Effects of bisphenol-A and other endocrine disruptors compared with abnormalities of schizophrenia: an endocrine-disruption theory of schizophrenia

In recent years, numerous substances have been identified as so-called "endocrine disruptors" because exposure to them results in disruption of normal endocrine function with possible adverse health outcomes. The pathologic and behavioral abnormalities attributed to exposure to endocrine disruptors like bisphenol-A (BPA) have been studied in animals. Mental conditions ranging from cognitive impairment to autism have been linked to BPA exposure by more than one investigation. Concurrent with these developments in BPA research, schizophrenia research has continued to find evidence of possible endocrine or neuroendocrine involvement in the disease. Sufficient information now exists for a comparison of the neurotoxicological and behavioral pathology associated with exposure to BPA and other endocrine disruptors to the abnormalities observed in schizophrenia. This review summarizes these findings and proposes a theory of endocrine disruption, like that observed from BPA exposure, as a pathway of schizophrenia pathogenesis. The review shows similarities exist between the effects of exposure to BPA and other related chemicals with schizophrenia. These similarities can be observed in 11 broad categories of abnormality: physical development, brain anatomy, cellular anatomy, hormone function, neurotransmitters and receptors, proteins and factors, processes and substances, immunology, sexual development, social behaviors or physiological responses, and other behaviors. Some of these similarities are sexually dimorphic and support theories that sexual dimorphisms may be important to schizophrenia pathogenesis. Research recommendations for further elaboration of the theory are proposed.     

Sex difference in the bed nucleus of the stria terminalis of the human brain.

A quantitative analysis of the volume of the darkly staining region of the posteromedial bed nucleus of the stria terminalis was performed on the brains of 26 age-matched male and female human subjects. We suggest the term "darkly staining posteromedial" component of the bed nucleus of the stria terminalis (BNST-dspm) to describe this sexually dimorphic region of the human brain. The volume of the BNST-dspm was 2.47 times greater in males than in females. This region in humans appears to correspond to an area of the bed nucleus of the stria terminalis in laboratory animals that exhibits volumetric and neurochemical sexual dimorphisms, concentrates gonadal steroids, and is anatomically connected to several other sexually dimorphic nuclei. Furthermore, the bed nucleus of the stria terminalis is involved in sexually dimorphic functions, including aggressive behavior, sexual behavior, and gonadotropin secretion, which are also influenced by gonadal steroids. Therefore, it is possible that in human beings as well, gonadal hormones influence the sexual dimorphism in the BNST-dspm and that this morphological difference, in part, underlies sexually dimorphic function.     

Oxytocin, vasopressin, and human social behavior

There is substantial evidence from animal research indicating a key role of the neuropeptides oxytocin (OT) and arginine vasopressin (AVP) in the regulation of complex social cognition and behavior. As social interaction permeates the whole of human society, and the fundamental ability to form attachment is indispensable for social relationships, studies are beginning to dissect the roles of OT and AVP in human social behavior. New experimental paradigms and technologies in human research allow a more nuanced investigation of the molecular basis of social behavior. In addition, a better understanding of the neurobiology and neurogenetics of human social cognition and behavior has important implications for the current development of novel clinical approaches for mental disorders that are associated with social deficits (e.g., autism spectrum disorder, social anxiety disorder, and borderline personality disorder). This review focuses on our recent knowledge of the behavioral, endocrine, genetic, and neural effects of OT and AVP in humans and provides a synthesis of recent advances made in the effort to implicate the oxytocinergic system in the treatment of psychopathological states.     

Brief report: pitocin induction in autistic and nonautistic individuals

Oxytocin plays an important role in social-affiliative behaviors. It has been proposed that exposure to high levels of exogenous oxytocin at birth, via pitocin induction of delivery, might increase susceptibility to autism by causing a downregulation of oxytocin receptors in the developing brain. This study examined the rates of labor induction using pitocin in children with autism and matched controls with either typical development or mental retardation. Birth histories of 41 boys meeting the criteria for autistic disorder were compared to 25 age- and IQ-matched boys without autism (15 typically developing and 10 with mental retardation). There were no differences in pitocin induction rates as a function of either diagnostic group (autism vs. control) or IQ level (average vs. subaverage range), failing to support an association between exogenous exposure to oxytocin and neurodevelopmental abnormalities.     

Oxytocin improves "mind-reading" in humans.

