Papers of the Month
By Kathleen Foley, Salahuddin Syed, Janelle Weaver, and Qing Xu
Bisphenol AF is absorbed rapidly in rodents
Researchers from the National Toxicology Program (NTP) and their collaborators found that orally administered bisphenol AF (BPAF), which is structurally similar to bisphenol A (BPA), can be rapidly absorbed in rodents. The research provides insight into the potential effects of BPAF on animal and human health.
BPAF is an industrial chemical used to produce synthetic rubber and plastic. Studies have reported that BPAF is toxic to aquatic organisms and could cause hormones imbalances in rats. To provide further safety data for BPAF, NTP researchers conducted toxicity testing of BPAF in rodents. The absorption, distribution, metabolism, and excretion data that they published previously showed BPAF could be deposited in tissue and eliminated from the body. This study provided further comprehensive toxicokinetic data for BPAF.
The researchers observed that BPAF was rapidly absorbed in both rats and mice, with maximum plasma concentrations reached within a couple of hours after oral administration. Following absorption, BPAF was extensively conjugated and rapidly removed, with low bioavailability in both species. Similar results were found in both male and female rats and mice. The researchers concluded that the deposition pattern of BPAF resembles that of well-researched BPA. (QX)
Citation: Waidyanatha S, Black SR, Aillon K, Collins B, Patel PR, Riordan F, Sutherland V, Robinson VG, Fernando R, Fennell TR2019. Toxicokinetics and bioavailability of bisphenol AF following oral administration in rodents: a dose, species, and sex comparison. Toxicol Appl Pharmacol 373:39–47.
Mouse model of Paget’s Disease exhibits key clinical features
After NIEHS researchers and their collaborators created a mouse model that lacked the protein optineurin, they found that mice displayed clinical features seen in patients with Paget’s disease of the bone (PDB). PDB, an age-dependent disease in which the patient’s bones are fragile and deformed, has been linked to mutations in the gene for optineurin (Optn). Before this work, approximately 10% of other mouse models with Optn mutations developed PDB, so this new model, in which 100% of the mice developed PDB, will help scientists understand the condition.
Optn is normally responsible for mediating delivery of cellular components that need to be degraded by the cell, such as damaged organelles or invading pathogens, but the research team found it is also an important negative regulator of new bone formation in mice. Knocking out Optn globally in mice leads to bone lesions and osteoclasts, or when bone cells absorb bone tissue during healing and growth. Optn promotes the production of type I interferons, a group of signaling proteins that trigger the body’s immune system to attack invading pathogens, as well as inducing bone differentiation. These Optn-deficient mice have defective interferon activity, and the authors suggest that this may contribute to PDB. This new mouse model may uncover how PDB develops in humans and could lead to better treatment of PDB. (KF)
Citation: Wong SW, Huang BW, Hu X, Ho Kim E, Kolb JP, Padilla RJ, Xue P, Wang L, Oguin TH 3rd, Miguez PA, Tseng HC, Ko CC, Martinez J2019. Global deletion of optineurin results in altered type I IFN signaling and abnormal bone remodeling in a model of Paget’s disease. Cell Death Differ; doi: 10.1038/s41418-019-0341-6. [Online 10 May 2019].
New mouse model of lung cancer reveals key disease drivers
New findings from NIEHS researchers point to a novel strategy for preventing or treating a common type of lung cancer called lung squamous cell carcinoma (LSCC). LSCC includes approximately 25-30% of all lung cancers, which are the leading cause of cancer-related death. The initial stages of human LSCC have been described, but there is a lack of animal models to mimic the process.
Using a new genetic mouse model, the researchers found that a signaling pathway called JNK1-2, which regulates the cellular stress response, plays a key role in suppressing LSCC development. The findings suggest that activating the JNK1-2 pathway could represent a promising therapeutic approach against LSCC.
