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Profound health disparities are widespread among Native Hawaiians, other Pacific Islanders, and Filipinos in Hawai‘i. Efforts to reduce and eliminate health disparities are limited by a shortage of investigators trained in addressing the genetic, socio economic, and environmental factors that contribute to disparities. In this conference proceedings report from the 2022 RCMI Consortium National Conference, we describe our mentoring program, with an emphasis on community-engaged research. Elements include our encouragement of a team-science, customized Pilot Projects Program (PPP), a Mentoring Bootcamp, and a mentoring support network. During 2017–2022, we received 102 PPP preproposals. Of these, 45 (48%) were invited to submit full proposals, and 22 (19%) were awarded (8 basic biomedical, 7 clinical, 7 behavioral). Eighty-three percent of awards were made to early-career faculty (31% ethnic minority, 72% women). These 22 awards generated 77 related publications; 84 new grants were submitted, of which 31 were awarded with a resultant return on investment of 5.9. From 5 to 11 investigators were supported by PPP awards each year. A robust usage of core services was observed. Our descriptive report (as part of a scientific conference session on RCMI specialized centers) focuses on a mentoring vehicle and shows how it can support early-stage investigators in pursuing careers in health disparities research.

Fifty years have passed since the discovery of the first selenoprotein by Rotruck and colleagues. In that time, the essential nature of selenium has come to light including the dependence of the brain on selenium to function properly. Animal models have shown that a lack of certain selenoproteins in the brain is detrimental for neuronal health, sometimes leading to neurodegeneration. There is also potential for selenoprotein-mediated redox balance to impact neuronal activity, including neurotransmission. Important insights on these topics have been gained over the past several years. This review briefly summarizes the known roles of specific selenoproteins in the brain while highlighting recent advancements regarding selenoproteins in neuronal function. Hypothetical models of selenoprotein function and emerging topics in the field are also provided.

The ability of the body to maintain homeostasis requires constant communication between the brain and peripheral tissues. Different organs produce signals, often in the form of hormones, which are detected by the hypothalamus. In response, the hypothalamus alters its regulation of bodily processes, which is achieved through its own pathways of hormonal communication. The generation and transmission of the molecules involved in these bi-directional axes can be affected by redox balance. The essential trace element selenium is known to influence numerous physiological processes, including energy homeostasis, through its various redox functions. Selenium must be obtained through the diet and is used to synthesize selenoproteins, a family of proteins with mainly antioxidant functions. Alterations in selenium status have been correlated with homeostatic disturbances in humans and studies with animal models of selenoprotein dysfunction indicate a strong influence on energy balance. The relationship between selenium and energy metabolism is complicated, however, as selenium has been shown to participate in multiple levels of homeostatic communication. This review discusses the role of selenium in the various pathways of communication between the body and the brain that are essential for maintaining homeostasis.

The Research Centers in Minority Institu­tions (RCMI) program was established by the US Congress to support the develop­ment of biomedical research infrastructure at minority-serving institutions granting doctoral degrees in the health professions or in a health-related science. RCMI institu­tions also conduct research on diseases that disproportionately affect racial and ethnic minorities (ie, African Americans/Blacks, American Indians and Alaska Natives, His­panics, Native Hawaiians and Other Pacific Islanders), those of low socioeconomic sta­tus, and rural persons. Quantitative metrics, including the numbers of doctoral science degrees granted to underrepresented stu­dents, NIH peer-reviewed research funding, peer-reviewed publications, and numbers of racial and ethnic minorities participat­ing in sponsored research, demonstrate that RCMI grantee institutions have made substantial progress toward the intent of the Congressional legislation, as well as the NIH/NIMHD-linked goals of addressing workforce diversity and health disparities. Despite this progress, nationally, many challenges remain, including persistent disparities in research and career develop­ment awards to minority investigators. The continuing underrepresentation of minority investigators in NIH-sponsored research across multiple disease areas is of concern, in the face of unrelenting national health inequities. With the collaborative network support by the RCMI Translational Research Network (RTRN), the RCMI community is uniquely positioned to address these chal­lenges through its community engagement and strategic partnerships with non-RCMI institutions. Funding agencies can play an important role by incentivizing such col­laborations, and incorporating metrics for research funding that address underrep­resented populations, workforce diversity and health equity.Ethn Dis. 2019;29(Suppl 1):135-144; doi:10.18865/ed.29.S1.135.

The stress response is an important tool in an organism’s ability to properly respond to adverse environmental conditions in order to survive. Intense acute or chronic elevation of glucocorticoids, a class of stress hormone, can have deleterious neurological effects, however, including memory impairments and emotional disturbances. In recent years, the protective role of the antioxidant micronutrient selenium against the negative impact of externally applied stress has begun to come to light. In this review, we will discuss the effects of stress on the brain, with a focus on glucocorticoid action in the hippocampus and cerebral cortex, and emerging evidence of an ability of selenium to normalize neurological function in the context of various stress and glucocorticoid exposure paradigms in rodent models.

The essential micronutrient selenium (Se) provides antioxidant defense and supports numerous biological functions. Obtained through dietary intake, Se is incorporated into selenoproteins via the amino acid, selenocysteine (Sec). Mice with genetic deletion of the Se carrier, selenoprotein P (SELENOP), and the Se recycling enzyme selenocysteine lyase (SCLY), suffer from sexually dimorphic neurological deficits and require Se supplementation for viability. These impairments are more pronounced in males and are exacerbated by dietary Se restriction. We report here that, by 10 weeks of age, female Selenop/Scly double knockout (DKO) mice supplemented with 1 mg/ml sodium selenite in drinking water develop signs of hyper-adiposity not seen in male DKO mice. Unexpectedly, this metabolic phenotype can be reversed by removing Se from the drinking water at post-natal day 22, just prior to puberty. Restricting access to Se at this age prevents excess body weight gain and restriction from either post-natal day 22 or 37 reduces gonadal fat deposits. These results provide new insight into the sex-dependent relationship between Se and metabolic homeostasis.

In this minireview, we provide a historical outline of the events that led to the identification and characterization of the deiodinases, the recognition that deiodination plays a major role in thyroid hormone action, and the cloning of the 3 deiodinase genes. The story starts in 1820, when it was first determined that elemental iodine was important for normal thyroid function. Almost 100 years later, it was found that the primary active principle of the gland, T4, contains iodine. Once radioactive iodine became available in the 1940s, it was demonstrated that the metabolism of T4 included deiodination, but at the time it was assumed to be merely a degradative process. However, this view was questioned after the discovery of T3 in 1952. We discuss in some detail the events of the next 20 years, which included some failures followed by the successful demonstration that deiodination is indeed essential to normal thyroid hormone action. Finally, we describe how the 3 deiodinases were identified and characterized and their genes cloned.

