Decreased levels of G protein-coupled estrogen receptor in children with autism spectrum disorders
Introduction
Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders including autism, asperger's syndrome, childhood disintegrative disorder and pervasive developmental disorders not otherwise specified (Gillberg et al., 2006). ASDs are characterized by impairments in social interaction and communication, and the development of unusual stereotyped behaviors. There is still a lack of full understanding of the etiology of autism. Multiple hypotheses have been proposed to explain autism etiology including genetic, neurobiological, psychosocial factors, environmental or iatrogenic causes (Geier et al., 2010, Herbert, 2010). It has been suggested that there may be a possible role of sex hormones in the pathophysiology of ASDs as prevalence is higher in boys than in girls, at a ratio of 5:1 for ASD (Gillberg et al., 2006; Centers for Disease Control and Prevention 2012). High levels of testosterone during early development have been reported to be a possible risk factor for ASDs (Pfaff et al., 2011).
The most significant regulators of the reproductive systems in both genders are human estrogens, which a sex hormone consist of a group of structurally related steroid molecules, namely 17β- estradiol, estrone, and estriol. Estrogens are also involved in interactions with other non-reproductive organs, including bone tissue, cardiovascular, endocrine, immune and central nervous systems (Gruber et al., 2002). 17β-estradiol demonstrates effects in the central and peripheral nervous system including maintenance of homeostasis, neuroprotection, neurotrophic, the regulation of synaptic plasticity and cognition (Brailoiu et al., 2007, Dun et al., 2009, Hazell et al., 2009). In addition, estrogen promotes neuronal cell survival, reduces neuronal injury, protects against neurotoxins, facilitates axonal sprouting and neuronal repair, and enhances synaptic transmission and neurogenesis (Cheng et al., 2014).
Estradiol, ERα and ERβ, which are better known for these functions and G protein-coupled estrogen receptor (GPER) which was previously known as GPR30, create a connection to estrogen receptor (Heldring et al., 2007, Prossnitz and Barton, 2011, Revankar et al., 2005). There is a wide distribution of ERα and ERβ throughout different brain regions including the amygdala-hippocampal area, periamygdaloid cortex, posterior cortical nucleus, cerebral cortex, hippocampus, and cerebellum of the brain (Bodo and Rissman, 2006, Ostlund et al., 2003). ERα and ERβ (a nuclear receptors) are genetically similar, nuclear and are better known for their effects on gene transcription (Heldring et al., 2007). The orphan receptor GPER, which is genetically and structurally distinct from ERα and ERβ, is a 7-transmembrane receptor which partners with G proteins to be able to function and execute signaling pathways. It has various subcellular locations, such as the nucleus, plasma membrane, endoplasmic reticulum and it binds agonists, such as chemokines, vasoreactive substances and neurotransmitters (Revankar et al., 2005). In animal model experiments, GPER have been found throughout the central and peripheral nervous system of male and female rodents, including in the hypothalamus, hippocampus, midbrain, spinal cord and dorsal root ganglia (Altun and Kurutas, 2015, Brailoiu et al., 2007, Cheng et al., 2014, Dun et al., 2009). GPER is also known to be widely expressed in many human organs, including adipose tissue, immune, central nervous, renal, reproductive and cardiovascular systems (Meyer et al., 2009, Prossnitz and Barton, 2009, Prossnitz and Barton, 2011). Additionaly, estrogen receptors have been identified in polymorphonuclear and mononuclear leukocytes isolated from peripheral blood and blood vessel endothelium of both men and women. (Stygar et al., 2006; Han et al., 2013). Preclinical findings of in vitro and animal models, have demonstrated the estrogenic effects in schizophrenia, depression, anxiety, and neurodegenerative disorders. There has been observed to be a correlation between decreased estrogen levels (e.g., premenstrually, during the postpartum period, and perimenopausally) and increased anxiety and depressive symptoms (Osterlund et al., 2005, Ryan and Ancelin, 2012, Watson et al., 2010). Recent data have indicated that the estrogen receptor (ER) seems to be a major mediator of the estrogenic effects in depression and anxiety (Osterlund and Hurd, 2001, Ryan and Ancelin, 2012). The importance of sex steroid related genes in ASDs is supported by studies reporting associations between polymorphisms in genes involved in sex steroid synthesis/metobolism and ASDs (Chakrabarti et al., 2009, Zettergren et al., 2013). Recent studies of ASD patients revealed a significant association of lowered levels of ERβ gene (Chakrabarti et al., 2009, Crider et al., 2014). To the best of our knowledge, there has been no study to date which has examined serum GPER level in ASD patients. The aim of this study was to evaluate the potential role of GPER in children with ASD by measuring serum levels of GPER and comparing them with age and gender-matched healthy children and associations between GPER and the severity of ASD.
Section snippets
Patients
The study included 45 children, aged 3–12 years, with confirmed ASD and 40 age-matched healty children. The diagnosis of ASD was made by a child psychiatrist according to clinical features and the criteria defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-V) (American Psychiatric Association 2013). The severity of ASD in the children was evaluated with the Childhood Autism Rating Scale (CARS) Score (Schopler et al., 1980). The CARS is widely used for
Results
This study included 45 patients with ASD aged 3–12 years and 40 normal control subjects, who were age and gender-matched. No significant difference was determined between the groups in respect of age (patients: 5,33±2,61, controls: 6,12±2,55 (mean±sd), p=0.163) and gender (patients male/female:40/5, controls male/ female: 32/8, p=0256). The median CARS score on admission in ASD patients was 41,3±7,87 (min-max:30–60) (Table 1). The levels of estradiol were found to be similar in both groups
Discussion
The aim of this study was to determine whether or not there was any change in serum GPER levels in children with ASD compared to a healthy control subject. From the results of the study it was determined that serum GPER levels were statistically significantly low in the children with ASD. In addition, our results showed that the reduction in GPER levels of patients was independent of gender. This finding indicates that GPER could have a potential role in the pathogenesis of ASD. To the best of
Conclusion
In conclusion, the molecular mechanisms through which the sex hormones may play a role in autism susceptibility have still not been fully clarified. In the present study, GPER level was determined to be decreased in the serum of ASD patients, significantly and negatively correlated with the severity of ASD. The dates of the present study demonstrate that GPER may play an important role in the etiology of ASD, ıt's role is seem to be independent from the serum estradiol levels in our study. But
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