The researchers also discovered that silencing a gene called Lkb1 in lung airway cells is sufficient to induce LSCC in mice. This is the first demonstration that a single mutation is sufficient to induce LSCC. The findings suggest that Lkb1 plays a greater role in driving LSCC development than previously thought.
According to the authors, this animal model could be used to identify environmental agents that promote lung cancer development, as well as molecules that could be used as diagnostic and therapeutic tools to treat the disease. (JW)
Citation: Liu J, Wang T, Creighton CJ, Wu SP, Ray M, Janardhan KS, Willson CJ, Cho SN, Castro PD, Ittmann MM, Li JL, Davis RJ, DeMayo FJ2019. JNK1-2 represses Lkb1-deficiency-induced lung squamous cell carcinoma progression. Nat Commun 10(1):2148. (Story)
Mapping molecular changes during early embryonic development
NIEHS researchers have generated the most comprehensive molecular maps to date that characterize stem cells as they transition through different stages of early embryonic development. The findings provide a foundation for investigating mechanisms that regulate early human embryonic development and how various environmental exposures might affect fetal development.
Pluripotency refers to the potential of a cell to give rise to any cell type in the body. During embryonic development, pluripotent stem cells transition through a continuum of different states. The two bookends of this continuum, naive and primed, are well characterized, but knowledge about the intermediate states remains incomplete.
To address this question, the researchers characterized sequences of molecular events in mouse embryonic stem cells transitioning from naive to primed pluripotency. They studied all proteins, RNA molecules, and chemical modifications to DNA and DNA-packaging proteins. These molecules make up the proteome, transcriptome, and epigenome, respectively.
During pluripotent state transitions, rapid and widespread changes occurred to the phosphoproteome — proteins containing a phosphate group — before changes to the epigenome, transcriptome, and proteome. Moreover, three distinct waves of proteomic changes marked discrete phases of pluripotency. According to the authors, these results shed the first light on proteome-wide changes during the phased progression of pluripotency. (JW)
Citation: Yang P, Humphrey SJ, Cinghu S, Pathania R, Oldfield AJ, Kumar D, Perera D, Yang JYH, James DE, Mann M, Jothi R2019. Multi-omic profiling reveals dynamics of the phased progression of pluripotency. Cell Syst 8(5):427−445.e10. (Story)
Oxidative stress causes distinct mutational signatures
Scientists at NIEHS have found a common feature in the mutational signatures of single-strand DNA (ssDNA) of budding yeast and aged human mitochondrial DNA. The target of oxidative damage in DNA, common for both signatures, is the DNA base cytosine (C). Unexpectedly, the most frequent substitution caused by oxidative stress appeared to be a C to thymine (T) change. Oxidative stress is a result of unresolved reactive oxygen species and can be detrimental to the cell.
Mutational signatures provide valuable insight into determining the sources of mutations in genomes of cells. The authors set out to look at signatures of redox stress-induced oxidative damage in ssDNA and aged human mitochondrial DNA. They used a yeast reporter system that was optimized for looking at clustered mutation events in ssDNA and compared this to previously sequenced mitochondrial DNA from aged human brains. Using the yeast reporter system, the researchers provided a previously unknown mutational signature of redox stress in ssDNA and found that redox stress causes increased frequencies of C to T substitutions. The authors propose several mechanisms that may result in this mutational event and highlight the importance for the identification of mutational signatures in cancers, which may also have potential therapeutic implications. (SS)
Citation: Degtyareva NP, Saini N, Sterling JF, Placentra VC, Klimczak LJ, Gordenin DA, Doetsch PW2019. Mutational signatures of redox stress in yeast single-strand DNA and of aging in human mitochondrial DNA share a common feature. PLoS Biol 17(5):e3000263. (Story)
(Kathleen Foley is an Intramural Research Training Award [IRTA] postbaccalaureate fellow in the NIEHS Receptor Biology Group. Salahuddin Syed, Ph.D., is an IRTA 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. Qing Xu is a biologist in the NIEHS Metabolism, Genes, and Environment Group.)