Laura J. Raymond

Dietary selenium's protective effects against methylmercury toxicity.

Dietary selenium (Se) status is inversely related to vulnerability to methylmercury (MeHg) toxicity. Mercury exposures that are uniformly neurotoxic and lethal among animals fed low dietary Se are far less serious among those with normal Se intakes and are without observable consequences in those fed Se-enriched diets. Although these effects have been known since 1967, they have only lately become well understood. Recent studies have shown that Se-enriched diets not only prevent MeHg toxicity, but can also rapidly reverse some of its most severe symptoms. It is now understood that MeHg is a highly specific, irreversible inhibitor of Se-dependent enzymes (selenoenzymes). Selenoenzymes are required to prevent and reverse oxidative damage throughout the body, particularly in the brain and neuroendocrine tissues. Inhibition of selenoenzyme activities in these vulnerable tissues appears to be the proximal cause of the pathological effects known to accompany MeHg toxicity. Because Hgs binding affinities for Se are up to a million times higher than for sulfur, its second-best binding partner, MeHg inexorably sequesters Se, directly impairing selenoenzyme activities and their synthesis. This may explain why studies of maternal populations exposed to foods that contain Hg in molar excess of Se, such as shark or pilot whale meats, have found adverse child outcomes, but studies of populations exposed to MeHg by eating Se-rich ocean fish observe improved child IQs instead of harm. However, since the Se contents of freshwater fish are dependent on local soil Se status, fish with high MeHg from regions with poor Se availability may be cause for concern. Further studies of these relationships are needed to assist regulatory agencies in protecting and improving child health.

Dietary and tissue selenium in relation to methylmercury toxicity

Selenium (Se) supplementation in the nutritionally relevant range counteracts methylmercury (MeHg) toxicity. Since Se tends to be abundant in fish, MeHg exposures alone may not provide an accurate index of risk from fish consumption. Molar ratios of MeHg:Se in the diets and Hg:Se in tissues of exposed individuals may provide a more accurate index. This experiment compared MeHg toxicity in relation to MeHg exposure vs. Hg:Se molar ratios in diets and tissues. Diets were prepared using low-Se torula yeast basal diets supplemented with Na(2)SeO(4) to contain 0.1, 1.0, or 10.0 micromol Se/kg ( approximately 0.01, 0.08, or 0.8 ppm Se), reflecting low-, adequate-, or rich-Se intakes, respectively. Diets contained either low or high (0.5 micromol or 50 micromol MeHg/kg) ( approximately 0.10 or 10 ppm Hg). Sixty weanling male Long Evans rats were distributed into six weight-matched groups (three Se levels x two MeHg levels) that were supplied with water and their respective diets ab libitum for 18 weeks. No Se-dependent differences in growth were noted among rats fed low-MeHg diets, but growth impairments among rats fed high-MeHg were inversely related to dietary Se. After 3 weeks on the diet, growth impairments were evident among rats fed high-MeHg with low- or adequate-Se and after 10 weeks, rats fed low-Se, high-MeHg diets started to lose weight and displayed hind limb crossing. No weight loss or hind limb crossing was noted among animals fed high-MeHg, rich-Se diets. Methylmercury toxicity was not predictable by tissue Hg, but was inversely related to tissue Se (P<0.001) and directly related to Hg:Se ratios (P<0.001). Methylmercury-selenocysteine complexes (proposed name; pseudomethionine) appear likely to impair Se bioavailability, interrupting synthesis of selenium-dependent enzymes (selenoenzymes) that provide antioxidant protection in brain. Therefore, selenoenzymes may be the molecular target of methylmercury toxicity.

Selenium Health Benefit Values: Updated Criteria for Mercury Risk Assessments

Selenium (Se)-dependent enzymes (selenoenzymes) protect brain tissues against oxidative damage and perform other vital functions, but their synthesis requires a steady supply of Se. High methylmercury (CH3Hg) exposures can severely diminish Se transport across the placenta and irreversibly inhibit fetal brain selenoenzymes. However, supplemental dietary Se preserves their activities and thus prevents pathological consequences. The modified Se health benefit value (HBVSe) is a risk assessment criterion based on the molar concentrations of CH3Hg and Se present in a fish or seafood. It was developed to reflect the contrasting effects of maternal CH3Hg and Se intakes on fetal brain selenoenzyme activities. However, the original equation was prone to divide-by-zero-type errors whereby the calculated values increased exponentially in samples with low CH3Hg contents. The equation was refined to provide an improved index to better reflect the risks of CH3Hg exposures and the benefits provided by dietary Se. The HBVSe provides a biochemically based perspective that confirms and supports the FDA/EPA advice for pregnant and breast-feeding women regarding seafoods that should be avoided vs. those that are beneficial to consume. Since Se can be highly variable between watersheds, further evaluation of freshwater fish is needed to identify locations where fish with negative HBVSe may arise and be consumed by vulnerable subpopulation groups.

