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Environmental Factor, October 2012

Intramural papers of the month

By Brant Hamel, Sonika Patial, and Jeffrey Stumpf

Maternal smoking during pregnancy leads to modifications in child’s DNA

A recent study conducted by NIEHS researchers identified a DNA modification in children born to mothers who smoked during pregnancy. This modification, known as cytosine DNA methylation, has been proposed to be one of the mechanisms that may lead to a variety of adverse health effects in these children, such as low birth weights, childhood cancers, respiratory illness, obesity, and high blood pressure.

In the present study, researchers determined if maternal smoking during pregnancy could affect cytosine DNA methylation in a child’s DNA. The researchers took advantage of the new Infinium HumanMethylation450 Beadchip (450K) technology, which has the capability of identifying DNA methylation at over 470,000 cytosine-guanine dinucleotide (CpG) sites, common markers of DNA methylation, across the genome. They used this platform to measure DNA methylation in 1,062 infant cord blood samples from a birth cohort in Norway.

Researchers identified significantly different methylation for 26 CpGs and mapped them to 10 different genes. The identified genes play a key role in tobacco smoke detoxification and diverse developmental processes. These findings implicate DNA methylation changes as a potential pathogenic mechanism responsible for adverse health outcomes in children from mothers who smoked during pregnancy. (SP)

CitationJoubert BR, Håberg SE, Nilsen RM, Wang X, Vollset SE, Murphy SK, Huang Z, Hoyo C, Midttun O, Cupul-Uicab LA, Ueland PM, Wu MC, Nystad W, Bell DA, Peddada SD, London SJ. 2012. 450K epigenome-wide scan identifies differential DNA methylation in newborns related to maternal smoking during pregnancy. Environ Health Perspect; doi:10.1289/ehp.1205412 [Online 31 July]. Story

Novel protein limits programmed mutagenesis to antibody-producing genes

In the July 25, 2012 edition of the Journal of Biological Chemistry, NIEHS researchers reported that the newly characterized SLIP-GC protein protects B lymphocytes genome from the mutagenic actions of activation-induced deaminase (AID) activity. Led by the Somatic Hypermutation Group, the study suggests SLIP-GC may be a key component regulating AID such that it only targets the regions in the DNA that encode highly variable antibodies.

Immune responses produce a myriad of different antibodies to increase the chances of developing antibodies that bind to the infectious agent. Antibody diversification requires drastic changes in the DNA sequence at specific regions of the immunoglobulin genes (Ig). AID is a cytosine deaminase that alters nucleotides and produces DNA breaks, thus randomly altering the genetic code and producing antibodies with different amino acid sequences. Targeting of AID to regions that promote antibody diversity is crucial, as untargeted AID activity could lead to genome instability.

The study used a newly created mouse model deficient in SLIP-GC and showed increases in the types of mutations that are expected from AID activity in both Ig and non-Ig regions. This initial characterization shows the importance of SLIP-GC on limiting untargeted mutagenesis, and future studies will use this model to understand how SLIP-GC negatively regulates AID activity. (JS)

CitationRichter K, Burch L, Chao F, Henke D, Jiang C, Daly J, Zhao ML, Kissling G, Diaz M. 2012. Altered pattern of immunoglobulin hypermutation in mice in SLIP-GC. J Biol Chem; doi:10.1074/jbc.M112.340661 [Online 25 July 2012].

Cerium dioxide nanoparticles may lead to human immune cell death

A new study by NIEHS researchers using human peripheral blood monocytes from healthy donors shows that cerium dioxide (CeO2) nanoparticles at environmentally relevant exposure levels causes cell death via apoptosis and autophagy. It is the first report on the effects of CeO2 nanoparticles in primary human cells and given the fact that CeO2 emissions from diesel fuel are estimated to reach 22 million pounds per year in Europe, it is vital to understand their potential impact on human health.

Researchers exposed isolated human monocytes to low doses of CeO2 nanoparticles for 20 to 40 hours. Significant increases in cell death were observed through an apoptotic mechanism that was independent of caspase activation, but dependent on mitochondrial damage and induction of apoptosis-inducing factor. Cell death was also mediated through autophagy, which increased if the p53 tumor suppressor protein was inhibited. Given that monocytes are crucial for human immunity, the work suggests even at low doses CeO2 nanoparticles may have detrimental effects on human health. Furthermore, the results underscore the need for critical evaluation of environmentally relevant concentrations of other nanomaterials on primary human cells. (BH)

CitationHussain S, Al-Nsour F, Rice AB, Marshburn J, Yingling B, Ji Z, Zink JI, Walker NJ, Garantziotis S. 2012. Cerium dioxide nanoparticles induce apoptosis and autophagy in human peripheral blood monocytes. ACS Nano 6(7):5820-5829.

Study dissects regulation of innate immunity by p53 tumor suppressor

NIEHS researchers demonstrated that innate immune responses can be enhanced by DNA damage. They established a chain of events in which the lesions stabilize the p53 tumor suppressor that then increases expression of immune genes. Published in Cancer Research, the paper suggests that induction of the p53 tumor suppressor might provide opportunities to kill tumor cells through the immune response. This important link between p53 and immune response also suggests an exciting possibility of therapeutic vaccination to treat cancer.

The studies, performed by researchers in the Chromosome Stability Group, were based on their previous characterization of the consensus sequence in gene promoters bound by p53 and the identification of Toll-like receptor (TLR) family of innate immunity genes as being likely candidates for p53 regulation. The authors used human cancer cell lines with a variety of p53 mutations to show that a change in p53 function affects its ability to induce some TLR genes.

Both DNA damaging agents and TLR activating ligands are widely used in cancer treatment. Since each of the 10 member TLR gene family tested was induced differently in cell-type and agent-dependent manners, these findings suggest that the matrix of p53 status, chromosome stress and responsiveness of individual TLRs should be considered in cancer diagnosis and in cancer therapeutic strategies that target the TLR pathway. (JS)

CitationShatz M, Menendez D, Resnick MA. 2012. The human TLR innate immune gene family is differentially influenced by DNA stress and p53 status in cancer cells. Cancer Res 72(16):3948-3957.

(Brant Hamel, Ph.D., is an Intramural Research Training Award (IRTA) fellow in the NIEHS Laboratory of Signal Transduction. Sonika Patial, D.V.M., Ph.D., is a visiting fellow in the NIEHS Laboratory of Signal Transduction. Jeffrey Stumpf, Ph.D., is a research fellow in the NIEHS Laboratory of Molecular Genetics.)

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