The glutaredoxin GLRX-21 functions to prevent selenium-induced oxidative stress in Caenorhabditis elegans.
Selenium is an essential micronutrient that functions as an antioxidant. Yet, at higher concentrations, selenium is pro-oxidant and toxic. In extreme cases, exposures to excess selenium can lead to death or selenosis, a syndrome characterized by teeth, hair and nail loss, and nervous system alterations. Recent interest in selenium as an anti- tumorigenic agent has reemphasized the need to understand the mechanisms underlying the cellular consequences of increased selenium exposure. We show here, that in the nematode, Caenorhabditis elegans, selenium has a concentration range in which it functions as an antioxidant, but beyond this range it exhibits a dose- and time-dependent lethality. Oxidation-induced fluorescence emitted by the dye, carboxy-H(2)DCFDA, indicative of reactive oxygen species formation was significantly higher in animals after a brief exposure to 5mM sodium selenite. Longer-term exposures lead to a progressive selenium-induced motility impairment that could be partially prevented by coincident exposure to the cellular antioxidant-reduced glutathione. The C elegans glrx-21 gene belongs to the family of glutaredoxins (glutathione-dependent oxidoreductases) and the glrx-21(tm2921) allele is a null mutation that renders animals hypersensitive for the selenium-induced motility impairment, but not lethality. In addition, the lethality of animals with the tm2921 mutation exposed to selenium was unaffected by the addition of reduced glutathione, suggesting that GLRX-21 is required for glutathione to moderate this selenium-induced lethality. Our findings provide the first description of selenium-induced toxicity in C elegans and support its use as a model for elucidating the mechanisms of selenium toxicity.
Morgan
Kathleen L
KL
Department of Neurology, Veterans Affairs Pittsburgh Healthcare System, Research and Development (151U), University Drive C, Pittsburgh, Pennsylvania 15240, USA.
Estevez
Annette O
AO
Mueller
Catherine L
CL
Cacho-Valadez
Briseida
B
Miranda-Vizuete
Antonio
A
Szewczyk
Nathaniel J
NJ
Estevez
Miguel
M
D000826:Animal Testing Alternatives; D000818:Animals; D030801:Animals, Genetically Modified; D000975:Antioxidants / Q000633:toxicity*; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D054477:Glutaredoxins / Q000235:genetics / Q000378:metabolism*; D008136:Longevity / Q000187:drug effects; D009068:Movement / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020539:Sequence Analysis, Protein; D018038:Sodium Selenite / Q000633:toxicity*; D013997:Time Factors; D023382:Toxicity Tests, Acute
D000975:Antioxidants; D054477:Glutaredoxins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018038:Sodium Selenite