as well as in male and female mice. The findings suggest that estimates of transcriptomics-based potency from short-term in vivo assays can, in the absence of other data, provide a rapid and effective estimate of toxicological potency.
Citation: Gwinn WM, Auerbach SS, Parham F, Stout MD, Waidyanatha S, Mutlu E, Collins B, Paules RS, Merrick BA, Ferguson S, Ramaiahgari S, Bucher JR, Sparrow B, Toy H, Gorospe J, Machesky N, Shah RR, Balik-Meisner MR, Mav D, Phadke DP, Roberts G, DeVito MJ. 2020. Evaluation of 5-day in vivo rat liver and kidney with high-throughput transcriptomics for estimating benchmark doses of apical outcomes. Toxicol Sci 176(2):343–354. (Synopsis(https://factor.niehs.nih.gov/2020/8/papers/dir/#a1))
Perinatal boric acid exposure restricts growth in rats
Researchers from DNTP studied the effects of gestational and postnatal boron exposure on developing rat pups. The team was the first to show that pups exposed to boric acid, an oxidized form of boron commonly found in the environment, gained significantly less weight during postnatal development.
Pregnant rats were exposed to varying concentrations of boric acid once daily by oral gavage dosing, a technique that administered it directly to the stomach. Food intake, body weight, boron blood plasma levels, and any signs of morbidity were evaluated during gestation. After birth, the pups received boric acid at the same concentration as their mothers, and the scientists monitored the same parameters in the pups for the next 28 days. The team observed that the pups that received the highest dose of boric acid had a 23% reduction in weight gain.
Citation: Watson ATD, Sutherland VL, Cunny H, Miller-Pinsler L, Furr J, Hebert C, Collins B, Waidyanatha S, Smith L, Vinke T, Aillon K, Xie G, Shockley KR, McIntyre BS. 2020. Postnatal effects of gestational and lactational gavage exposure to boric acid in the developing Sprague Dawley rat. Toxicol Sci 176(1):65–73. (Synopsis(https://factor.niehs.nih.gov/2020/7/papers/dir/#a1))
Mouse tumors resemble human tumors
When scientists from DNTP analyzed the entire genetic code of tumors in rodent cancer studies, they determined that most rodent tumors —whether arising spontaneously or induced by chemicals — had DNA mutation signatures resembling those seen in human cancers.
Tumors can form as a result of DNA damage or they can arise spontaneously when physiological processes do not function properly. To understand the mechanism of cancer formation, members of the research team sequenced lung and liver tumor DNA from mice exposed to 20 carcinogens. They compared the sequences to those from tumors that formed spontaneously and from normal tissue. DNA signatures from exposure to 17 of the chemicals were similar to those from spontaneous tumors in mice. The finding suggests chemicals promote tumor formation through mechanisms that build on existing cancer processes.
Citation: Riva L, Pandiri AR, Li YR, Droop A, Hewinson J, Quail MA, Iyer V, Shepherd R, Herbert RA, Campbell PJ, Sills RC, Alexandrov LB, Balmain A, Adams DJ. 2020.The mutational signature profile of known and suspected human carcinogens in mice. Nat Genet 52(11):1189–1197. (Story)