**Background:** Selenium (Se) is an essential human micronutrient critical for many biological functions, with a recommended daily intake of 55 mcg for adults. Once absorbed, selenium is incorporated into selenocysteine-containing proteins known as selenoproteins, of which there are 25 known types. These include glutathione peroxidases (GPX1-4, GPX6), thioredoxin reductases (Trx1-3), deiodinases (DIO1-3), and other selenoproteins (SELENOH, SELENOK, SELENOM, SELENON, SELENOO, SELENOP, SELENOR, SELENOS, SELENOT, SELENOV, SELENOW, SELENOI, SELENOF, SEPHS2). Most selenoproteins exhibit antioxidant activity. Selenium deficiency during pregnancy leads to reduced placental weight and reduced fetal blood glucose levels in mice. Selenoproteins are widely expressed in the brain, particularly in the olfactory bulb, cerebral cortex, hippocampus, and cerebellar cortex. Autism spectrum disorder (ASD) affects 1 in 44 children in the United States and is characterized by repetitive behaviors and social interaction difficulties. A recent study by the authors' group demonstrated lower serum and nail selenium levels in boys aged 24 to 47 months with ASD compared to sex-matched controls, with a negative correlation between Autism Diagnostic Observation Schedule (ADOS) scores and selenium levels.
**Methods:** This is a narrative review of the literature on selenium, selenoproteins, and their role in neurodevelopment and neurological function, with a focus on implications for ASD. The authors also conducted a search of ClinicalTrials.gov using the keyword 'Selenium' (381 hits, 222 completed studies) and specifically for 'Autism' with 'selenium' (2 studies). They additionally searched for 'Selenium supplementation' alone (95 hits, 63 completed).
**Key Results:** The review details the functions of individual selenoproteins in the brain. GPX4 prevents developmental delays caused by apoptosis and lipid peroxidation during embryonic brain development; its knockout leads to neurodegeneration and reduction of PV+ interneurons. A common genetic variant of GPX1 was found to be under-transmitted from parents to children with ASD, suggesting a protective effect of wild-type GPX1. Trx1 deficiency in mice leads to severe ataxia, while overexpression decreases reactive oxygen species and improves motor function. SELENOP, which accounts for 60% of total body selenium, is a transport carrier; its knockout in mice leads to irreversible neurological dysfunction, and children with intellectual disability have significantly lower serum SELENOP levels. SELENOR knockout mice exhibit impaired spatial learning and memory. SELENOT knockout mice have brains 17% smaller in volume with a 53% increase in caspase-3 activity and 46% increase in reactive oxygen species. SELENOW is highly expressed in the brain and spinal cord of rat embryos and localized to the hippocampus by postnatal day 25. An exon-skipping mutation in SELENOI was discovered in a patient with hereditary spastic paraplegia, deafness, and blindness. Regarding ASD specifically, one meta-analysis found decreased blood levels of glutathione and glutathione peroxidases in ASD patients. However, a literature review of 10 studies comparing hair trace element levels found only 4 with significant differences in selenium levels (2 increased, 2 decreased). A meta-analysis found no significant differences in mean hair or erythrocyte selenium concentrations among 12 studies. A retrospective Norwegian study found no association between prenatal Se levels and ASD risk, while a prospective US study found an association between elevated maternal Se levels and increased ASD risk.
**Clinical Implications:** The authors propose several hypotheses for ASD etiology related to selenoproteins: (1) increased oxidative stress during neurodevelopment leads to reduced selenoprotein function, causing increased neuronal apoptosis; (2) ferroptosis may be decreased in oxidative stress conditions, with TRX1 and GPX4 working together to modulate ferroptosis; (3) oxidative stress may lead to incorrect formation of neuronal connections during neurodevelopment. The authors note that selenium supplementation trials lack clear definitions of the type of selenium used. Major forms include selenium-enriched yeast, selenium-containing amino acids (selenomethionine and selenocysteine), selenium salts (selenates, Na2SeO3, Na2SeO4), and selenium nanoparticles. Only two clinical trials have focused on ASD and selenium. The authors conclude that larger and better-defined trials are needed to understand the role of selenium and selenoproteins in ASD etiology and to determine the ideal type of selenium for supplementation.