OBJECTIVES: The trace element selenium (Se) is known mainly for its antioxidant properties and is critical for proper brain function. The role of Se in regulating energy metabolism, and the sexually dimorphic nature of Se functions, however, are underappreciated, and warrant increased attention. Recent work in our lab has highlighted the importance of Se utilization in hypothalamic regulation of energy metabolism. Dietary Se is incorporated into selenoproteins in the form of the unique amino acid selenocysteine (Sec). The objective of this study was to assess the role of selenoproteins in Agouti-related peptide (Agrp)-positive neurons, an orexigenic sub-population of the hypothalamus. METHODS: We generated mice with Agrp-Cre-driven deletion of selenocysteine tRNA (Trsp-Agrp KO mice), which is essential for Sec incorporation into selenoproteins, thus ablating selenoprotein synthesis in Agrp-positive neurons. The metabolic phenotype of Trsp-Agrp KO mice challenged with a high-fat diet was characterized via glucose tolerance test (i.p. injection) and the use of analytical chambers to measure food intake and respiratory metabolism. Prior to sacrifice, mice were challenged with leptin (i.p. injection) to assess neuronal leptin responsivity via immunohistochemistry and western blot. Brown adipose tissue (BAT) morphology and thermogenic protein expression were also analyzed. RESULTS: Female Trsp-Agrp KO mice displayed resistance to diet-induced obesity, which was accompanied by improved glucose tolerance and elevated energy expenditure levels without changes in food intake. Female Trsp-Agrp KO mice also had greater leptin sensitivity and showed signs of elevated BAT thermogenesis. Male Trsp-Agrp KO mice displayed no changes in metabolic phenotype. CONCLUSIONS: Loss of selenoproteins in Agrp-positive neurons of the hypothalamus promotes energy expenditure and reduces diet-induced obesity in a sexually dimorphic manner, leading to resistance to a high-fat diet in females. FUNDING SOURCES: This work was funded by grant support from the National Institute of Diabetes and Digestive and Kidney Diseases (MJB) and Ola HAWAII, a grant from the National Institute on Minority Health and Health Disparities.

OBJECTIVES: Americans are a selenium-replete population with high use of statins, a drug commonly prescribed to ameliorate hypercholesterolemia. Statins act by inhibiting the first step of cholesterol biosynthesis in the liver, the mevalonate pathway. This pathway is also important for the maturation of the selenocysteine tRNA, responsible for the expression of selenoproteins. Selenoprotein deficits were suggested as responsible for side effects of statins, such as increased oxidative stress leading to muscle cramps and myopathies. Selenium for selenoprotein synthesis can be provided by diet or by the actions of the selenium recycling enzyme selenocysteine lyase (Scly). Our objective was to investigate the effects of the use of statins in an animal model lacking the enzyme Scly and fed a high-fat, Se-supplemented diet. METHODS: Age-matched homozygous littermates wild-type C57BL/6 N (WT) and Scly knockout (Scly KO) mice were fed a high-fat diet containing a 1 ppm blend of selenite plus selenomethionine, and were daily treated with simvastatin (5 mg/kg of body weight) for 21 days. We analyzed serum cholesterol levels, oxidative stress and creatine kinase (CK) activity, and liver and skeletal muscle gene expression of selenoproteins and enzymes involved in creatine metabolism. RESULTS: Obese Scly KO mice had a sex-dependent response statin treatment. While female Scly KO mice improved their body weight after statin treatment, male Scly KO mice further gained weight. Statin treatment improved serum oxidative stress in the Scly KO mice, despite sharp elevation of CK activity. Statin treatment did not affect hepatic selenoprotein gene expression of Scly KO mice, but impaired glutathione peroxidase 1 expression in the muscle of male Scly KO mice, while enhancing it in females. CONCLUSIONS: Responses to statin treatment in Scly KO mice fed a high-fat, Se-supplemented diet vary according to sex, benefiting more female than male mice, and are mostly independent of selenoprotein expression. FUNDING SOURCES: National Institutes of Health (NIH) grants U54MD007601 Ola Hawaii (subproject 5544) and R01DK47320, and Fundação de Amparo à Pesquisa do Estado de São Paulo fellowship 2018/0,9478–4. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

BACKGROUND The amino acid selenocysteine (Sec) is an integral part of selenoproteins, a class of proteins mostly involved in strong redox reactions. The enzyme Sec lyase (SCLY) decomposes Sec into selenide allowing for the recycling of the selenium (Se) atom via the selenoprotein synthesis machinery. We previously demonstrated that disruption of the Scly gene (Scly KO) in mice leads to the development of obesity and metabolic syndrome, with effects on glucose homeostasis, worsened by Se deficiency or a high-fat diet, and exacerbated in male mice. Our objective was to determine whether Se supplementation could ameliorate obesity and restore glucose homeostasis in the Scly KO mice. METHODS Three-weeks old male and female Scly KO mice were fed in separate experiments a diet containing 45 % kcal fat and either sodium selenite or a mixture of sodium selenite and selenomethionine (selenite/SeMet) at moderate (0.25 ppm) or high (0.5–1 ppm) levels for 9 weeks, and assessed for metabolic parameters, oxidative stress and expression of selenoproteins. RESULTS Se supplementation was unable to prevent obesity and elevated epididymal white adipose tissue weights in male Scly KO mice. Serum glutathione peroxidase activity in Scly KO mice was unchanged regardless of sex or dietary Se intake; however, supplementation with a mixture of selenite/SeMet improved oxidative stress biomarkers in the male Scly KO mice. CONCLUSION These results unveil sex- and selenocompound-specific regulation of energy metabolism after the loss of Scly, pointing to a role of this enzyme in the control of whole-body energy metabolism regardless of Se levels.

Sexual dimorphism, the condition in which males and females in a species differ beyond the morphology of sex organs, delineates critical aspects of the biology of higher eukaryotes, including selenium metabolism. While sex differences in selenium biology have been described by several laboratories, delineation of the effects of sex in selenium function and regulation of selenoprotein expression is still in its infancy. This review encompasses the available information on sex-dependent parameters of selenium metabolism, as well as the effects of selenium on sex hormones. Gaps in the current knowledge of selenium and sex are identified and discussed.

