Selenium
Selenium is an essential micronutrient. Recently, a specific selenium salt, sodium selenate, was discovered to be a specific enhancer of the enzyme protein phosphatase 2A (PP2A). PP2A removes phosphate groups from target proteins, including tau, a protein implicated in Alzheimer’s disease Corcoran 2010a PMID 20537899, van Eersel 2010 PMID 20643941, and many other proteins implicated in the control of cancer (Corcoran 2010b PMID 20648008).
Because phosphatases like PP2A remove phosphate groups that activate other proteins, PP2A can be considered a “brake” on the activity of cells, including neurons involved in learning and memory. We have previously shown that inhibiting phosphatase PP2A with the non-specific blocker okadaic acid increased the strength of learned conditioned taste aversions in rats. In other words, blocking PP2A “cut the brakes” on the learning mechanism, causing the rats to acquire a stronger memory of a toxic fluid (saccharin paired with lithium chloride).
Because sodium selenate can act as an enhancer of PP2A, we hypothesize that administering sodium selenate before a conditioning trial will decrease the strength of conditioned taste aversion learning (i.e., the “brakes” will be enhanced, thus diminishing the learning.)
Sodium Selenate
CAS Number: 13410-01-0
Linear Formula: Na2SeO4
Molecular Weight: 188.94
EC Number: 236-501-8
MDL number: MFCD00003490
PubChem Substance ID: 24899787
Tonicity of Systemic Injection
Osmolarity of Na2Se04 at 12 mg/ml (63 mM) = 189 mOsm
So Na2Se04 at 12 mg/ml (63 mM), NaCl at 3.2 mg/ml (55mM) = 300 mOsm
Calculation of suggested i.c.v. injection concentration.
Assuming a 500 g rat, then systemic dose is 0.25 mg ( 250 µg). A central dose might be 1/100th of the system dose -> 2.5 µg.
Volume of i.c.v injection would be 5 µl; site specific injection 0.5 µl
So central dose would be 2.5 µg / 5 µl = 0.5 µg/ 1 µl = 0.5 g / L.
MW of sodium selenate is 188.94, so 0.5 g = 2.65 mmole
so central injection dose is 5 µl at 2.65 mM.
(Osmolarity is sufficiently low that can be diluted with saline).
Toxicity of Selenate
Selenium is an essential micronutrient and is naturally found a wide variety of food stuffs. As an antioxidant, it is frequently used to treat, e.g., heavy metal toxicosis or liver disease. The recommended dietary intake for adults is 55 micrograms/day, and selenium supplements of 200-300 micrograms/day have been recommended for prevention of several types of cancer. High doses of 1.5 to 5 mg/ day are associated with adverse effects (Brozmanova 2010, Reid 2004). The chemical form of selenium also contributes to toxicity. The form we will use, sodium selenate (Na2Se04), is well-tolerated in human trials (Corcoran 2010b).
Corcoran (2010a) administered sodium selenate to mice acutely at 12 mg/kg, and chronically at ~192 mg/kg per day in drinking water, and did not report any aversive or toxic effects on the mice. van Eersel (2010) administered sodium selenate to mice chrionically at ~ 1.9 mg/kg per day in drinking water, and also did not report any aversive or toxic effects.
Abdo (1994) reported on the effects of administering sodium selenate in the drinking water for 13 weeks. It was estimated that the "no-observed adverse level" in rat was 0.4 mg/kg per day of sodium selenate for 13 weeks. Doses of 0.6 mg/kg or 1.1 mg/kg per day for 13 weeks caused changes in mortality, body weight depression, decreased water consumption, and renal papillary lesions. However, these were chronic studies so that rats received a total dose of 54.6 mg/kg or 100.1 mg/kg sodium selenate over 13 weeks.
Aasif Mandvi ran a story on selenium pollution of Idaho rivers as a consequence of phosphate mining.
Selenium Ingestion and Aversions
Selenium is an essential micronutrient. The mammalian selenoproteome consists of some 2 dozen selenocysteine-containing proteins (24 in rodents, 25 in human) including the glutathione peroxidase, thioredoxin reductase and iodothyronine deiodinase enzymes [PMID 12775843]. However, at doses not much higher than the dietary requirement, selenium is also toxic [PMID 3527390]. Selenium toxicity is due to the generation of superoxide and other reactive oxygen species, the oxidation of thiols, and by substituting for sulfur in methionine to form selenomethione which then may be incorporated into many sulfur containing proteins [PMID 11879936].
