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Environmental Factor, September 2014

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Intramural papers of the month

By Monica Frazier, John House, Kelly Lenox, Mallikarjuna Metukuri, Jordan St. Charles

NTP research finds low doses of inorganic arsenic cause lung tumors in male mice

Researchers at NIEHS found that exposure to low doses of inorganic arsenic caused lung tumors in male mice. While arsenic exposures in the parts-per-million range were known to be carcinogenic, this research is the first evidence of such effect in the parts-per-billion (ppb) range. This concentration is cause for concern, because it mimics the level of arsenic millions of people are exposed to in their drinking water.

Using a whole-life mouse model, the researchers exposed mice to inorganic arsenic in their drinking water beginning three weeks before breeding, continuing through pregnancy and lactation, up through two years of age. Arsenic concentrations were 50 ppb, 500 ppb, and 5,000 ppb. More than half of the male offspring in the study developed significant increases in benign and malignant lung tumors at the two lower doses. The researchers noted that the lowest dose, 50 ppb, is only five times the maximum contaminant level set by the U.S. Environmental Protection Agency for drinking water.

These findings provide further support for earlier studies that note differing responses to arsenic in male versus female mice. The authors call for further work to assess the carcinogenic potential of inorganic arsenic in mice at human relevant doses. (KL)

CitationWaalkes MP, Qu W, Tokar EJ, Kissling GE, Dixon D. 2014. Lung tumors in mice induced by “whole-life” inorganic arsenic exposure at human-relevant doses. Arch Toxicol 88(8):1619-1629. [Story]

Maternal smoking linked to altered DNA in newborns

New research demonstrates that mothers who choose to smoke during pregnancy may actually alter their offspring’s epigenetic DNA profile. In one of the largest studies of its kind, to date, researchers from NIEHS and Norway have identified specific modified regions in the genomes of children from mothers who smoked during pregnancy compared with children of nonsmokers.

Investigators interrogated DNA methylation marks in blood collected from 889 newborns, with 287 newborns from mothers with self-reported smoking during the first trimester, and discovered altered methylation patterns in or near 110 genes. Strikingly, some of these genes are related to the ability to quit smoking, nicotine addiction, and fetal development.

This work adds to the growing body of evidence that maternal exposure and behavior can modify DNA during fetal development. Additional research is needed to understand both the persistence of these DNA alterations, as children mature, and if these DNA alterations are related to established adverse outcomes in children born to maternal smokers, or are simply markers of exposure. It also establishes the critical importance of additional research needed to understand how maternal exposures during pregnancy affect the developing child. (JH)

CitationMarkunas CA, Xu Z, Harlid S, Wade PA, Lie RT, Taylor JA, Wilcox AJ. 2014. Identification of DNA methylation changes in newborns related to maternal smoking during pregnancy. Environ Health Perspect; doi:10.1289/ehp.1307892 [Online 6 June 2014].

Control of histone expression by phosphorylation of an mRNA processing protein

By examining phosphorylation of the stem-loop-binding protein (SLBP), which has a role in processing histone mRNA, NIEHS scientists and their collaborators have detailed a new method of histone expression regulation. This research is important, because levels of histones, proteins that package DNA within the nucleus, have to be controlled carefully throughout the cell cycle. While DNA is replicating, histone levels must increase to package the new DNA, and following DNA replication, the presence of extra histones can be toxic to the cell.

Initially using biochemical assays, the scientists found that phosphorylation of SLBP at two different regions, increases the ability of the protein to bind to RNA. Interestingly, phosphorylation at the C-terminal tail of the protein increases RNA binding without actually coming into contact with the RNA. Further crystallography and nuclear magnetic resonance experiments showed that phosphorylation of this region caused a conformational change that increases RNA-binding abilities of the whole protein. The authors suggest this change occurs because phosphorylation increases the negative charges at the C-terminal tail that interact with and attract positive charges elsewhere in the protein. The process results in a more compact form that has a higher affinity for RNA. (JS)

CitationZhang J, Tan D, DeRose EF, Perera L, Dominski Z, Marzluff WF, Tong L, Hall TM. 2014. Molecular mechanisms for the regulation of histone mRNA stem-loop-binding protein by phosphorylation. Proc Natl Acad Sci U S A 111(29):E2937-E2946.

