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Intramural Papers of the Month

By Robin Arnette and Laura Hall
August 2009

Multivitamin Intake Is Associated with Longer Telomeres

Telomeres, comprised of a repeated DNA sequence (TTAGGG) and proteins that occur at chromosome ends, prevent chromosomal damage and degradation. Because telomere length decreases during each cycle of cell division, it has been linked to a higher risk of several chronic diseases and mortality. Researchers in the field have proposed that shortened telomeres might be associated with accelerated "human aging."

Investigators from NIEHS and the University of Utah have determined that multivitamin use is associated with longer telomeres in women. This examination is the first epidemiologic link between multivitamin consumption and longer telomeres.

The research team analyzed leukocyte DNA samples from participants in the NIEHS Sister Study, ( a prospective cohort of healthy sisters of breast cancer patients. Team members used quantitative polymerase chain reaction (PCR) to measure the relative length of leukocyte telomeres and combined the data with participant information regarding the type, frequency and duration of multivitamin intake.

The age of these women ranged from 35 to 74 at the time of blood collection. The investigators found that on average, daily multivitamin users had 5.1 percent longer telomeres then non-users. The findings also corroborated preliminary experimental evidence from others that vitamins C and E may protect telomeres in vitro. The analysis took into account known or suspected factors that were associated with telomere length such as age, smoking and perceived stress, but could not rule out potential impact from other unmeasured lifestyle factors.

Citation: Xu Q, Parks CG, DeRoo LA, Cawthon RM, Sandler DP, Chen H ( Exit NIEHS. 2009. Multivitamin use and telomere length in women. Am J Clin Nutr 89(6):1857-1863.

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Pesticides Are Associated With Allergic Asthma in Male Farmers

Using data from the Agricultural Health Study (AHS), ( researchers from NIEHS, the National Institute for Occupational Safety and Health (NIOSH) and the National Cancer Institute (NCI) have concluded that specific pesticides are associated with allergic asthma and that self-reported high pesticide exposure events (HPEE) are associated with both allergic and non-allergic asthma.

Enrolled between 1993 and 1997, the AHS is a prospective cohort of pesticide applicators and their spouses in Iowa and North Carolina. Fifty-two thousand licensed private pesticide applicators were enrolled in the AHS, but the analysis for this publication was limited to the 19,704 male farmers who completed both the initial and follow-up questionnaires. The questionnaires provided a complete medical history and information about smoking habits, body mass, respiratory and allergic symptoms, other respiratory illnesses and farming practices. The team members' goal was to evaluate the lifetime use of 48 pesticides and the prevalence of adult-onset asthma.

A history of a high pesticide exposure event doubled the rates of allergic and non-allergic asthma. Out of the 48 pesticides, 12 were associated with allergic asthma, with five exhibiting significant exposure-response trends: coumaphos, heptachlor, parathion, 80/20 mix (carbon tetrachloride/carbon disulfide) and ethylene dibromide. Four additional pesticides were associated with non-allergic asthma, with DDT having the strongest effect estimate.

Citation: Hoppin JA, Umbach DM, London SJ, Henneberger PK, Kullman GJ, Coble J, Alavanja MC, Beane Freeman LE, Sandler DP ( Exit NIEHS. 2009. Pesticide use and adult-onset asthma among male farmers in the Agricultural Health Study. Eur Respir J June 18. [Epub ahead of print]

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A Missense Mutation in repro32 Mutant Male Mice Causes Infertility

Investigators at NIEHS, in collaboration with the researchers who created the repro32 N-ethyl-N-nitrosourea (ENU)-induced mutated mouse line at the Jackson Laboratory in Bar Harbor, Maine, have determined that a missense mutation in the "capping protein muscle Z-line alpha 3" (Capza3) gene is responsible for abnormal spermiogenesis and a decrease in sperm production in repro32 homozygous mutant mice. The CAPZA3 protein is a filamentous actin (F-actin) regulatory protein that likely forms a heterodimer with the sperm-specific variant CAPZB3 in order to regulate F-actin dynamics.

Male repro32 mutant mice produce sperm that have irregularly-shaped heads and poor motility. Because the mutant sperm are unable to shed excess cytoplasm from the middle piece of the flagellum during spermiogenesis, a bag of cytoplasm encases both the abnormally developed flagellum and the sperm head.

The research team demonstrated that F-actin is involved in the development of normal sperm and that the abnormalities seen in the mutant sperm were due to the inability of CAPZA3 and F-actin to organize properly. This disorganization was caused by an N-terminal missense mutation in Capza3. The data indicate that CAPZA3 is required for the maintenance of male fertility in the mouse and possibly other mammalian species.

Citation: Geyer CB, Inselman AL, Sunman JA, Bornstein S, Handel MA, Eddy EM ( Exit NIEHS. 2009. A missense mutation in the Capza3 gene and disruption of F-actin organization in spermatids of repro32 infertile male mice. Dev Biol 330(1):142-152.

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Elucidation of the Cu,Zn-Superoxide Dismutase Peroxide Cycle

NIEHS researchers have shown that peroxymonocarbonate (HOOCO2-) is a key intermediate in the Cu,Zn-superoxide dismutase (SOD1) peroxidase cycle and a precursor of carbonate radical anions. This finding discounts the assumption that SOD1 involves the formation of hypervalent metal states similar to those in the heme-peroxidase catalytic mechanism.

SOD1 is an enzyme found in mammalian cells and tissues that protects them against damage generated by superoxide anion and other oxygen free radicals. SOD1 peroxidase activity has been proposed to be involved in the development of amyotrophic lateral sclerosis (ALS), a motor neuron disease that leads to progressive paralysis and death. Results indicate that the carbonate radical production from the peroxymonocarbonate intermediated SOD1 peroxidase cycle would not be sufficient at physiological pH to be a main contributor to the development of ALS.

The authors used electron paramagnetic resonance (EPR) to show that the rate limiting first step in the SOD1 peroxidase cycle uses the hydroxide anion (HOO-) to reduce SOD1-CU(II) to SOD1-Cu(I). Nuclear magnetic resonance (NMR) and EPR studies confirmed that HOO- and carbon dioxide (CO2), combine to form HOOCO2-. NMR studies established peroxymonocarbonate as the main substrate for the SOD1-CU(I) oxidative conversion back to SOD1-Cu(II) having an estimated second-order rate constant 10 times higher than that of hydrogen peroxide (H2O2).

Citation: Bonini MG, Gabel SA, Ranguelova K, Stadler K, Derose EF, London RE, Mason RP ( Exit NIEHS. 2009. Direct magnetic resonance evidence for peroxymonocarbonate involvement in the cu,zn-superoxide dismutase peroxidase catalytic cycle. J Biol Chem 284(21):14618-14627.

(Laura Hall is a biologist in the NIEHS Laboratory of Pharmacology currently on detail as a writer for the Environmental Factor.)

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