Reduced intake and avoidance of toxic diets containing selenium compounds has been demonstrated in many species. Because selenium is concentrated by certain species of plants in selenium-rich geographies, selenosis is a potential hazard for livestock and native herbivores. Waste from mining or agricultural run-off can also introduce selenium into the environment and hence into the food-chain. It has therefore been of interest to determine whether species can avoid selenium-rich food sources due to an aversive taste or odor of selenium compounds, or acute toxic effects, or learned food aversions. Aphids [PMID 17831208, JSTOR 1514562], crickets and grasshoppers [PMID 17635224], southern armyworms [PMID 10467057] mallard ducks [Heinz 1990], owls [Wiemeyer 1996], prairie dogs [PMID 21628258], sheep [Pfister 2010, PMID 3527390], and cattle [PMID 3527390] have been shown to reduce intake of selenium-containing foods, or show reduced preference for selenium-containing foods over control diets.
In laboratory studies, rats show a preference for control or low selenium-diets over high selenium diets [PMID 17788901][Franke and Potter 1935]. Consistent with the effects of other selenium compounds, selenate adulteration also causes a reduction of food [Franke and Moxon 1937] [Smith Stohlman Lillie 1937] or water intake [PMID 6053743, PMID 1255264] Acute injection of selenate can also reduce food intake and body weight gain [PMID 2609019]
Only a few of these studies (e.g. [Pfister 2010, PMID 3527390, Heinz & Sanderson 1990] ) have determined if animals were responding to an acute perception of selenium compounds, or if the animals used food-associated cues, to avoid consumption, after acquiring a selenium-induced conditioned food aversion. Selenium absorbing plants may themselves have salient taste or odor: for example, Provenza et al. have demonstrated that the odor of Astragalus bisulcatus, a sulfur-containing selenium-absorbing plant, can serve as a CS that reduced preference for CS+barley-straw after pairing with oral-intubation of LiCl. [Oikos 88(2000)424-432.] Selenium compounds may also present distinctive cues, e.g., the volatile dimethyldiselenide, a major metabolite of selenite and selenate, has a pungent garlic odor to humans, that may be innately aversive or serve as an indicative CS in learned selenium aversions.
Government Documents on Selenium Safety
National Toxicology Program / NIEHS: NTP Technical Report on Toxicity Studies of Sodium Selenate and Sodium Selenite (1994)
CDC/NIOSH: Selenium compounds (as Se) from NIOSH Documentation for immediately dangerous to life or health concentrations (IDLHs)
WHO: Environmental Health Criteria 58: Selenium (1987) from International Programme on Chemical Safety
HHS: Toxicological Profile for Selenium (2003)
Agency for Toxic Substances and Disease Registry: ToxFAQs for Selenium (2003)
Agency for Toxic Substances and Disease Registry: ToxGuide for Selenium
Division 9 of NRDC: Chemical Warfare Agents and Related Chemical Problems, Parts I-II, Chapter 11 (1946)
References
Abdo, K.M. 1994. NTP Technical Report on Toxicity Studies of Sodium Selenate and Sodium Selenite (CAS Nos. 13410-01-0 and 10102-18-8) Administered in Drinking Water to F344/N Rats and B6C3F1 Mice. NIH Publication 9a4-3387. National Toxicology Program. Toxicity Report Series Number 38.
Brozmanova et al., 2010. Selenium: a double-edged sword for defense and offence in cancer, Arch. Toxicol. 84:919–938. PMID 20871980.
Corcoran NM, et al., 2010a. Sodium selenate specifically activates PP2A phosphatase, dephosphorylates tau and reverses memory deficits in an Alzheimer's disease model. J Clin Neurosci. 8:1025-33. PMID 20537899
Corcoran NM et al. 2010b. Open-label, phase I dose-escalation study of sodium selenate, a novel activator of PP2A, in patients with castration-resistant prostate cancer. Br J Cancer. 103:462-8. PMID 20648008
Mandvi, A. A Simple Plot. The Daily Show with Jon Stewart, aired June 14, 2012. https://www.cc.com/video/jucn2a/the-daily-show-with-jon-stewart-a-simple-plot
Reid ME et al. 2004 A report of high-dose selenium supplementation: response and toxicities. J Trace Elem Med Biol 18:69–74 PMID 15487766
van Eersel J et al. 2010. Sodium selenate mitigates tau pathology, neurodegeneration, and functional deficits in Alzheimer's disease models. PNAS 107:13888-93. PMID 20643941