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Environmental Factor, October 2014

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Intramural papers of the month

By Raj Gosavi, John House, Mallikarjuna Metukuri, Simone Otto, and Shannon Whirledge

NTP involved in study of testosterone production in fetal rat

NTP researchers contributed to a study that found in utero exposure to the cholesterol-lowering drug simvastatin lowers fetal testosterone production and fetal lipid profiles in both male and female rats. Exposure to simvastatin, combined with a plasticizer, dipentyl phthalate (DPeP), appeared to additively reduce testosterone production, despite distinct modes of action for the two chemicals. Reduced testosterone levels disrupt androgen signaling in the early fetus, which may contribute to congenital disorders.

The authors exposed time-mated rats for 5 days, during the critical developmental window of sexual differentiation, to simvastatin, DPeP, and a mixture of both, to assess dose-response effects on fetal testosterone production. In addition to finding that simvastatin exposure altered fetal lipid profiles, they observed that it reduced testosterone production by lowering cholesterol levels, a precursor in testosterone biosynthesis.

Exposure to DPeP is known to lower testosterone production through downregulation of the genes involved in steroid synthesis. The authors report that these different modes of action allow the mixture of simvastatin and DPeP to additively decrease testosterone production. The dose-response effect on gene expressions through gene array experiments further confirmed no overlap in the actions of simvastatin and DPeP.

This study highlights the potential reproductive and developmental defects in humans as a consequence of inadvertent exposure to statin drugs during early pregnancy. (RG)

CitationBeverly BE, Lambright CS, Furr JR, Sampson H, Wilson VS, McIntyre BS, Foster PM, Travlos G, Gray LE Jr. 2014. Simvastatin and dipentyl phthalate lower ex vivo testicular testosterone production and exhibit additive effects on testicular testosterone and gene expression via distinct mechanistic pathways in the fetal rat. Toxicol Sci; doi:10.1093/toxsci/kfu149 [Online 23 July 2014].

Mechanisms of scar formation in lung cells after exposure to nanoparticles

Scientists at the NIEHS Clinical Research Unit determined a new mechanism by which multiwalled carbon nanotubes induce scar formation in the lung. Because nanotube use is projected to increase in multiple applications, including electronics, composite materials, and engineering, this work will help researchers understand how these particles lead to airway scarring.

The team collected human bronchial epithelia, or cells that line the airways, from volunteers and exposed the cells to carbon nanotubes. The researchers discovered that the nanotubes caused a specific type of response, called NLRP3 inflammasome activation, and cell death. They then exposed lung fibroblast cells, which are responsible for scar formation after injury, to culture media that had previously bathed the injured lung cells. The fibroblasts were induced by these media to produce scar tissue, but did not do so when the investigators neutralized inflammasome-specific messaging molecules.

This work builds upon science that suggests airway-lining cells play an important role in the lung response to inhaled pollutants. It also lays the groundwork for further research that will focus on how preexisting airway disease, such as asthma, may further complicate the development of lung scarring after exposure to carbon nanotubes. (JH)

CitationHussain S, Sangtian S, Anderson SM, Snyder RJ, Marshburn JD, Rice AB, Bonner JC, Garantziotis S. 2014. Inflammasome activation in airway epithelial cells after multi-walled carbon nanotube exposure mediates a profibrotic response in lung fibroblasts. Part Fibre Toxicol 11:28.

SIRT1 regulates retinoic acid signaling and stem cell differentiation

NIEHS researchers and their collaborators have shed light on the mechanisms by which the cellular metabolic sensor Sirtuin 1 (SIRT1) regulates stem cell differentiation and mouse embryonic development. SIRT1 is a protein deacetylase that coordinates the activation of transcription factors in response to cellular stress, which allows the cell to react to environmental cues. The study demonstrates that the stem cell differentiation signals stemming from retinoic acid (RA), an active metabolite of vitamin A, involve SIRT1.

In mice, deletion of SIRT1 results in embryonic lethality and severe developmental defects in surviving offspring. The authors show that loss of SIRT1 in mouse embryonic stem cells accelerates RA-induced differentiation. The authors were able to demonstrate that hyperacetylation of cellular retinoic acid binding protein II (CRABPII) at amino acid K102 is partially responsible for the RA-mediated hyperdifferentiation of SIRT1 deficient embryonic stem cells.