Potential Role of Selenoenzymes and Antioxidant Metabolism in relation to Autism Etiology and Pathology

Autism and autism spectrum disorders (ASDs) are behaviorally defined, but the biochemical pathogenesis of the underlying disease process remains uncharacterized. Studies indicate that antioxidant status is diminished in autistic subjects, suggesting its pathology is associated with augmented production of oxidative species and/or compromised antioxidant metabolism. This suggests ASD may result from defects in the metabolism of cellular antioxidants which maintain intracellular redox status by quenching reactive oxygen species (ROS). Selenium-dependent enzymes (selenoenzymes) are important in maintaining intercellular reducing conditions, particularly in the brain. Selenoenzymes are a family of ~25 genetically unique proteins, several of which have roles in preventing and reversing oxidative damage in brain and endocrine tissues. Since the brains high rate of oxygen consumption is accompanied by high ROS production, selenoenzyme activities are particularly important in this tissue. Because selenoenzymes can be irreversibly inhibited by many electrophiles, exposure to these organic and inorganic agents can diminish selenoenzyme-dependent antioxidant functions. This can impair brain development, particularly via the adverse influence of oxidative stress on epigenetic regulation. Here we review the physiological roles of selenoproteins in relation to potential biochemical mechanisms of ASD etiology and pathology.

The Nail as a Noninvasive Indicator of Methylmercury Exposures and Mercury/Selenium Molar Ratios in Brain, Kidney, and Livers of Long-Evans Rats

Animal studies indicate that the toxic effects of methylmercury (MeHg) exposures increase when selenium (Se) status is low. Toxicity is directly proportional to Hg/Se molar ratios in critical tissues such as brain and increase dramatically as molar ratios exceed 1:1. In this study, we examined the nail as a biomonitor of Hg/Se molar ratios in kidney, liver, and brain tissues of weanling male Long-Evans rats fed controlled diets containing varying amounts of Se and MeHg. Linear regression analyses indicate that the natural log transform of the Hg/Se ratio in the nails is strongly related to the Hg/Se molar ratio in kidney, liver, and brain (p < 0.01 in all cases). The nail appears to be a reliably accurate noninvasive biomonitor of the Hg/Se molar ratio in tissues and should, therefore, be considered for use in human studies.

Mercury-Dependent Inhibition of Selenoenzymes and Mercury Toxicity

Selenoenzymes are required to prevent and reverse oxidative damage in the brain and neuroendocrine system, but these enzymes are vulnerable to irreversible inhibition by methylmercury (MeHg). Selenoenzyme inhibition appears likely to cause most if not all of the pathological effects of mercury toxicity. This biochemically based understanding seems to explain why certain tissues are affected by mercury, why the latency effect is unique to mercury poisoning, why selenium status is inversely related to mercury toxicity, why fetal exposures are so much more harmful than adult exposures, and why prenatal inhibition of selenoenzymes by high MeHg results in sustained loss of their activities.

Seafood Selenium in Relation to Assessments of Methylmercury Exposure Risks

Selenium, an important nutrient present in many foods and especially abundant in ocean fish, is known to counteract mercury toxicity. This effect has been attributed to the high-binding affinities between mercury and selenium, whereby selenium was assumed to sequester mercury and thus prevent its harmful effects. However, recent research indicates that methylmercury is a highly specific irreversible inhibitor of selenium-dependent enzymes (selenoenzymes). Therefore, selenium may not act as a “tonic” that sequesters mercury, but may instead be the “target” of mercury binding which inhibits essential selenoenzyme functions. Since methylmercury readily crosses the placental and blood–brain barriers, its affinity for selenium enables it to impair synthesis and activities of selenoenzymes that are required for healthy fetal brain development. Effects of high methylmercury exposures depend on dietary selenium intakes and selenium status.

Mercury Information Clearinghouse

The Canadian Electricity Association (CEA) identified a need and contracted the Energy & Environmental Research Center (EERC) to create and maintain an information clearinghouse on global research and development activities related to mercury emissions from coal-fired electric utilities. With the support of CEA, the Center for Air Toxic Metals{reg_sign} (CATM{reg_sign}) Affiliates, and the U.S. Department of Energy (DOE), the EERC developed comprehensive quarterly information updates that provide a detailed assessment of developments in the various areas of mercury monitoring, control, policy, and research. A total of eight topical reports were completed and are summarized and updated in this final CEA quarterly report. The original quarterly reports can be viewed at the CEA Web site (www.ceamercuryprogram.ca). In addition to a comprehensive update of previous mercury-related topics, a review of results from the CEA Mercury Program is provided. Members of Canadas coal-fired electricity generation sector (ATCO Power, EPCOR, Manitoba Hydro, New Brunswick Power, Nova Scotia Power Inc., Ontario Power Generation, SaskPower, and TransAlta) and CEA, have compiled an extensive database of information from stack-, coal-, and ash-sampling activities. Data from this effort are also available at the CEA Web site and have provided critical information for establishing and reviewing a mercury standard for Canada that is protective of environment and public health and is cost-effective. Specific goals outlined for the CEA mercury program included the following: (1) Improve emission inventories and develop management options through an intensive 2-year coal-, ash-, and stack-sampling program; (2) Promote effective stack testing through the development of guidance material and the support of on-site training on the Ontario Hydro method for employees, government representatives, and contractors on an as-needed basis; (3) Strengthen laboratory analytical capabilities through analysis and quality assurance programs; and (4) Create and maintain an information clearinghouse to ensure that all parties can keep informed on global mercury research and development activities.

JV Task - 116 Selenium's Role in the Seafood Safety Issue

BACKGROUND The reason why high doses of methylmercury cause harm in the body appears to be because mercury interferes with normal metabolic activities of selenium, an essential dietary nutrient. Supplementation with additional selenium has long been known to protect the body from adverse effects of mercury exposure. It now appears that this occurs because the additional selenium replaces the selenium that becomes unusable because of mercury binding. Selenium is a required component of a number of different types of enzymes that perform important functions in the body. These enzymes are normally present in all cells of all animal life, but they perform especially important functions in pituitary, thyroid, and adrenal glands as well as in brain tissues.