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October 2011

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Intramural papers of the month

By Raluca Dumitru, Ian Thomas, and Darshini Trivedi
October 2011

Neonatal exposure to estrogenic environmental chemicals may contribute to infertility

In a new study from NIEHS, scientists found that giving newborn female mice genistein, a compound that behaves like estrogen and is found in soybean-derived products, altered proper development of the reproductive tract. As adults, these mice had oviducts with characteristics of the cervix and vagina, and failed to support proper early embryo development. Because human infants consuming soy-based formulas have similar blood levels of genistein, this work could have implications for unexplained infertility in humans.  

Investigators treated a group of female mouse pups with genistein, and measured various regions of their reproductive tracts for alterations in structure and gene expression. When compared to corn oil-treated controls, the genistein-treated mice had substantial changes in expression of genes that control neonatal oviduct development. An estrogen receptor antagonist blocked these effects, demonstrating that genistein's estrogenic activity induced the changes in gene expression. Many of the oviduct changes persisted through adulthood, even though the treatment was for only five days at birth.

The results of this study support the hypothesis that mammalian exposure to low levels of estrogenic environmental chemicals, during sensitive developmental windows, may alter certain aspects of human reproductive development. These changes could manifest later in life as an infertility phenotype.

Citation: Jefferson WN, Padilla-Banks E, Phelps JY, Gerrish KE, Williams CJ( Exit NIEHS 2011. Permanent oviduct posteriorization following neonatal exposure to the phytoestrogen genistein. Environ Health Perspect; doi:10.1289/ehp.1104018 [Online 2 August 2011].

New software analyzes next-generation sequencing data

Recently, NIEHS investigators reported the development of EpiCenter, a novel statistical method and software tool for the analysis of high-throughput next-generation sequencing (NGS) data. The software, which is freely available to the public, may be used to detect changes in epigenetic marks with ChiP-seq data or gene expression with mRNA-seq data. Since the researchers have proven its effectiveness by successfully analyzing histone Chip-seq and mRNA-seq data from multiple studies, EpiCenter promises to become an indispensable tool in bioinformatics.

Before the creation of EpiCenter, the large volume of NGS data, together with the evolution of new technologies and applications, made NGS data analysis a barrier in biomedical research. EpiCenter changes all of that by providing multiple normalization methods to achieve appropriate normalization under different scenarios, using a sequence of three statistical tests to eliminate background regions and to account for different sources of variation, and allowing adjustment for multiple testing to control false discovery rate or family-wise type I error.

In addition, the software can identify genome-wide epigenetic changes or differentially expressed genes, find transcription factor binding sites, and convert multiple-sample sequencing data into a single read-count data matrix.

Citation: Huang W, Umbach DM, Vincent Jordan N, Abell AN, Johnson GL, Li L( Exit NIEHS 2011. Efficiently identifying genome-wide changes with next-generation sequencing data. Nucleic Acids Res; doi:10.1093/nar/gkr592 [Online 29 July 2011].

Mitochondrial targeting of phospholipid scramblase 3 depends on palmitoylation

A new collaborative effort between three laboratories within NIEHS identified an important role for palmitoylation in the subcellular localization of the mitochondrial protein phospholipid scramblase 3. S-palmitoylation, a post-translational modification, promotes the subcellular localization of proteins in several biological pathways, making it an attractive means for manipulating protein targeting. However, study of palmitoylation has been hampered due to limited understanding of its enzymology and consensus motifs. This research effort is the first to show the targeting of a protein to mitochondria by palmitoylation.

The authors identified palmitoylated proteins by performing an acyl-biotinyl exchange proteomic screen in macrophages. One of the identified palmitoylated proteins was phospholipid scramblase 3 (Plscr3), a protein that regulates mitochondrial function by remodeling the mitochondrial outer membrane. Next, the authors identified the region of Plscr3 involved in palmitoylation and demonstrated, by site-directed mutagenesis, that the locus is important for Plscr3 targeting mitochondria, as well as for macrophage apoptosis.

This study provides an important insight into how a proteomic approach can identify acylated proteins. Moreover, the manipulation of protein palmitoylation may offer a promising opportunity for intervention in macrophage biology.   

Citation: Merrick BA, Dhungana S, Williams JG, Aloor JJ, Peddada S, Tomer KB, Fessler MB( Exit NIEHS 2011. Proteomic profiling of S-acylated macrophage proteins identifies a role for palmitoylation in mitochondrial targeting of phospholipid scramblase 3. Moll Cell Proteomics; doi:10.1074/mcp.M110.006007 [Online 23 July 2011].

COX-2 is a key regulator of Th17 cell differentiation in allergic lung inflammation

A new study from NIEHS uncovers the role that cyclooxygenase (COX) enzymes play during allergic lung inflammation. COXs are responsible for the production of prostaglandins (PGs), which regulate inflammatory responses. This report is the first to show that one of the COX enzymes, COX-2, is the key regulator of T helper 17 (Th17) cell differentiation and function in the allergic lung. Th17 cells secrete IL-17 which promotes inflammation by increasing cytokine and chemokine secretion in multiple lung cell types and by increasing the number of neutrophils in the lung.

To determine whether COX-1 or COX-2 regulated Th17 cells, the authors used ovalbumin to induce allergic airway inflammation in wild-type, COX-1 knockout and COX-2 knockout mice. The results showed that the number of Th17 cells in the lung was dramatically reduced in COX-2 knockout mice, but not in COX-1 knockout mice, relative to wild-type. Also, the researchers found that Th17 cell differentiation and function was impaired in COX-2 knockout mice. Importantly, PG production was decreased in Th17 cells from COX-2 knockout mice and the Th17 cell defects were reversed by giving PGs in vitro and in vivo.

The results of this study demonstrate that COX-2 is a critical regulator of Th17 differentiation and function. The research opens up the possibility that COXs could regulate the function and differentiation of other T-cell subsets. The investigators speculate that targeting COX-2 and/or PG signaling pathways may represent a novel approach to the treatment of allergic lung disease in humans.

Citation: Li H, Bradbury JA, Dackor RT, Edin ML, Graves JP, DeGraff LM, Wang PM, Bortner CD, Maruoka S, Lih FB, Cook DN, Tomer KB, Jetten AM, Zeldin DC( Exit NIEHS 2011. Cyclooxygenase-2 regulates Th17 cell differentiation during allergic lung inflammation. Am J Respir Crit Care Med 184(1):37-49.

(Raluca Dumitru, M.D., Ph.D., is an Intramural Research Training Award fellow in the NIEHS Stem Cell Biology Group of the Laboratory of Molecular Carcinogenesis. Ian Thomas is a public affairs specialist in the NIEHS Office of Communications and Public Liaison. Darshini Trivedi, Ph.D., is an Intramural Research Training Award fellow in the NIEHS Metabolism and Molecular Mechanism Group of the Laboratory of Toxicology and Pharmacology.)

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