In addition, they found that whole body SIRT1-deficient mice exhibit elevated RA signaling at early stages of development. Furthermore, hepatic specific deletion of SIRT1 led to an increase in many RA target genes in response to exogenous RA in adult mice. Enhanced RA signaling likely underlies many of the developmental defects seen in the SIRT1 deficient mice. Understanding the signaling pathways that SIRT1 is responsible for mediating will provide insight into how the environment affects mammalian development. (SW)

CitationTang S, Huang G, Fan W, Chen Y, Ward JM, Xu X, Xu Q, Kang A, McBurney MW, Fargo DC, Hu G, Baumgart-Vogt E, Zhao Y, Li X. 2014. SIRT1-mediated deacetylation of CRABPII regulates cellular retinoic acid signaling and modulates embryonic stem cell differentiation. Mol Cell 55(6):843-855.

Histone-fold domain protein NF-Y promotes chromatin accessibility for cell specification

Researchers from NIEHS have unearthed a novel function for NF-Y in promoting chromatin accessibility and specification of cell identity. Histone-fold protein NF-Y, a ubiquitously expressed transcription factor, was previously known for its role in the regulation of cell cycle progression in proliferating cells. These key findings were published in the journal Molecular Cell.

The authors investigated NF-Y’s function and mechanism of action using genome-wide occupancy and transcriptomic analyses in embryonic stem cells and neurons and discovered that NF-Y uses distinct modes to regulate housekeeping and cell identity programs. While NF-Y regulates housekeeping genes through cell type-invariant promoter-proximal binding, they also showed that NF-Y regulates genes required for cell identity by binding to cell type-specific enhancers. At enhancers, NF-Y promotes the binding of master transcription factors by facilitating a permissive chromatin conformation. Based on these results, the authors propose a potential mechanism for NF-Y in the recruitment of pioneer transcription factors for cell specification. (MM)

CitationOldfield AJ, Yang P, Conway AE, Cinghu S, Freudenberg JM, Yellaboina S, Jothi R. 2014. Histone-fold domain protein NF-Y promotes chromatin accessibility for cell type-specific master transcription factors. Mol Cell 55(5):708-722.

Duking it out? My CA2 made me do it

In collaboration with the National Institute of Mental Health (NIMH), researchers at NIEHS have discovered that activation of the vasopressin 1b receptor (Avpr1b) in a certain part of the brain is necessary for social aggression. Within the brain, this receptor is expressed uniquely in the CA2 region of the hippocampus, a part of the brain more commonly associated with learning and memory.

Earlier work from NIMH scientists showed that when the scientists knocked out the Avpr1b in mice, they saw a dramatic abatement of social aggression. When the authors replaced the lost receptor directly into CA2, aggressive behavior was restored to levels near that of normal mice. Social aggression is important for mothers protecting their young and for animals defending their territory. Interestingly, some neurons in the CA2 are missing in people who have schizophrenia.

To understand the mechanism of Avpr1b action, scientists measured the synaptic strength in brain slices from rats and mice. They found that vasopressin caused synaptic potentiation, but only in the CA2. Further studies indicated this response was exactly the same as that induced by oxytocin, which is another social neuropeptide. This research could lead to exciting new treatments for patients with psychiatric disorders who have inappropriate social aggression. (SO)

CitationPagani JH, Zhao M, Cui Z, Williams Avram SK, Caruana DA, Dudek SM, Young WS. 2014. Role of the vasopressin 1b receptor in rodent aggressive behavior and synaptic plasticity in hippocampal area CA2. Mol Psychiatry; doi:10.1038/mp.2014.47 [Online 27 May 2014]. [Story]

(Raj Gosavi, Ph.D., is a research fellow in the NIEHS Structure and Function Research Group. John House, Ph.D., is an Intramural Research Training Award (IRTA) fellow in the NIEHS Genetic Epidemiology Group. Mallikarjuna Metukuri, Ph.D., is a research fellow in the NIEHS Metabolism, Genes, and Environment Group. Simone Otto, Ph.D., is an IRTA fellow in the NIEHS Ion Channel Physiology Group. Shannon Whirledge, Ph.D., is a research fellow in the NIEHS Molecular Endocrinology Group.)

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