A randomized, double-blind, intervention study will be conducted. Briefly, the protocol will be as follows: Subject recruitment: Healthy men (120) and women (120) will be recruited by the Grand Forks Human Nutrition Research Center (GFHNRC) from the Grand Forks, ND, community. Each prospective volunteer, will sign an informed consent and be evaluated for eligibility on the basis of a physical examination, standard clinical chemistries, health and diet histories. Treatment: Subjects will be assigned randomly to treatments consisting of 0, 50, 100, or 200 ug Se/day (as L-selenomethionine) administered in daily oral doses. Each subject will receive a 30 day supply of pills and must return to the Center monthly to receive a new supply. Endpoints: Fasting blood samples and 24-hr. urine samples will be drawn one week prior to and at the beginning of the study, and at three mo. intervals for a year of supplementation. Selenium, homocysteine, vitamin B12 and folate (potential effectors of the methylation-dependent excretion of Se) and glutathione peroxidase activity will be determined in plasma. Selenium and 8-OH-deoxyguanosine will be determined in urine. Blood will be analyzed for DNA damage utilizing flow cytometric methods and the comet assay. At the beginning of the study, lymphocytes will be prepared from whole blood samples from each subject;cellular DNA will be prepared and archived for future determinations of the allelic variants of Se-dependent enzymes (e.g., glutathione peroxidases [GPX] 1 and 4), selenoprotein P and selenoprotein 15 and/or other relevant enzymes (e.g., glutathione S-transferase). Analytical results will be used to compute the relationship of final-plateau plasma (9-12 mos.) Se concentration as a function of baseline (0 mos.) Se level, Se dose (μg/d), metabolic body size (k 0.75) and urinary Se, as well as outcomes related to carcinogenesis (lymphocyte DNA damage and urinary 8-OH-deoxyguanosine). Other parameters will be tested for significance as covariants: sex;plasma homocysteine, folate and vitamin B12;and selenoprotein genotypes. Subject Compensation: Subjects will be compensated for their participation in the supplementation study, $300/subject using a graded payment schedule. Human Subjects Protection: The study protocol will be reviewed and approved by the University of North Dakota Human Subjects Committee, which provides that service to the GFHNRC. Addendum: In this addendum to the statement of work, the GFHNRC will continue to conduct short term studies to examine changes in gene expression in response to the chemical form of selenium supplementation and an individual's genotype for GPX1.