People with obesity are often dyslipidemic and prescribed statins to prevent cardiovascular events. A common side effect of statin use is myopathy. This could potentially be caused by the reduction of selenoproteins that curb oxidative stress, in turn, affecting creatine metabolism. We determined if statins regulate hepatic and muscular selenoprotein expression, oxidative stress and creatine metabolism. Mice lacking selenocysteine lyase (Scly KO), a selenium-provider enzyme for selenoprotein synthesis, were fed a high-fat, Se-supplemented diet and treated with simvastatin. Statin improved creatine metabolism in females and oxidative responses in both sexes. Male Scly KO mice were heavier than females after statin treatment. Hepatic selenoproteins were unaffected by statin and genotype in females. Statin upregulated muscular Gpx1 in females but not males, while Scly loss downregulated muscular Gpx1 in males and Selenon in females. Osgin1 was reduced in statin-treated Scly KO males after AmpliSeq analysis. These results refine our understanding of the sex-dependent role of selenium in statin responses.

Selenium, an essential trace element known mainly for its antioxidant properties, is critical for proper brain function and regulation of energy metabolism. Whole-body knockout of the selenium recycling enzyme, selenocysteine lyase (Scly), increases susceptibility to metabolic syndrome and diet-induced obesity in mice. Scly knockout mice also have decreased selenoprotein expression levels in the hypothalamus, a key regulator of energy homeostasis. This study investigated the role of selenium in whole-body metabolism regulation using a mouse model with hypothalamic knockout of Scly. Agouti-related peptide (Agrp) promoter-driven Scly knockout resulted in reduced weight gain and adiposity while on a high-fat diet (HFD). Scly-Agrp knockout mice had reduced Agrp expression in the hypothalamus, as measured by Western blot and immunohistochemistry (IHC). IHC also revealed that while control mice developed HFD-induced leptin resistance in the arcuate nucleus, Scly-Agrp knockout mice maintained leptin sensitivity. Brown adipose tissue from Scly-Agrp knockout mice had reduced lipid deposition and increased expression of the thermogenic marker uncoupled protein-1. This study sheds light on the important role of selenium utilization in energy homeostasis, provides new information on the interplay between the central nervous system and whole-body metabolism, and may help identify key targets of interest for therapeutic treatment of metabolic disorders.

Selenium is an essential dietary micronutrient. Ingested selenium is absorbed by the intestines and transported to the liver where it is mostly metabolized to selenocysteine (Sec). Sec is then incorporated into selenoproteins, including selenoprotein P (SELENOP), which is secreted into plasma and serves as a source of selenium to other tissues of the body. Herein, we provide an overview of the biology of selenium from its absorption and distribution to selenoprotein uptake and degradation, with a particular focus on the latter. Molecular mechanisms of selenoprotein degradation include the lysosome-mediated pathway for SELENOP and endoplasmic reticulum-mediated degradation of selenoproteins via ubiquitin-activated proteasomal pathways. Ubiquitin-activated pathways targeting full-length selenoproteins include the peroxisome proliferator-activated receptor gamma-dependent pathway and substrate-dependent ubiquitination. An alternate mechanism is utilized for truncated selenoproteins, in which cullin-RING E3 ubiquitin ligase 2 targets the defective proteins for ubiquitin-proteasomal degradation. Selenoproteins, particularly SELENOP, may have their Sec residues reutilized for new selenoprotein synthesis via Sec decomposition. This review will explore these aspects in selenium biology, providing insights to knowledge gaps that remain to be uncovered.

IntroductionPreeclampsia is a medical condition complicated with hypertension and proteinuria during pregnancy. While preeclampsia affects approximately 5% of pregnancies, it remains without a cure. In addition, women who had preeclampsia during pregnancy have been reported to have an increased risk for cardiovascular disease later in life. However, the disease etiology and molecular mechanisms remain poorly understood. The paucity in the literature on preeclampsia associated maternal cardiovascular risk in different ethnic populations also present a need for more research. Therefore, the objective of this study was to identify cardiovascular/metabolic single nucleotide polymorphisms (SNPs), genes, and regulatory pathways associated with early-onset preeclampsia.Materials and methodsWe compared maternal DNAs from 31 women with early-onset preeclampsia with those from a control group of 29 women without preeclampsia who delivered full-term normal birthweight infants. Women with multiple gestations and/or known medical disorders associated with preeclampsia (pregestational diabetes, chronic hypertension, renal disease, hyperthyroidism, and lupus) were excluded. The MetaboChip genotyping array with approximately 197,000 SNPs associated with metabolic and cardiovascular traits was used. Single nucleotide polymorphism analysis was performed using the SNPAssoc program in R. The Truncated Product Method was used to identify significantly associated genes. Ingenuity Pathway Analysis and Ingenuity Causal Network Analysis were used to identify significantly associated disease processes and regulatory gene networks respectively.ResultsThe early-onset preeclampsia group included 45% Filipino, 26% White, 16% other Asian, and 13% Native Hawaiian and other Pacific Islanders, which did not differ from the control group. There were no SNPs associated with early-onset preeclampsia after correction for multiple comparisons. However, through gene-based tests, 68 genes and 23 cardiovascular disease-related processes were found to be significantly associated. Associated gene regulatory networks involved cellular movement, cardiovascular disease, and inflammatory disease.ConclusionsMultiple cardiovascular genes and diseases demonstrate associations with early-onset preeclampsia. This unfolds new areas of research regarding the genetic determinants of early-onset preeclampsia and their relation to future cardiovascular disease.