BACKGROUND: The ability to "read the mind" of other individuals, that is, to infer their mental state by interpreting subtle social cues, is indispensable in human social interaction. The neuropeptide oxytocin plays a central role in social approach behavior in nonhuman mammals. METHODS: In a double-blind, placebo-controlled, within-subject design, 30 healthy male volunteers were tested for their ability to infer the affective mental state of others using the Reading the Mind in the Eyes Test (RMET) after intranasal administration of 24 IU oxytocin. RESULTS: Oxytocin improved performance on the RMET compared with placebo. This effect was pronounced for difficult compared with easy items. CONCLUSIONS: Our data suggest that oxytocin improves the ability to infer the mental state of others from social cues of the eye region. Oxytocin might play a role in the pathogenesis of autism spectrum disorder, which is characterized by severe social impairment.     

Autism: neuroimaging

Autism is a neurodevelopmental disorder with a range of clinical presentations. These presentations vary from mild to severe and are referred to as autism spectrum disorders. The most common clinical sign of autism spectrum disorders is social interaction impairment, which is associated with verbal and non-verbal communication deficits and stereotyped and repetitive behaviors. Thanks to recent brain imaging studies, scientists are getting a better idea of the neural circuits involved in autism spectrum disorders. Indeed, functional brain imaging, such as positron emission tomography, single foton emission tomography and functional MRI have opened a new perspective to study normal and pathological brain functioning. Three independent studies have found anatomical and rest functional temporal lobe abnormalities in autistic patients. These alterations are localized in the superior temporal sulcus bilaterally, an area which is critical for perception of key social stimuli. In addition, functional studies have shown hypoactivation of most areas implicated in social perception (face and voice perception) and social cognition (theory of mind). These data suggest an abnormal functioning of the social brain network in autism. The understanding of the functional alterations of this important mechanism may drive the elaboration of new and more adequate social re-educative strategies for autistic patients.     

Distribution of alpha 2-adrenergic receptors in the brain of the Japanese quail as determined by quantitative autoradiography: implications for the control of sexually dimorphic reproductive processes

With the use of [3H]p-aminoclonidine (PAC), alpha 2-adrenergic binding sites were mapped in the brain of the Japanese quail (Coturnix coturnix japonica). The sites were labeled with the use of in vitro quantitative autoradiography. Special attention was given to areas implicated in the control of sexually dimorphic reproductive processes including sexual behavior. Preliminary competition experiments found that [3H]PAC binding on tissue sections exhibited a pharmacology appropriate to the alpha 2 receptor. Binding sites were found to be heterogeneously distributed throughout the brain. Some of the highest levels of specific binding were found in several areas regulating reproductive function such as the preoptic area, the supraoptic nucleus, the infundibulum, and the medial mammillary nucleus of the infundibulum. [3H]PAC labeled precisely the morphologically dimorphic preoptic medial nucleus but no sexual dimorphism in density of receptor binding was identified. However, dimorphism in density of receptor binding was identified in two areas: the medial mammillary nucleus and the mesencephalic intercollicular nucleus. The former area appears to be involved in the regulation of gonadotrophin secretion and the latter area has been implicated in the control of vocal behavior. These neurochemical dimorphisms may contribute to the regulation of two sexually dimorphic reproductive processes, gonadotropin secretion and courtship vocalizations.     

The orbitofrontal-amygdala circuit and self-regulation of social-emotional behavior in autism

Individuals with an autistic spectrum disorder are impaired not only in understanding others' mental states, but also in self-regulation of social-emotional behavior. Therefore, a model of the brain in autism must encompass not only those brain systems that subserve social-cognitive and emotional functioning, but also those that subserve the self-regulation of behavior in response to a changing social environment. We present evidence to support the hypothesis that developmental dysfunction of the orbitofrontal-amygdala circuit of the brain is a critical factor in the development of autism and that some of the characteristic deficits of persons with autism in socio-emotional cognition and behavioral self-regulation are related to early dysfunction of different components of this circuit. A secondary hypothesis posits that the degree of intellectual impairment present in individuals with autism is directly related to the integrity of the dorsolateral prefrontal-hippocampal circuit of the brain. Together, these hypotheses have the potential to help explain the neurodevelopmental basis of some of the primary manifestations of autism as well as the heterogeneity of outcomes.     

The effects of oxytocin on social cognition in borderline personality disorder

Introduction

Deficits in social cognition and interpersonal difficulties are key features in borderline personality disorder. Social cognition refers to the function of perceiving and adequately dealing with social signals, leading to the establishment and maintenance of healthy and positive social relationships. Evidence suggests that oxytocin (OT) may improve social cognition and human social behavior. Recently, several studies have highlighted the beneficial effects of oxytocin in several psychiatric conditions involving social cognition deficits such as schizophrenia, autism or social phobia. However, despite growing interest, the effects of oxytocin in patients with borderline personality disorder are far from being clearly demonstrated.

