Papers of the Month
By Samantha Hall, Gabriel Knudsen, Emily Mesev, Simone Otto, and Kelly Shipkowski
NTP involved in identifying characteristics of carcinogenicity
A National Toxicology Program researcher participated in an international working group that identified 10 key characteristics of cancer-causing compounds. Hosted by the International Agency for Research on Cancer (IARC), the working group concluded these characteristics may be used to mechanistically identify and evaluate human carcinogenic agents.
The workgroup was established after the IARC updated its list of Group 1 carcinogens using mechanistic data in literature. During the IARC review, several members noticed that the evaluation lacked a generally accepted method of identifying mechanistic data on human cancer risks. To establish consistency in evaluating cancer risks, scientists met during two workshops and identified features common to many known human carcinogens, such as the ability to affect DNA repair, cause epigenetic changes, and alter cell proliferation, cell death, or nutrient supplies.
To illustrate how this approach would work, the experts performed a systematic literature review, using the 10 key characteristics to organize information for benzene and polychlorinated biphenyls (PCBs), two Group 1 carcinogens. Their analysis indicated that eight of the 10 proposed characteristics were associated with benzene carcinogenicity, while seven of the 10 were associated with PCBs. The continued development of this model will help assess the potential human cancer risk of newly available compounds. (KS)
Smith MT, Guyton KZ, Gibbons CF, Fritz JM, Portier CJ, Rusyn I, DeMarini DM, Caldwell JC, Kavlock RJ, Lambert PF, Hecht SS, Bucher JR, Stewart BW, Baan RA, Cogliano VJ, Straif K. 2016. Key characteristics of carcinogens as a basis for organizing data on mechanisms of carcinogenesis. Environ Health Perspect 124(6):713-721.
Farm exposures associated with rheumatoid arthritis
Researchers from NIEHS, the National Cancer Institute, and other institutions have reported a possible connection between the systemic autoimmune disease rheumatoid arthritis (RA), pesticides, and other farm exposures. The study found that wives of licensed pesticide applicators who themselves used pesticides were more likely to have or develop RA than those who did not mix or apply pesticides. Conversely, participants with lifetime exposure to livestock were less likely to develop RA.
The Agricultural Health Study has followed licensed pesticide applicators, who are mostly farmers, and their spouses since the 1990s. Here, the researchers examined the health of the female spouses through 2010. The study confirmed self-reported RA through medical records and information on medications, and used questionnaire data to evaluate links between RA and lifetime pesticide use and other farm exposures.
Overall, RA was associated with reporting any use of specific pesticides, and risk of the disease was significantly associated with use of the fungicide maneb or mancozeb and the herbicide glyphosate. Using solvents for cleaning and applying chemical fertilizers also increased risk of RA. Childhood livestock exposure appeared to protect against RA in women exposed to animals as adults, supporting the idea that early-life exposures can influence the adult immune system.
Results suggest that specific pesticides may be linked with a systemic autoimmune disease, while lifetime contact with livestock may reduce risk. (EM)
Parks CG, Hoppin JA, DeRoos AJ, Costenbader KH, Alavanja MC, Sandler DP. 2016. Rheumatoid arthritis in Agricultural Health Study spouses: associations with pesticides and other farm exposures. Environ Health Perspect; doi:10.1289/EHP129 [Online 10 June 2016].
Researchers develop novel biomarker of maternal smoking in newborns
Scientists at NIEHS and their collaborators have developed a new biomarker in newborns to detect exposure to sustained maternal smoking during pregnancy. The biomarker may allow scientists to identify novel health effects of maternal smoking in pregnancy, and better adjust for this important potential confounder in studies of effects of other prenatal exposures.
Smoking during pregnancy causes serious adverse outcomes, such as lower birth weight and early respiratory illness. Cotinine, the primary metabolite of nicotine, is a good objective biomarker for smoking status, but it is short-lived in the body. Prior to this report, no long-term biomarker of this in utero exposure in newborns existed.
The NIEHS team, and later others, measured genome-wide methylation, using a commercial platform to identify replicable DNA methylation changes at specific sites in newborns from sustained maternal smoking during pregnancy. The study used blood from newborns in the Norwegian Mother and Child Cohort Study.