T3 action is locally modulated by the intracellular type 2 (D2) and type 3 (D3) iodothyronine-deiodinases which convert the prohormone T4 to active T3, and inactivate T4 and T3, respectively. The synchronized expression of D3 followed by D2 is necessary for proper muscle development and regeneration. D2 and D3 are selenoproteins containing selenium (Se) at their active site in the form of the rare amino acid selenocysteine (Sec) which is incorporated during translation by the recoding of an UGA stop codon. Consequently, dietary Se is essential for TH metabolism. During times of Se deficiency, selenocysteine lyase (Scly) decomposes Sec to Se allowing it to be recycled into new selenoproteins. We hypothesized that Scly is involved in preserving the production of the deiodinases and other selenoproteins when dietary Se levels are low. During the neonatal period when muscle is maturing, and deiodinase expression is high, we found that between P1 and P15 Scly expression increases 2-fold in soleus and 15-fold in the extensor digitalis longus (EDL) muscle. Further, we found that Scly mRNA expression was 2.5-fold higher in the adult slow oxidative soleus muscle versus the fast glycolytic EDL. Next, we fed male WT and Scly knockout (Scly-/-) mice a Se adequate or deficient diet and evaluated gene expression in the soleus and EDL via qPCR. In WT soleus, low Se diet decreased expression of many selenoproteins, likely in part due to nonsense-mediated decay of the non-translated UGA containing transcripts. In contrast, the expression of these selenoproteins was unchanged in the EDL. Scly-/- mice fed a Se adequate diet demonstrated a trend towards increased Dio2, SelenoN, SelenoM, SelenoP, Txnrd1, and Sephs2 expression in soleus when compared to WT mice on the same diet, but this was abolished under low Se conditions. In the soleus, diet had no effect on SelenoH in WT mice, while notably, SelenoH was significantly decreased in Scly-/- mice fed a low Se diet. In the EDL, expression of SelenoW and SelenoH was unchanged under low Se conditions in WT mice, but was decreased in Scly-/-. This suggests that the expression of a subset of genes relies upon the Se provided by Scly recycling when Se is limiting. Finally, to investigate the possible role of Scly in muscle differentiation, we induced the murine myoblast C2C12 cell line to differentiate via serum withdrawal in the presence of 100 nM total Se to control for the effects of decreased serum on Se levels. Scly mRNA expression reached peak induction by 48h after differentiation. Dio2, Gpx3, SelenoP, SelenoM, SelenoN, and the selenoprotein synthesis factor SBP2 exhibited similar expression profiles. Our results suggest a role for Scly in skeletal muscle development, differentiation, and adult muscle homeostasis. Further, expression of some muscle selenoproteins, including Dio2, appears to be sensitive to low dietary Se when Scly mediated Se recycling is impaired. Funding: NIH-NIDDK

The Research Centers in Minority Institutions (RCMI) Program was congressionally mandated in 1985 to build research capacity at institutions that currently and historically recruit, train, and award doctorate degrees in the health professions and health-related sciences, primarily to individuals from underrepresented and minority populations. RCMI grantees share similar infrastructure needs and institutional goals. Of particular importance is the professional development of multidisciplinary teams of academic and community scholars (the “workforce”) and the harnessing of the heterogeneity of thought (the “thinkforce”) to reduce health disparities. The purpose of this report is to summarize the presentations and discussion at the RCMI Investigator Development Core (IDC) Workshop, held in conjunction with the RCMI Program National Conference in Bethesda, Maryland, in December 2019. The RCMI IDC Directors provided information about their professional development activities and Pilot Projects Programs and discussed barriers identified by new and early-stage investigators that limit effective career development, as well as potential solutions to overcome such obstacles. This report also proposes potential alignments of professional development activities, targeted goals and common metrics to track productivity and success.

Previous studies demonstrated that selenium in the form of sodium selenate reduces neurofibrillary tangle formation in Alzheimer's disease models. Hyperphosphorylation of tau, which leads to formation of neurofibrillary tangles in Alzheimer's disease, is increased by endoplasmic reticulum (ER) stress. Selenoprotein S (SelS) is part of an ER membrane complex that removes misfolded proteins from the ER as a means to reduce ER stress. Selenate, as with other forms of selenium, will increase selenoprotein expression. We therefore proposed that increased SelS expression by selenate would contribute to the beneficial actions of selenate in Alzheimer's disease. SelS expression increased with ER stress and decreased under conditions of elevated glucose concentrations in the SH-SY5Y neuronal cell line. Reducing expression of SelS with siRNA promoted cell death in response to ER stress. Selenate increased SelS expression, which significantly correlated with decreased tau phosphorylation. Restricting SelS expression during ER stress conditions increased tau phosphorylation, and also promoted aggregation of phosphorylated tau in neurites and soma. In human postmortem brain, SelS expression coincided with neurofibrillary tangles, but not with amyloid-β plaques. These results indicate that selenate can alter phosphorylation of tau by increasing expression of SelS in Alzheimer's disease and potentially other neurodegenerative disorders.

Selenoprotein P (SelenoP) functions as a plasma transporter of selenium (Se) from liver to other tissues via incorporation into multiple selenocysteine (Sec) residues. Selenocysteine lyase (Scly) is an intracellular enzyme that decomposes Sec into selenide, providing Se for the synthesis of new selenoproteins. Both SelenoP and Scly are mostly produced by the liver. Previous studies demonstrated that male mice lacking SelenoP (SelenoP KO) or Scly (Scly KO) had increased or decreased total hepatic Se, respectively. While SelenoP regulation by Se is well-studied, Scly regulation by Se has not been reported. We hypothesize that Scly is negatively regulated by Se levels, and that absence of SelenoP jeopardizes Scly-dependent Se recycling. Using in vitro and in vivo models, we unveiled a tissue-specific Se regulation of Scly gene expression. We also determined that SelenoP, a considered source of intracellular Se, affects Scly expression and activity in vitro but not in vivo, as in the absence of SelenoP, Scly levels and activity remain normal. We also showed that absence of SelenoP does not increase levels of transsulfuration pathway enzymes, which would result in available selenocompounds being decomposed by the actions of cystathionine γ-lyase (CGL or CTH) and cystathionine β-synthase (CBS). Instead, it affects levels of thioredoxin reductase 1 (Txnrd1), an enzyme that can reduce selenite to selenide to be used in selenoprotein production. This study evaluates a potential interplay between SelenoP and Scly, providing further insights into the regulation of selenium metabolism.

The hypothalamus is the central neural site governing food intake and energy expenditure. During the past 25 years, understanding of the hypothalamic cell types, hormones, and circuitry involved in the regulation of energy metabolism has dramatically increased. It is now well established that the adipocyte-derived hormone, leptin, acts upon two distinct groups of hypothalamic neurons that comprise opposing arms of the central melanocortin system. These two cell populations are anorexigenic neurons expressing proopiomelanocortin (POMC) and orexigenic neurons that express agouti-related peptide (AGRP). Several important studies have demonstrated that reactive oxygen species and endoplasmic reticulum stress significantly impact these hypothalamic neuronal populations that regulate global energy metabolism. Reactive oxygen species and redox homeostasis are influenced by selenoproteins, an essential class of proteins that incorporate selenium co-translationally in the form of the 21st amino acid, selenocysteine. Levels of these proteins are regulated by dietary selenium intake and they are widely expressed in the brain. Of additional relevance, selenium supplementation has been linked to metabolic alterations in both animal and human studies. Recent evidence also indicates that hypothalamic selenoproteins are significant modulators of energy metabolism in both neurons and tanycytes, a population of glial-like cells lining the floor of the 3rd ventricle within the hypothalamus. This review article will summarize current understanding of the regulatory influence of redox status on hypothalamic nutrient sensing and highlight recent work revealing the importance of selenoproteins in the hypothalamus.

