Papers of the Month
By Robin Arnette, Salahuddin Syed, Janelle Weaver, Frieda Wiley, and Qing Xu
NTP scientists offer recommendations for dietary supplement safety
National Toxicology Program scientists and their collaborators reviewed current approaches for conducting absorption, distribution, metabolism, and excretion (ADME) studies of botanical dietary supplements, identified knowledge gaps, and presented recommendations for advancing the field.
An estimated 18 percent of United States residents consume botanical dietary supplements, but safety and toxicity data for these compounds are rarely available. ADME data can help scientists design toxicity studies, clarify potential botanical-drug interactions, and extrapolate animal toxicity data for human safety assessment. The authors used a case study with Ginkgo biloba extract to highlight challenges of studying botanicals and to demonstrate the usefulness of ADME data in botanical dietary supplement safety assessment.
The authors identified four key areas scientists should keep in mind when generating data for assessing the safety of a botanical dietary supplements: phytochemical characterization; robust ADME study design; investigation of human relevance; and in vitro or in vivo studies to identify pharmacokinetic botanical-drug interactions and active or marker constituents. (FW)
Citation: Waidyanatha S, Ryan K, Roe AL, Jia W, Paine MF, Ferguson S, Gurley BJ, Welch K, Chow MSS, Devito M, Rider C. 2018. Follow that botanical: challenges and recommendations for assessing absorption, distribution, metabolism and excretion of botanical dietary supplements. Food Chem Toxicol 121:194–202.
Tumor suppressor p53 has broad role in homeostasis
The cancer-fighting protein p53 plays a broader role in human biology than previously thought, according to a study by NIEHS researchers. Their unprecedented insights may lead to the discovery of novel therapeutic targets for cancer and other diseases.
p53 binds to DNA to turn genes on and off, and mutations that silence the p53 gene occur in most human cancers. Yet there are still significant gaps in knowledge about p53’s functions and the genes under its control. Past studies have reported conflicting results due to differences in methodology. To address this challenge, NIEHS researchers applied a uniform, rigorous analysis workflow to a large number of previously obtained p53 data sets, as well as their own data in normal immune cells.
The results tripled the number of known cistrome genes, or those directly targeted by p53, to a total of 943. Moreover, the researchers identified a core signature of 28 cistrome genes that are consistently activated by p53. The core signature could act as a biomarker to assess the effectiveness of chemotherapies. Additional findings suggested that p53 is also involved in nervous system function and cardiovascular signaling, and explained the p53-immune axis that the researchers described previously. This study provides a new dimension to the role of p53 in human biology, beyond its traditional function as guardian of the genome. (JW)
Citation: Nguyen TT, Grimm SA, Bushel PR, Li J, Li Y, Bennett BD, Lavender CA, Ward JM, Fargo DC, Anderson CW, Li L, Resnick MA, Menendez D. 2018. Revealing a human p53 universe. Nucleic Acids Res 46(16):8153–8167. (Story)
Phenobarbital promotes development of hepatocellular carcinoma
Researchers at NIEHS have found that treating rodents with phenobarbital, a hepatocarcinogen, causes repression of the tumor suppressor p38 MAPK and results in hepatocyte proliferation. Hepatocyte proliferation is an important response to chronic liver diseases, because hepatocytes are destroyed by inflammation and need to be replaced for proper liver function. However, increased proliferation may lead to hepatocellular carcinoma (HCC), which is a leading cause of cancer-related death in the world. In rodents, HCC development is promoted by phenobarbital.
A mouse model involving long-term treatment with phenobarbital has long been used as a means to study HCC. The nuclear receptor constitutive active/androstane receptor (NR1I3/CAR) has been shown to promote its activities. This study demonstrated that CAR regulates the activities of the growth arrest and of the DNA-damage−inducible 45 beta (GADD45B)-MAPK kinase 6 (MKK6) scaffold. The researchers also reported that CAR causes repression of p38 MAPK. Explaining the components of phenobarbital-induced HCC development will help scientists better understand the molecular mechanisms involved in hepatocyte proliferation. (SS)
Citation: Hori T, Saito K, Moore R, Flake GP, Negishi M. 2018. Nuclear receptor CAR suppresses GADD45B-p38 MAPK signaling to promote phenobarbital-induced proliferation in mouse liver. Mol Cancer Res 16(8):1309–1318.
Multiethnic study reveals new genetic variants for lung function
Using meta-analysis of data from studies around the world, NIEHS researchers and their collaborators identified new genetic variants that are associated with lung function and risk of pulmonary disorders. By using integrative genomic tools and a large multiethnic population, the research expands current information about genes related to respiratory health and provides insights into potential drug targets for lung diseases.
