NTP finds that cedarwood oil causes skin lesions in mice and rats

National Toxicology Program (NTP) researchers and collaborators have revealed that cedarwood oil, a fragrance material used in many household products, can cause lesions to the skins of mice and rats in a dose-dependent manner. The finding raises concerns over current widespread human exposure to cedarwood oil and may help scientists develop guidelines for its daily use.

As an essential oil extracted from cedar, cedarwood oil is generally considered harmless and commonly used in insect repellents and personal products, including perfumes, lotions, and soaps. However, some data have implied potential adverse effects for the extract and its components in animals or humans.

In the 3-month study, researchers applied concentrations of cedarwood oil varying from 0 to 100 percent to the skins of mice and rats. The treatment led to reduced body weight and survival, and the animals developed systemic inflammation and skin lesions, including irritations, thickened skin, and ulcerations. The severity of the lesions increased with higher doses, with the mice exhibiting more severe symptoms than the rats. The oil concentrations that caused skin lesions in the rodents are used in products on the market, suggesting that the amount of cedarwood oil in consumer goods is a cause for concern. (QX)

Citation: Catlin NR, Herbert R, Janardhan K, Hejtmancik MR, Fomby LM, Vallant M, Kissling GE, DeVito MJ. 2016. Dose-response assessment of the dermal toxicity of Virginia cedarwood oil in F344/N rats and B6C3F1/N mice. Food Chem Toxicol 98(Pt B):159−168.

CNOT3 role in pluripotent state of embryonic stem cells

NIEHS researchers and collaborators have found that Ccr4-NOT complex subunit 3 (CNOT3), a part of the Ccr4-Not deadenylase complex, is important in regulating the pluripotent state by controlling the length of poly(A) tails and influencing deadenylation and degradation of mRNAs. This study clarifies how the pluripotent state is maintained in embryonic stem cells (ESCs), which have multiple applications, including investigation of the effects of environmental factors on human development.

ESCs have the ability to become any cell type in the body and can propagate continually while remaining pluripotent, which is the ability to develop into different cell types. Earlier studies have found that the pluripotent state is controlled by a variety of factors such as signal transduction pathways, transcription factors, and epigenetic modifications. Researchers in this study wanted to determine if post-transcriptional mechanisms play a role in ESC pluripotency. Focusing on the mRNA deadenylase complex, Ccr4-Not, which shortens poly(A) tails, they found that regulation of the poly(A) tail length controls gene expression during ESC maintenance, and CNOT3 plays a critical role in this process. (SS)

Citation: Zheng X, Yang P, Lackford B, Bennett BD, Wang L, Li H, Wang Y, Miao Y, Foley JF, Fargo DC, Jin Y, Williams CJ, Jothi R, Hu G. 2016. CNOT3-dependent mRNA deadenylation safeguards the pluripotent state. Stem Cell Reports 7(5):897−910.

Dust mite allergens are more stable and abundant

NIEHS scientists and their colleagues from other institutions are the first to determine that allergy-causing proteins from the house dust mite (Dermatophagoides pteronyssinus) are more stable and abundant than other dust mite proteins. The work may help researchers understand how humans develop dust mite allergies and aid in the design of improved allergy treatments.

The researchers used RNA-Seq methods to determine that the 19 allergenic dust mite proteins were produced in much larger quantities than other nonallergenic proteins. To assess protein stability, the team used a mass spectrometry−based proteomics technique to evaluate which group of dust mite proteins tended to denature or lose their three-dimensional structure in the presence of a chemical denaturant. The authors found that the 19 allergy-inducing proteins were more resistant to unfolding than 656 nonallergens from the dust mite, and therefore, were more stable.

This work used whole dust mite extracts to ensure good statistical data, but humans rarely breathe in whole dust mites, because they are too large to become airborne. Future studies will focus on particles that humans are exposed to, such as dust mite fecal material, house dust, and pollen grains. (CN)

Citation: Ogburn RN, Randall TA, Xu Y, Roberts JH, Mebrahtu B, Karnuta JM, Rider SD, Kissling GE, London RE, Pomes A, Arlian L, Fitzgerald MC, Mueller GA. 2016. Are dust mite allergens more abundant and/or more stable than other Dermatophagoides pteronyssinus proteins? J Allergy Clin Immunol; doi:10.1016/j.jaci.2016.08.016 [Online 19 Oct 2016]. (Story)

Gata2 involved in novel uterine signaling network

NIEHS researchers and their collaborators discovered that the transcription factor Gata2 and the progesterone receptor (PGR) ensure hormonal balance between estrogen and progesterone during pregnancy. Because progesterone signaling plays a large role in female fertility, the work helps scientists understand how the two proteins prepare the uterus to support embryo implantation and growth.

Using a genetic mouse model that lacked Gata2 expression in the uterus, the researchers discovered that the mice were unable to implant embryos and failed to exhibit endometrial changes, making them infertile. Further work identified an overlapping and interdependent regulatory network between Gata2 and PGR in these mice.

To assess whether a similar regulatory network existed in human uteri, the researchers combed existing databases of uterine gene expression and identified a correlation among Gata2 and its target genes, and Gata2 and PGR. Together with other transcription factors shown to work in concert with PGR, Gata2 represents an intricate network of regulators of uterine function, which can be explored as potential therapeutic targets for female cancers and reproductive disorders. (AD)

Citation: Rubel CA, Wu SP, Lin L, Wang T, Lanz RB, Li X, Kommagani R, Franco HL, Camper SA, Tong Q, Jeong JW, Lydon JP, DeMayo FJ. 2016. A Gata2-dependent transcription network regulates uterine progesterone responsiveness and endometrial function. Cell Rep 17(5):1414−1425. (Story)

Environmental stress response gene product promotes cancer

Scientists at NIEHS have found that a novel environmental stress response gene product, tumor necrosis factor-alpha−induced protein 8 variant 2 (TNFAIP8 v2), is upregulated in several human cancers. They also observed that in response to the chemotherapeutic agent doxorubicin, TNFAIP8 blocks tumor suppression and promotes cancer growth and chemotherapy resistance by repressing transcription factor p53. The research suggests that TNFAIP8 v2 may hold potential as a target for cancer treatment.

RNA-sequencing data showed that TNFAIP8 v2 was upregulated in eight of 11 different tumor types, with additional upregulation in cancer cells treated with p53 activators nutlin or doxorubicin. Using ChIP-sequencing, or chromatin immunoprecipitation sequencing, and ChIP−polymerase chain reaction, the researchers found that p53 can bind to a specific region of TNFAIP8 v2, which may act as an intragenic enhancer.

Suggesting feedback of TNFAIP8 on p53, overexpression of TNFAIP8 v2 appeared to lower p53 activity by inhibiting p53 binding to targets, whereas silencing TNFAIP8 v2 promoted p53 target binding and p53-dependent cell cycle arrest. Taken together, TNFAIP8 v2 and p53 appear to engage in reciprocal regulation, with TNFAIP8 v2 promoting cancer cell growth and survival by offsetting p53-dependent tumor suppression. (EM)

Citation: Lowe JM, Nguyen TA, Grimm SA, Gabor KA, Peddada SD, Li L, Anderson CW, Resnick MA, Menendez D, Fessler MB. 2016. The novel p53 target TNFAIP8 variant 2 is increased in cancer and offsets p53-dependent tumor suppression. Cell Death Differ; doi:10.1038/cdd.2016.130 [Online 11 Nov 2016].