Selenium (Se) is an essential micronutrient known for its antioxidant properties and health benefits, attributed to its presence in selenoproteins as the amino acid, selenocysteine. Selenocysteine lyase (Scly) catalyzes hydrolysis of selenocysteine to selenide and alanine, facilitating re-utilization of Se for de novo selenoprotein synthesis. Previously, it was reported that male Scly−/− mice develop increased body weight and body fat composition, and altered lipid and carbohydrate metabolism, compared to wild type mice. Strikingly, females appeared to present with a less severe phenotype, suggesting the relationship between Scly and energy metabolism may be regulated in a sex-specific manner. Here, we report that while body weight and body fat gain occur in both male and female Scly−/− mice, strikingly, males are susceptible to developing glucose intolerance, whereas female Scly−/− mice are protected. Because Se is critical for male reproduction, we hypothesized that castration would attenuate the metabolic dysfunction observed in male Scly−/− mice by eliminating sequestration of Se in testes. We report that fasting serum insulin levels were significantly reduced in castrated males compared to controls, but islet area was unchanged between groups. Finally, both male and female Scly−/− mice exhibit reduced hypothalamic expression of selenoproteins S, M, and glutathione peroxidase 1.

Selenium (Se) is essential for both brain development and male fertility. Male mice lacking two key genes involved in Se metabolism (Scly−/−Sepp1−/−mice), selenoprotein P (Sepp1) and Sec lyase (Scly), develop severe neurological dysfunction, neurodegeneration, and audiogenic seizures that manifest beginning in early adulthood. We demonstrate that prepubescent castration ofScly−/−Sepp1−/−mice prevents behavioral deficits, attenuates neurodegeneration, rescues maturation of GABAergic inhibition, and increases brain selenoprotein levels. Moreover, castration also yields similar neuroprotective benefits toSepp1−/−and wild-type mice challenged with Se-deficient diets. Our data show that, under Se-compromised conditions, the brain and testes compete for Se utilization, with concomitant effects on neurodevelopment and neurodegeneration.SIGNIFICANCE STATEMENTSelenium is an essential trace element that promotes male fertility and brain function. Herein, we report that prepubescent castration provides neuroprotection by increasing selenium-dependent antioxidant activity in the brain, revealing a competition between the brain and testes for selenium utilization. These findings provide novel insight into the interaction of sex and oxidative stress upon the developing brain and have potentially significant implications for the prevention of neurodevelopmental disorders characterized by aberrant excitatory/inhibitory balance, such as schizophrenia and epilepsy.

Seafood is an important source of nutrients for fetal neurodevelopment. Most individuals are exposed to the toxic element mercury through seafood. Due to the neurotoxic effects of mercury, United States government agencies recommend no more than 340 g (12 oz) per week of seafood consumption during pregnancy. However, recent studies have shown that selenium, also abundant in seafood, can have protective effects against mercury toxicity. In this study, we analyzed mercury and selenium levels and selenoprotein mRNA, protein, and activity in placenta of a cohort of women in Hawaii in relation to maternal seafood consumption assessed with dietary surveys. Fish consumption resulted in differences in mercury levels in placenta and cord blood. When taken as a group, those who consumed no fish exhibited the lowest mercury levels in placenta and cord blood. However, there were numerous individuals who either had higher mercury with no fish consumption or lower mercury with high fish consumption, indicating a lack of correlation. Placental expression of selenoprotein mRNAs, proteins and enzyme activity was not statistically different in any region among the different dietary groups. While the absence of seafood consumption correlates with lower average placental and cord blood mercury levels, no strong correlations were seen between seafood consumption or its absence and the levels of either selenoproteins or selenoenzyme activity.

Subjects with Alzheimer’s disease (AD) have elevated brain levels of the selenium transporter selenoprotein P (Sepp1). We investigated if this elevation results from increased release of Sepp1 from the choroid plexus (CP). Sepp1 is significantly increased in CP from AD brains in comparison to non-AD brains. Sepp1 localizes to the trans-Golgi network within CP epithelia, where it is processed for secretion. The cerebrospinal fluid from AD subjects also contains increased levels Sepp1 in comparison to non-AD subjects. These findings suggest that AD pathology induces increased levels of Sepp1 within CP epithelia for release into the cerebrospinal fluid to ultimately increase brain selenium.

Both HIV infection and Methamphetamine (Meth) use disorders are associated with greater depressive symptoms and oxidative stress; whether the two conditions would show additive or interactive effects on the severity of depressive symptoms, and whether this is related to the level of oxidative stress in the CNS is unknown. 123 participants were evaluated, which included 41 HIV-seronegative subjects without substance use disorders (Control), 25 with recent (

Selenoproteins are ubiquitously expressed, act on a variety of physiological redox-related processes, and are mostly regulated by selenium levels in animals. To date, the expression of most selenoproteins has not been verified in euryhaline fish models. The Mozambique tilapia, Oreochromis mossambicus, a euryhaline cichlid fish, has a high tolerance for changes in salinity and survives in fresh water (FW) and seawater (SW) environments which differ greatly in selenium availability. In the present study, we searched EST databases for cichlid selenoprotein mRNAs and screened for their differential expression in FW and SW-acclimated tilapia. The expression of mRNAs encoding iodothyronine deiodinases 1, 2 and 3 (Dio1, Dio2, Dio3), Fep15, glutathione peroxidase 2, selenoproteins J, K, L, M, P, S, and W, was measured in the brain, eye, gill, kidney, liver, pituitary, muscle, and intraperitoneal white adipose tissue. Gene expression of selenophosphate synthetase 1, Secp43, and selenocysteine lyase, factors involved in selenoprotein synthesis or in selenium metabolism, were also measured. The highest variation in selenoprotein and synthesis factor mRNA expression between FW- and SW-acclimated fish was found in gill and kidney. While the branchial expression of Dio3 was increased upon transferring tilapia from SW to FW, the inverse effect was observed when fish were transferred from FW to SW. Protein content of Dio3 was higher in fish acclimated to FW than in those acclimated to SW. Together, these results outline tissue distribution of selenoproteins in FW and SW-acclimated tilapia, and indicate that at least Dio3 expression is regulated by environmental salinity.

