title: Flowers for Algernon: steroid dysgenesis, epigenetics and brain disorders.
abstract: While a recent study has reported that early citalopram exposure alters cortical network function and produces autistic-like behaviors in male rats, when evaluating antidepressant animal models of autism spectrum disorder (ASD) it is important to note that some selective serotonin (5-HT) reuptake inhibitors alter 3α-hydroxysteroid dehydrogenase activity, and thus steroidogenesis. At least one study has examined the effect of repeated citalopram administration on the serum and brain concentration of testosterone (T) and its metabolites and shown that citalopram increases serum T. Several in vitro studies also suggest that sex steroid can alter 5-HT homeostasis. While research efforts have demonstrated that transgenic mice expressing the most common of multiple gain-of-function 5-HT reuptake transporter (SERT) coding variants, SERT Ala56, previously identified in children with ASD, exhibit autistic-like behaviors, elevated p38 MAPK-dependent transporter phosphorylation, enhanced 5-HT clearance rates and hyperserotonemia, a few studies provide some evidence that 5-HT may alter gonadal steroidogenesis. T, 17β-estradiol and synthetic estrogens are known inhibitors of AKR1C21 (BRENDA, E.C. 1.1.1.209), the epitestosterone (epiT) producing enzyme in rodents. EpiT is a naturally occurring steroid in mammals, including man. An analysis of the literature suggests that epiT may be the central mediator in the epigenetic regulation of gene expression. Over thirty years ago, it was shown that rat brain epiT production is higher in females than in males. A similar finding in humans could explain the sex differences in the incidence of autism and other brain disorders. Despite this, the role of epiT in brain development remains a long neglected area of research.
authors: College of Letters and Science (Alumnus), University of California, Durant Hall, MC 2920, Berkeley, CA 94720, USA. bksanders@cal.berkeley.edu
authors: Bryan K
authors: BK
authors: Sanders
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D015283:Citalopram; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D010766:Phosphorylation; D012307:Risk Factors; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors; D012737:Sex Factors; D013739:Testosterone / Q000096:biosynthesis*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D015283:Citalopram; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D013739:Testosterone; D048051:p38 Mitogen-Activated Protein Kinases