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September 2011


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Extramural papers of the month

By Jerry Phelps
September 2011

SRP logo Research Brief

Discovery of the seventh and eighth bases of DNA

NIEHS Superfund Research Program grantees at the University of North Carolina Chapel Hill have discovered the seventh and eighth bases of DNA. These last two bases, called 5-formylcytosine and 5-carboxylcytosine, are actually versions of cytosine that have been modified by Tet proteins, molecular entities thought to play a role in DNA demethylation and stem cell reprogramming. The finding could have important implications for stem cell research, as it could provide researchers with new tools to erase previous methylation patterns to reprogram adult cells. The discovery also could inform cancer research, as it could give scientists the opportunity to reactivate tumor suppressor genes that had been silenced by DNA methylation.

Citation: Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, He C, Zhang Y. (http://www.ncbi.nlm.nih.gov/pubmed/21778364) Exit NIEHS 2011. Tet Proteins Can Convert 5-Methylcytosine to 5-Formylcytosine and 5-Carboxylcytosine. Science; doi:10.1126/science.1210597 [Online 21 July 2011]

Autism and prenatal vitamins

In a population-based case control study of 566 subjects comparing a group of autistic children to a matched control group of children with normal development, researchers found that mother who didn't take prenatal vitamins were at greater risk of having an autistic child, and certain genetic markers greatly increased the risk.

Researchers examined maternal intake of prenatal vitamins in the three months before conception and the first month of pregnancy, and they looked for genotypes associated with autism. There was a dose/response relationship - the more prenatal vitamins a woman took, the less likely she would have an autistic child. There was no association with other types of multivitamins, and no association with prenatal vitamin intake during months two through nine of pregnancy. Having certain genotypes also increased the odds that a woman would have an autistic child. Children with the COMT 472 AA gene were at increased risk of autism. If their mothers took prenatal vitamins, the odds ratio for the risk of autism was 1.8 - if their mothers didn't, the odds ratio jumped to 7.2. This suggests that the maternal-fetal environment can magnify the effects of a susceptibility gene.

The authors think there are plausible biological explanations. Folate and other B vitamins are critical to neurodevelopment. The gene variants were in one-carbon metabolism pathways, therefore suggesting that methylation mechanisms may be responsible.

Citation: Schmidt RJ, Hansen RL, Hartiala J, Allayee H, Schmidt LC, Tancredi DJ, Tassone F, Hertz-Picciotto I(http://www.ncbi.nlm.nih.gov/pubmed/21610500). Exit NIEHS 2011. Prenatal vitamins, one-carbon metabolism gene variants, and risk for autism. Epidemiology 22(4):476-485. Story(http://www.niehs.nih.gov/news/newsletter/2011/june/science-early/index.cfm)

Microparticle delivery increases efficacy of doxorubicin in treatment of mesothelioma

NIEHS-supported researchers at the University of Vermont report possible new advances in the treatment of malignant mesothelioma by microparticle delivery of the chemotherapeutic agent doxorubicin. The research was carried out in laboratory animals and builds on previous findings from the same investigators.

Malignant mesotheliomas have a poor prognosis, largely because of their resistance to anti-cancer drugs like doxorubicin and others. The current study investigated the use of acid-prepared mesoporous microspheres (APMS) as a delivery vehicle for doxorubicin. APMS have been shown in previous research to be non-toxic in laboratory animals. The investigators injected APMS-doxorubicin intraperitoneally or directly into subcutaneous tumors. In comparison to doxorubicin alone, APMS-doxorubicin enhanced intracellular uptake of the drug and mesothelioma cell death. In the intraperitoneal-treated animals, decrease tumor numbers and tumor size was achieved with one-third the dose of doxorubicin in the combined form.

This finding suggests that APMS delivery of doxorubicin is an effective treatment for malignant mesotheliomas and reduces the dosage of the drug necessary to achieve tumor regression.

Citation: Hillegass JM, Blumen SR, Cheng K, MacPherson MB, Alexeeva V, Lathrop SA, Beuschel SL, Steinbacher JL, Butnor KJ, Ramos-NiƱo ME, Shukla A, James TA, Weiss, DJ, Taatjes DJ, Pass HI, Carbone M, Landry CC, Mossman BT(http://www.ncbi.nlm.nih.gov/pubmed/20830711). Exit NIEHS 2011. Increased efficacy of doxorubicin delivered in multifunctional microparticles for mesothelioma therapy. Int J Cancer 129(1):233-244.

Genetic map of African-Americans will aid the study of diseases

A large multi-institutional team of researchers, including NIEHS grantees, has constructed a detailed genetic map from a population of more than 30,000 African-Americans that will be used to better understand the causes of disease and human evolution. This new map is the first built from an African-American population.

The map holds promise for both broad genome-wide applications and narrowly focused single disease research. It will be helpful in studying diseases with a genetic basis especially those that strike African-Americans frequently, such as hypertension and diabetes. A surprising finding was that the map turned out to be very different than maps based on people of European and other non-African ancestry. The authors think this is due to recombination that has occurred in the U.S. population over the last two or three centuries. It turns out that African-Americans have genetic machinery for recombination that is different than Europeans. The team discovered that a 13 base-pair motif, responsible for many recombination hotspots in Europeans, accounts for only two-thirds as much recombination in African-Americans. The remaining third is connected to a newly identified motif of 17 base-pairs.

These findings are expected to help researchers understand the underlying causes of congenital conditions that occur more often in African-Americans and will also be invaluable in discovering new disease genes in all populations.

Citation: Hinch AG, Tandon A, Patterson N, Song Y, Rohland N, Palmer CD, Chen GK, Wang K, Buxbaum SG, Akylbekova EL, Aldrich MC, Ambrosone CB, Amos C, Bandera EV, Berndt SI, Bernstein L, Blot WJ, Bock CH, Boerwinkle E, Cai Q, Caporaso N, Casey G, Cupples LA, Deming SL, Diver WR, Divers J, Fornage M, Gillanders EM, Glessner J, Harris CC, Hu JJ, Ingles SA, Isaacs W, John EM, Kao WH, Keating B, Kittles RA, Kolonel LN, Larkin E, Le Marchand L, McNeill LH, Millikan RC, Murphy A, Musani S, Neslund-Dudas C, Nyante S, Papanicolaou GJ, Press MF, Psaty BM, Reiner AP, Rich SS, Rodriguez-Gil JL, Rotter JI, Rybicki BA, Schwartz AG, Signorello LB, Spitz M, Strom SS, Thun MJ, Tucker MA, Wang Z, Wiencke JK, Witte JS, Wrensch M, Wu X, Yamamura Y, Zanetti KA, Zheng W, Ziegler RG, Zhu X, Redline S, Hirschhorn JN, Henderson BE, Taylor HA Jr, Price AL, Hakonarson H, Chanock SJ, Haiman CA, Wilson JG, Reich D, Myers SR(http://www.ncbi.nlm.nih.gov/pubmed/21775986). Exit NIEHS 2011. The landscape of recombination in African Americans. Nature 476(7359):170-175.

(Jerry Phelps is a program analyst in the NIEHS Division of Extramural Research and Training.)



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