Pre-eclampsia is the leading cause of fetal and maternal morbidity and mortality. Early onset pre-eclampsia (EOPE) is a disorder that has severe maternal and fetal outcomes, whilst its etiology is poorly understood. We hypothesize that epigenetics plays an important role to mediate the development of EOPE and conducted a case–control study to compare the genome-wide methylome difference between chorioamniotic membranes from 30 EOPE and 17 full-term pregnancies using the Infinium Human Methylation 450 BeadChip arrays. Bioinformatics analysis tested differential methylation (DM) at CpG site level, gene level, and pathway and network level. A striking genome-wide hypermethylation pattern coupled with hypomethylation in promoters was observed. Out of 385 184 CpG sites, 9995 showed DM (2.6%). Of those DM sites, 91.9% showed hypermethylation (9186 of 9995). Over 900 genes had DM associated with promoters. Promoter-based DM analysis revealed that genes in canonical cancer-related pathways such as Rac, Ras, PI3K/Akt, NFκB and ErBB4 were enriched, and represented biological functional alterations that involve cell cycle, apoptosis, cancer signaling and inflammation. A group of genes previously found to be up-regulated in pre-eclampsia, including GRB2, ATF3, NFKB2, as well as genes in proteasome subunits (PSMA1, PMSE1, PSMD1 and PMSD8), harbored hypomethylated promoters. Contrarily, a cluster of microRNAs, including mir-519a1, mir-301a, mir-487a, mir-185, mir-329, mir-194, mir-376a1, mir-486 and mir-744 were all hypermethylated in their promoters in the EOPE samples. These findings collectively reveal new avenues of research regarding the vast epigenetic modifications in EOPE.

Selenoproteins are a unique family of proteins, characterized by the co-translational incorporation of selenium as selenocysteine, which play key roles in antioxidant defense. Among selenoproteins, selenoprotein P (Sepp1) is particularly distinctive due to the fact that it contains multiple selenocysteine residues and has been postulated to act in selenium transport. Within the brain, Sepp1 delivers selenium to neurons by binding to the ApoER2 receptor. Upon feeding a selenium-deficient diet, mice lacking ApoER2 or Sepp1 develop severe neurological dysfunction and exhibit widespread brainstem neurodegeneration, indicating an important role for ApoER2-mediated Sepp1 uptake in normal brain function. Selenocysteine lyase (Scly) is an enzyme that plays an important role in selenium homeostasis, in that it catalyzes the decomposition of selenocysteine and allows selenium to be recycled for additional selenoprotein synthesis. We previously reported that constitutive deletion of Scly results in neurological deficits only when mice are challenged with a low selenium diet. To gain insight into the relationship between Sepp1 and Scly in selenium metabolism, we created novel transgenic mice constitutively lacking both genes (Scly(-/-)Sepp1(-/-)) and characterized the neurobehavioral phenotype. We report that deletion of Scly in conjunction with Sepp1 further aggravates the phenotype of Sepp1(-/-) mice, as these mice needed supraphysiological selenium supplementation to survive, and surviving mice exhibited impaired motor coordination, audiogenic seizures, and brainstem neurodegeneration. These findings provide the first in vivo evidence that Scly and Sepp1 work cooperatively to maintain selenoprotein function in the mammalian brain.

OBJECTIVES: We previously demonstrated that disruption of selenocysteine lyase (Scly) in mice leads to the development of obesity and metabolic syndrome under selenium deficiency, with effects on glucose homeostasis in the liver. It is unknown whether the physiology of skeletal muscle, a key tissue in glucose disposal, is also affected by the disruption of Scly. Here, we investigated the effects of a high-fat diet supplemented with selenium in the muscle physiology of Scly knockout (KO) mice METHODS: Age-matched homozygous male and female Scly KO and wild type (WT) from C57BL/6 J background were group-caged and fed for three months to a diet containing 45% kcal fat and 0.25 ppm (adequate) or 1 ppm (high) of selenium as sodium selenite. Serum, liver, soleus, and brown adipose tissue (BAT) were collected and assessed for total glutathione peroxidase (GPX) activity and creatine kinase (CK). Total RNA was extracted from soleus and liver, reverse-transcribed, and used in qPCR. RESULTS: Following an adequate selenium intake, total GPX activity in serum, mRNA of GPX1 and selenoprotein P in the liver, and mRNA of selenoprotein N in soleus were unchanged of Scly KO compared to WT mice, both in males and females. We observed five-fold increase of CK activity in serum and a one-fold decrease in soleus of Scly KO male mice when compared with WT. Increased CK levels in serum have been related with muscle impairment. Interestingly, when male Scly KO mice were fed a high selenium diet, we observed the opposite effect, with serum CK activity significantly decreased, while in soleus CK activity increased in Scly KO mice. CK activity levels on liver or BAT were unchanged. CK activity in serum was unchanged in female mice, corroborating to the previously described sexual dimorphism for these animals. These results suggest an improvement in Scly KO muscle health after selenium supplementation. CONCLUSIONS: Adequate selenium levels maintain selenium homeostasis and ensure the maintenance of selenoprotein levels, but high selenium intake may be necessary to preserve muscle health. FUNDING SOURCES: FAPESP/Brazil, NIDDK-NIH/USA, NIMHD-NIH/USA.

Selenium is an essential trace element linked to normal development and antioxidant defense mechanisms through its incorporation into selenoproteins via the amino acid, selenocysteine (Sec). Male mice lacking both the Se transporter, selenoprotein P (SELENOP), and selenocysteine lyase (Scly), which plays a role in intracellular Se utilization, require Se supplementation for viability and exhibit neuromotor deficits. Previously, we demonstrated that male SELENOP/Scly double knockout (DKO) mice suffer from loss of motor function and audiogenic seizures due to neurodegeneration, both of which are alleviated by prepubescent castration. The current study examined the neuromotor function of female DKO mice using the rotarod and open field test, as well as the effects of dietary Se restriction. Female DKO mice exhibited a milder form of neurological impairment than their male counterparts. This impairment is exacerbated by removal of Se supplementation during puberty. These results indicate there is a critical time frame in which Se supplementation is essential for neurodevelopment. These sex-specific differences may unveil new insights into dietary requirements for this essential nutrient in humans.

Background Selenoprotein W (Sepw1) is a selenium-containing protein that is abundant in brain and muscle of vertebrate animals. Muscular expression of Sepw1 is reduced by dietary selenium (Se) deficiency in mammals, whereas brain expression is maintained. However, expression of Sepw1 depends on the Se transporter selenoprotein P (Sepp1). Methods We assessed the regional and cellular expression of Sepw1 in the mouse brain and neuronal cultures. Results We found that Sepw1 is widespread in neurons and neuropil of mouse brain and appears in both the soma and processes of neurons in culture. Pyramidal neurons of cortex and hippocampus express high levels of Sepw1. It is also abundant in Purkinje neurons and their dendritic arbors in the cerebellum. Analysis of synaptosome fractions prepared from mice brains indicated that Sepw1 is present at synapses, as were several proteins involved in selenoprotein synthesis. Synaptic expression of Sepw1 expression is reduced in mice lacking Sepp1 compared with control mice, although selenoprotein synthesis factors were similarly expressed in both genotypes. Lastly, Sepw1 mRNA coimmunoprecipitates with Staufen 2 protein in a human neuronal cell line. Conclusions Our results suggest that Sepw1 may be locally synthesized in distal compartments of neurons including synapses.