By comparing DNA methylation changes in newborns to the cotinine levels in their mothers, and to questionnaire data, the researchers developed a smoking score based on methylation at 28 specific DNA sites. This methylation biomarker will be useful if information on maternal smoking during pregnancy is missing or incomplete, as well as to validate self-reports of nonsmoking. (SH)
Reese SE, Zhao S, Wu MC, Joubert BR, Parr CL, Haberg SE, Ueland PM, Nilsen RM, Midttun O, Vollset SE, Peddada SD, Nystad W, London SJ. 2016. DNA methylation score as a biomarker in newborns for sustained maternal smoking during pregnancy. Environ Health Perspect; doi:10.1289/EHP333 [Online 21 June 2016].
INO80 role in melanoma
NIEHS researchers and an international team of collaborators showed how INO80, a chromatin remodeling complex, regulates superenhancers (SEs) and oncogenic transcription in melanoma. SEs are large stretches of DNA containing high numbers of enhancer marks, and melanomas are some of the most common cancers diagnosed in the United States. The approach of disrupting SEs could provide a novel strategy for treating melanoma.
The investigators found that the expression of INO80, the SWI/SNF ATPase in the complex, is elevated in melanoma cell lines and primary melanomas, compared to normal primary melanocytes. Mechanistically, INO80 occupies SEs near genes that are important for tumor progression in melanoma cells. Its occupancy results in reduced nucleosomes and increased chromatin accessibility at enhancers, which facilitates the recruitment of Med1 and oncogenic transcription. Finally, driver mutations, the abnormally activated signaling pathways and transcription factors involved in melanoma, can hijack INO80 to rewire the transcription circuity in normal cells to a pathological state that supports tumorigenesis.
The results demonstrated a critical role for INO80 in SE function, oncogenic transcription, and the integration of extracellular and cytoplasmic signals in melanoma development. The study further suggests that INO80 may serve as a valuable target for therapeutic purposes, since it presents a novel approach for disrupting SEs and inhibiting oncogenic transcription. (GK)
Zhou B, Wang L, Zhang S, Bennett BD, He F, Zhang Y, Xiong C, Han L, Diao L, Li P, Fargo DC, Cox AD, Hu G. 2016. INO80 governs superenhancer-mediated oncogenic transcription and tumor growth in melanoma. Genes Dev 30(12):1440-1453.
Social net-working: CA2 neurons use perineuronal nets to suppress plasticity
CA2 pyramidal neurons in the mouse hippocampus, which have recently been implicated in social behavior, are novel sources of perineuronal nets (PNNs), a specialized extracellular matrix more typically localized around inhibitory neurons, according to NIEHS scientists and their collaborators. The researchers also determined that PNNs play a critical role in restricting synaptic plasticity, or the ability of the brain to respond to environmental stimuli, and that CA2 PNNs are modified by early-life experiences. Scientists hope that understanding the developmental regulation of PNNs may provide therapeutic targets for disorders involving PNNs, such as Rett syndrome and schizophrenia. The work may also shed light on the association of CA2 with social learning and memory.
Using immunohistochemistry, in situ hybridization, and electron microscopy to study the localization of PNNs, the researchers found that PNNs were situated around excitatory connections, or synapses, in CA2, and that early-life environmental enrichment caused an upregulation of PNNs there. Using electrophysiology, they further found that PNNs actually suppress synaptic plasticity.
PNN numbers increase during closure of critical windows in development and have been shown to limit plasticity. Scientists hope to further pursue this research by investigating the role of intrinsic factors and early-life events, such as seizures, on PNN development. (SO)
Carstens KE, Phillips ML, Pozzo-Miller L, Weinberg RJ, Dudek SM. 2016. Perineuronal nets suppress plasticity of excitatory synapses on CA2 pyramidal neurons. J Neurosci 36(23):6312-6320.
(Samantha Hall is a postbaccalaureate Cancer Research Training Award fellow in the National Cancer Institute Center for Cancer Research Laboratory of Toxicology and Toxicokinetics (CCRLTT). Gabriel Knudsen, Ph.D., is a research fellow in CCRLTT. Emily Mesev is an Intramural Research Training Award (IRTA) postbaccalaureate fellow in the NIEHS Intracellular Regulation Group. Simone Otto, Ph.D., is an IRTA fellow in the NIEHS Ion Channel Physiology Group. Kelly Shipkowski, Ph.D., is an IRTA fellow in the National Toxicology Program Systems Toxicology Group.)