Retinoic acid-related orphan receptors involved in novel signaling pathway

Scientists at NIEHS and their colleagues at several institutions revealed that two vitamin D derivatives function as antagonists of retinoic acid-related orphan receptor (ROR)alpha and RORgamma-mediated transactivation. This novel finding, along with the discovery that RORalpha and RORgamma are expressed in a wide range of immune and skin cells, sheds light on the complex regulation of the body’s largest organ, the skin.

RORalpha and RORgamma are members of a larger family of nuclear receptors, which regulate many physiological processes, by binding to ligands that produce a transcriptional response. The main ligands for these receptors include cholesterol and its derivatives, making the ROR receptors attractive targets for therapeutics.

Prior to this work, researchers were unaware that secosteroids, such as the vitamin D derivatives 20(OH)D3 and 20,23(OH)2D3, could act as endogenous antagonists of RORalpha and RORgamma. Using functional assays and molecular modeling techniques, the authors found that both molecules act as antagonists of ROR-mediated activation of transcriptional responses.

In addition, they determined that both RORalpha and RORgamma is expressed in a variety of skin cells, including, but not limited to, sweat glands, hair follicles, sebaceous glands, and melanoma skin cell lines. Furthermore, these vitamin D3 derivatives act on immune cells expressing RORalpha or RORgamma. By acting as antagonists of RORalpha  and RORgamma, these derivatives open new possibilities to modulate local (skin) or systemic (immune system) bioregulatory activities and the development of therapeutic strategies. (MF)

CitationSlominski AT, Kim TK, Takeda Y, Janjetovic Z, Brozyna AA, Skobowiat C, Wang J, Postlethwaite A, Li W, Tuckey RC, Jetten AM. 2014. RORalpha and RORgamma are expressed in human skin and serve as receptors for endogenously produced noncalcemic 20-hydroxy- and 20,23-dihyroxyvitamin D. FASEB J 28(7):2775-2789.

Crystal structure of an important inositol phosphate kinase

Researchers from NIEHS have identified the crystal structure of a bifunctional inositol phosphate kinase (IPK), IP6K/IP3K, from E. histoloytica (EhIP6KA), and extrapolated the findings to human IP6K. The IP6Ks play pivotal roles in metabolic homeostasis and regulate interferon transcription in response to viral infection.

The present study, published in Nature Communications, described the crystal structure of the EhIP6KA. The authors also used site-directed mutagenesis of the human IP6K2 to describe two structural elements, an alpha-helical pair and a rare two-turn helix, that together form a substrate-binding pocket with an open clamshell geometry. InsP6 has substantial contacts with both structural elements whereas InsP3 rotates 55 degrees closer to the alpha-helices, thus providing insight into the molecular determinants of both IP3Ks and IP6Ks.

The discovery of IP6K structure illuminates the molecular basis for its kinase activities and offers a description of how separate IP3 and IP6Ks evolved from a bi-functional ancestor. The study provides important information for the rational design of inhibitors that might selectively target PDKG catalytic motif containing kinases, both for research tools and therapeutic applications. (MM)

CitationWang H, DeRose EF, London RE, Shears SB. 2014. IP6K structure and the molecular determinants of catalytic specificity in an inositol phosphate kinase family. Nat Commun 5:4178.

(Monica Frazier, Ph.D., is an Intramural Research Training Award (IRTA) fellow in the NIEHS Mechanisms of Mutation Group. John House, Ph.D., is an IRTA fellow in the NIEHS Genetic Epidemiology Group. Mallikarjuna Metukuri, Ph.D., is a research fellow in the NIEHS Metabolism, Genes, and Environment Group. Jordan St. Charles, Ph.D., is a fellow in the NIEHS DNA Replication Fidelity Group.)

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