International audience; The human genome contains 25 genes coding for selenocysteine-containing proteins (selenoproteins). These proteins are involved in a variety of functions, most notably redox homeostasis. Selenoprotein enzymes with known functions are designated according to these functions: TXNRD1, TXNRD2, and TXNRD3 (thioredoxin reductases), GPX1, GPX2, GPX3, GPX4, and GPX6 (glutathione peroxidases), DIO1, DIO2, and DIO3 (iodothyronine deiodinases), MSRB1 (methionine sulfoxide reductase B1), and SEPHS2 (selenophosphate synthetase 2). Selenoproteins without known functions have traditionally been denoted by SEL or SEP symbols. However, these symbols are sometimes ambiguous and conflict with the approved nomenclature for several other genes. Therefore, there is a need to implement a rational and coherent nomenclature system for selenoprotein-encoding genes. Our solution is to use the root symbol SELENO followed by a letter. This nomenclature applies to SELENOF (selenoprotein F, the 15-kDa selenoprotein, SEP15), SELENOH (selenoprotein H, SELH, C11orf31), SELENOI (selenoprotein I, SELI, EPT1), SELENOK (selenoprotein K, SELK), SELENOM (selenoprotein M, SELM), SELENON (selenoprotein N, SEPN1, SELN), SELENOO (selenoprotein O, SELO), SELENOP (selenoprotein P, SeP, SEPP1, SELP), SELENOS (selenoprotein S, SELS, SEPS1, VIMP), SELENOT (selenoprotein T, SELT), SELENOV (selenoprotein V, SELV), and SELENOW (selenoprotein W, SELW, SEPW1). This system, approved by the HUGO Gene Nomenclature Committee, also resolves conflicting, missing, and ambiguous designations for selenoprotein genes and is applicable to selenoproteins across vertebrates.

Selenoprotein M (SELM) is an ER-resident thiol-disulfide oxidoreductase that is highly expressed in the brain and bestows neuroprotective properties. Its active site consists of a selenocysteine-containing thioredoxin-like domain that is postulated to mediate thiol-disulfide exchange. Studies performed in cell culture indicate that SELM promotes intracellular calcium homeostasis and protects against oxidative stress. Additionally, Selm knockout mice display increased body weight, elevated white adipose tissue levels, and reduced hypothalamic leptin sensitivity relative to wild type counterparts, suggesting that SELM supports normal energy homeostasis. Finally, in the context of human disease, altered levels of SELM expression have been linked to both familial early onset of Alzheimer’s disease and hepatocellular carcinoma. This review summarizes our current understanding of SELM with respect to structure, expression, and functional relevance.

Dietary selenium restriction in mammals causes bodily selenium to be preferentially retained in the brain relative to other organs. Almost all of the known selenoproteins are found in brain, where expression is facilitated by selenocysteine-laden selenoprotein P. The brain also expresses selenocysteine lyase, an enzyme that putatively salvages selenocysteine and recycles the selenium for selenoprotein translation. We compared mice with a genetic deletion of selenocysteine lyase to selenoprotein P knockout mice for similarity of neurological impairments, and whether dietary selenium modulates these parameters. We report that selenocysteine lyase knockout mice do not display neurological dysfunction comparable to selenoprotein P knockout mice. Feeding a low-selenium diet to selenocysteine lyase knockout mice revealed a mild spatial learning deficit without disrupting motor coordination. Additionally, we report that the neurological phenotype caused by the absence of selenoprotein P is exacerbated in male versus female mice. These findings indicate that selenocysteine recycling via selenocysteine lyase becomes limiting under selenium deficiency, and suggest the presence of a complementary mechanism for processing selenocysteine. Our studies illuminate the interaction between selenoprotein P and selenocysteine lyase in the distribution and turnover of body and brain selenium, and emphasize the consideration of sex differences when studying selenium and selenoproteins in vertebrate biology.

One of the primary lines of defense against oxidative stress is the selenoprotein family, a class of proteins that contain selenium in the form of the 21st amino acid, selenocysteine. Within this class of proteins, selenoprotein P (Sepp1) is unique, as it contains multiple selenocysteine residues and is postulated to act in selenium transport. Recent findings have demonstrated that neuronal selenoprotein synthesis is required for the development of parvalbumin (PV)-interneurons, a class of GABAergic neurons involved in the synchronization of neural activity. To investigate the potential influence of Sepp1 on PV-interneurons, we first mapped the distribution of the Sepp1 receptor, ApoER2, and parvalbumin in the mouse brain. Our results indicate that ApoER2 is highly expressed on PV-interneurons in multiple brain regions. Next, to determine whether PV-interneuron populations are affected by Sepp1 deletion, we performed stereology on several brain regions in which we observed ApoER2 expression on PV-interneurons, comparing wild-type and Sepp1−/− mice. We observed reduced numbers of PV-interneurons in the inferior colliculus of Sepp1−/− mice, which corresponded with a regional increase in oxidative stress. Finally, as impaired PV-interneuron function has been implicated in several neuropsychiatric conditions, we performed multiple behavioral tests on Sepp1−/− mice. Our behavioral results indicate that Sepp1−/− mice have impairments in contextual fear extinction, latent inhibition, and sensorimotor gating. In sum, these findings demonstrate the important supporting role of Sepp1 on ApoER2-expressing PV-interneurons.

Oxidative stress and oxidized dopamine contribute to the degeneration of the nigrostriatal pathway in Parkinson's disease (PD). Selenoproteins are a family of proteins containing the element selenium in the form of the amino acid selenocysteine, and many of these proteins have antioxidant functions. We recently reported changes in expression of the selenoprotein, phospholipid hydroperoxide glutathione peroxidase GPX4 and its co-localization with neuromelanin in PD brain. To further understand the changes in GPX4 in PD, we examine here the expression of the selenium transport protein selenoprotein P (Sepp1) in postmortem Parkinson's brain tissue. Sepp1 in midbrain was expressed in neurons of the substantia nigra (SN), and expression was concentrated within the centers of Lewy bodies, the pathological hallmark of PD. As with GPX4, Sepp1 expression was significantly reduced in SN from PD subjects compared with controls, but increased relative to cell density. In putamen, Sepp1 was found in cell bodies and in dopaminergic axons and terminals, although levels of Sepp1 were not altered in PD subjects compared to controls. Expression levels of Sepp1 and GPX4 correlated strongly in the putamen of control subjects but not in the putamen of PD subjects. These findings indicate a role for Sepp1 in the nigrostriatal pathway, and suggest that local release of Sepp1 in striatum may be important for signaling and/or synthesis of other selenoproteins such as GPX4.