Both environmental and genetic factors influence pulmonary function traits (PFTs) that assess the physiological state of the lungs and are used clinically to diagnose and monitor lung diseases. Previous genome-wide association studies discovered nearly 100 PFT-associated DNA variants, mostly among people with European ancestry. This study gathered information from a much larger and diverse population of individuals from European, African, Asian, and Hispanic origins. The team reported more than 50 new variants associated with PFTs.
In addition, the researchers identified causal genes that may be responsible for the associated traits by using newly developed genomic methods that incorporate linkage disequilibrium, functional annotation, and gene expression. Some identified genes are essential for biological pathways involved in development, immunity, and pulmonary biology. Several other genes are predicted or known targets of approved drugs, suggesting the results obtained in this study could also be clinically important. (QX)
Citation: Wyss AB, Sofer T, Lee MK, Terzikhan N, Nguyen JN, Lahousse L, Latourelle JC, Smith AV, Bartz TM, Feitosa MF, Gao W, Ahluwalia TS, Tang W, Oldmeadow C, Duan Q, de Jong K, Wojczynski MK, Wang XQ, Noordam R, Hartwig FP, Jackson VE, Wang T, M Obeidat M, Hobbs BD, Huan T, Gui H, Parker MM, Hu D, Mogil LS, Kichaev G, Jin J, Graff M, Harris TB, Kalhan R, Heckbert SR, Paternoster L, Burkart KM, Liu Y, Holliday EG, Wilson JG, Vonk JM, Sanders JL, Barr RG, de Mutsert R, Menezes AMB, Adams HHH, van den Berge M, Joehanes R, Levin AM, Liberto J, Launer LJ, Morrison AC, Sitlani CM, Celedon JC, Kritchevsky SB, Scott RJ, Christensen K, Rotter JI, Bonten TN, Wehrmeister FC, Bosse Y, Xiao S, Oh S, Franceschini N, Brody JA, Kaplan RC, Lohman K, McEvoy M, Province MA, Rosendaal FR, Taylor KD, Nickle DC, Williams LK, Burchard EG, Wheeler HE, Sin DD, Gudnason V, North KE, Fornage M, Psaty BM, Myers RH, O’Connor G, Hansen T, Laurie CC, Cassano PA, Sung J, Kim WJ, Attia JR, Lange L, Boezen HM, Thyagarajan B, Rich SS, Mook-Kanamori DO, Horta BL, Uitterlinden AG, Im HK, Cho MH, Brusselle GG, Gharib SA, Dupuis J, Manichaikul A, London SJ. 2018. Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function. Nat Commun 9(1):2976.
Intensity of asthma symptoms depends on genetics and pollution
According to NIEHS researchers and their collaborators at Rice University, asthma patients with a particular genetic profile exhibit more severe asthma symptoms after exposure to traffic pollution. The results are based on a common type of genetic variation called a single nucleotide polymorphism (SNP), which is a subtle change in DNA that makes each person unique.
Focusing on four SNPs involved in a biochemical pathway that leads to inflammatory responses in the body, team members gathered residential addresses and information on the severity of asthma symptoms from 2704 asthma patients participating in the NIEHS Environmental Polymorphisms Registry. Based on SNP data, the scientists divided the participants into three groups: hyper-responders, hypo-responders, and those who were in between. They then used participants’ addresses to calculate their distance from traffic pollution, either less than or more than 275 yards from a major roadway.
Results showed that individuals with asthma who were hyper-responders and lived closer to heavily travelled roads had the worst asthma symptoms. Asthma patients who were hypo-responders and lived further away from busy roads had milder symptoms. The research brings scientists closer to precision medicine, an emerging field that intends to prevent and treat disease based on factors specific to an individual. (RA)
Citation: Schurman SH, Bravo MA, Innes CL, Jackson WB 2nd, McGrath JA, Miranda ML, Garantziotis S. 2018. Toll-like receptor 4 pathway polymorphisms interact with pollution to influence asthma diagnosis and severity. Sci Rep 8(1):12713. (Story)
(Salahuddin Syed, Ph.D., is an Intramural Research Training Award fellow in the NIEHS DNA Replication Fidelity Group. Janelle Weaver, Ph.D., is a contract writer for the NIEHS Office of Communications and Public Liaison. Frieda Wiley, Pharm.D., is a contract writer for the NIEHS Office of Communications and Public Liaison. Qing Xu is a biologist in the NIEHS Metabolism, Genes, and Environment Group.)