Monocyte chemoattractant protein-1 (MCP-1) is an inflammatory chemokine up-regulated in obese subjects, contributing to the development of type 2 diabetes. The present study investigated the inhibitory effect of an ethanol–water extract from bamboo (BEX,Phyllostachys edulis) on the blood concentration of MCP-1. C57BL/6J mice were fed a standard diet or a high-fat diet with or without the BEX supplement (11 g dry mass/17 000 kJ) for 6 months. A total of ten mice were used in each group. Body weight and food consumption were measured weekly. After euthanisation, the weight of visceral fat and circulating MCP-1 concentration were measured. In comparison with the standard control group, the high-fat control group had increased body weight, abdominal fat storage and serum MCP-1 concentration by 60 % (P P P P P P

Bamboo leaves are used as a component in traditional Chinese medicine for the anti-inflammatory function. Our previous studies have demonstrated that an ethanol/water extract from Phyllostachys edulis ameliorated obesity-associated chronic systemic inflammation in mice, and therefore relieving the symptoms of type 2 diabetes. The aim of this project was to further investigate the effects of this bamboo extract on hepatic biotransformation enzymes in both lean and obese mice, as an initial step in the toxicological evaluation of using this traditional medicine in obese/diabetic population.Male C57BL/6J mice were randomized to 4 groups and fed standard (10% kcal from fat) diet with or without bamboo extract supplementation at a dose of 10 gram per kilogram diet (n=10 and n=9, respectively), or high fat (45% kcal from fat) diet with or without bamboo extract (n=8 and N=7, respectively). The dietary treatment lasted for 6 months. Subsequently, the activities and expression of the major Phase I and II hepatic biotransformation enzymes were assessed in subcellular fractions from murine livers.Three groups of mice, lean bamboo extract-supplemented, obese/diabetic, and bamboo extract-supplemented obese/diabetic, showed greater activities of cytochromes P450 1a2 and 3a11 compared to control but no changes in the expression level of these proteins. For Phase II enzymes, bamboo extract supplementation in lean mice caused decreased glutathione-S-transferase activity (-12%) and greater uridine diphosphate glucuronosyltransferase activity (+46%), but had no effect on sulfotransferase activity. Conversely, the obese/diabetic condition itself increased glutathione-S-transferase and uridine diphosphate glucuronosyltransferase activities, but decreased total sulfotransferase activity and sulfotransferase 2a1 expression.Bamboo extract and obesity/diabetes show significant independent effects on hepatic biotransformation as well as interaction effects in mice. These changes may alter the clearance of endo- and xenobiotics, including bamboo extract itself, hence this effect should be carefully considered in the medicinal application of bamboo extract as it has potential to alter its own metabolism and that of other medications concurrently administered to obese diabetic patients.

The immune-enhancing effects of selenium (Se) supplementation make it a promising complementary and alternative medicine modality for boosting immunity, although mechanisms by which Se influences immunity are unclear. Mice fed low (0.08 mg/kg), medium (0.25 mg/kg), or high (1.0 mg/kg) Se diets for 8 wk were challenged with peptide/adjuvant. Antigen-specific CD4(+) T cell responses were increased in the high Se group compared with the low and medium Se groups. T cell receptor signaling in ex vivo CD4(+) T cells increased with increasing dietary Se, with all 3 groups differing from one another in terms of calcium mobilization, oxidative burst, translocation of nuclear factor of activated T cells, and proliferation. The high Se diet increased expression of interleukin (IL)-2 and the high affinity chain of the IL-2 receptor compared with the low and medium Se diets. The high Se diet skewed the T helper (Th)1/Th2 balance toward a Th1 phenotype, leading to higher interferon-gamma and CD40 ligand levels compared with the low and medium Se diets. Prior to CD4(+) T cell activation, levels of reactive oxygen species did not differ among the groups, but the low Se diet decreased free thiols compared with the medium and high Se diets. Addition of exogenous free thiols eliminated differences in CD4(+) T cell activation among the dietary groups. Overall, these data suggest that dietary Se levels modulate free thiol levels and specific signaling events during CD4(+) T cell activation, which influence their proliferation and differentiation.

The family of selenoproteins have a broad range of functions, including protection against oxidative damage. Previous studies have shown that elevated levels of oxidative damage can induce accelerated loss of telomeric DNA during proliferation of mammalian cells. The incorporation of selenocysteine (Sec) into proteins in mammalian cells requires the Sec insertion sequence (SECIS) binding protein 2 (SBP2). Thus in the present study we have assessed the effect of knocking down the expression of SBP2 on telomere length. Following knock-down of SBP2 expression in two different human cell lines, the MSTO mesothelioma cell line ( approximately 5Kb average telomere length) and SY5Y neuroblastoma cell line (approximately 4.2Kb average telomere length), we observed a significant reduction (-0.6 to -1.1 Kb; Por= 0.01) in telomere length as compared to control cells. This reduction in telomere length was independent of affects on telomerase, since both telomerase activity levels and Tert mRNA expression levels were not altered by knock-down of SBP2 expression. Furthermore, telomeres were particularly sensitive to S1 nuclease digestion following SBP2 knock-down, indicating an increased frequency of oxidative damage-induced lesions in the telomeric DNA in these cells. Together, these observations imply that selenoproteins may help protect telomeric reserve in mammalian cells.

Mercury is a well-known environmental toxicant, particularly in its most common organic form, methylmercury. Consumption of fish and shellfish that contain methylmercury is a dominant source of mercury exposure in humans and piscivorous wildlife. Considerable efforts have focused on assessment of mercury and its attendant risks in the environment and food sources, including the studies reported in this issue. However, studies of mercury intoxication have frequently failed to consider the protective effects of the essential trace element, selenium. Mercury binds to selenium with extraordinarily high affinity, and high maternal exposures inhibit selenium-dependent enzyme activities in fetal brains. However, increased maternal dietary selenium intakes preserve these enzyme activities, thereby preventing the pathological effects that would otherwise arise in their absence. Recent evidence indicates that assessments of mercury exposure and tissue levels need to consider selenium intakes and tissue distributions in order to provide meaningful risk evaluations.