Brain Sex Differences and the Organisation of Juvenile Social Play Behaviour

Juvenile social play behaviour is one of the earliest forms of non-mother directed social behaviour in rodents. Juvenile social play behaviour is sexually dimorphic, with males exhibiting higher levels compared to females, making it a useful model to study both social development and sexual differentiation of the brain. As with most sexually dimorphic behaviour, juvenile play behaviour is organised by neonatal steroid hormone exposure. The developmental organisation of juvenile play behaviour also appears to be influenced by the early maternal environment. This review will focus briefly on why and how rats play, some brain regions controlling play behaviour, and how neurotransmitters and the social environment converge within the developing brain to influence sexual differentiation of juvenile play behaviour.     

Developmental deficits in social perception in autism: the role of the amygdala and fusiform face area

Autism is a severe developmental disorder marked by a triad of deficits, including impairments in reciprocal social interaction, delays in early language and communication, and the presence of restrictive, repetitive and stereotyped behaviors. In this review, it is argued that the search for the neurobiological bases of the autism spectrum disorders should focus on the social deficits, as they alone are specific to autism and they are likely to be most informative with respect to modeling the pathophysiology of the disorder. Many recent studies have documented the difficulties persons with an autism spectrum disorder have accurately perceiving facial identity and facial expressions. This behavioral literature on face perception abnormalities in autism is reviewed and integrated with the functional magnetic resonance imaging (fMRI) literature in this area, and a heuristic model of the pathophysiology of autism is presented. This model posits an early developmental failure in autism involving the amygdala, with a cascading influence on the development of cortical areas that mediate social perception in the visual domain, specifically the fusiform "face area" of the ventral temporal lobe. Moreover, there are now some provocative data to suggest that visual perceptual areas of the ventral temporal pathway are also involved in important ways in representations of the semantic attributes of people, social knowledge and social cognition. Social perception and social cognition are postulated as normally linked during development such that growth in social perceptual skills during childhood provides important scaffolding for social skill development. It is argued that the development of face perception and social cognitive skills are supported by the amygdala-fusiform system, and that deficits in this network are instrumental in causing autism.     

Astroglial cells as neuroendocrine targets in forebrain development: Implications for sex differences in psychiatric disease

Astroglial cells are the most abundant cell type in the mammalian brain. They are implicated in almost every aspect of brain physiology, including maintaining homeostasis, building and maintaining the blood brain barrier, and the development and maturation of neuronal networks. Critically, astroglia also express receptors for gonadal sex hormones, respond rapidly to gonadal hormones, and are able to synthesize hormones. Thus, they are positioned to guide and mediate sexual differentiation of the brain, particularly neuronal networks in typical and pathological conditions. In this review, we describe astroglial involvement in the organization and development of the brain, and consider known sex differences in astroglial responses to understand how astroglial cell-mediated organization may play a role in forebrain sexual dimorphisms in human populations. Finally, we consider how sexually dimorphic astroglial responses and functions in development may lead to sex differences in vulnerability for neuropsychiatric disorders.     

Oxytocin receptor gene (OXTR) DNA methylation is associated with autism and related social traits – A systematic review

There is emerging evidence implicating oxytocin receptor gene (OXTR) DNA methylation (DNAm) in social behaviour. This review investigated its association with autism spectrum disorder (ASD) characteristics and related social dimensions, both in individuals with and without ASD. Twelve articles investigating OXTR DNAm in relation to ASD, social perception/cognition and social anxiety were included. We found that hypermethylation is associated with (i) higher quantitative autism traits in adults, reflecting a higher incidence of autism characteristics, (ii) increased brain activity while performing social tasks (indicating a higher need for resources) and (iii) decreased functional connectivity. (iv) Contradictory, hypomethylation was found to be present in children (especially boys) with ASD and was also associated with more social anxiety. While the included studies displayed a large variability, for example in terms of population characteristics, analysed OXTR DNAm regions, and adopted scales/questionnaires, an initial developmental pattern of results emerged, suggesting an association between hypermethylation of OXTR and autism traits in adults. Nonetheless, future studies are warranted to corroborate these initial conclusions.     

Neuropeptides and the social brain: potential rodent models of autism

Conducting basic scientific research on a complex psychiatric disorder, such as autism, is a challenging prospect. It is difficult to dissociate the fundamental neurological and psychological processes that are disturbed in autism and, therefore, it is a challenge to discover accurate and reliable animal models of the disease. Because of their role in animal models of social processing and social bonding, the neuropeptides oxytocin and vasopressin are strong candidates for dysregulation in autism. In this review, we discuss the current animal models which have investigated oxytocin and vasopressin systems in the brain and their effects on social behavior. For example, mice lacking the oxytocin gene have profound deficits in social processing and social recognition, as do rats lacking vasopressin or mice lacking the vasopressin V1a receptor (V1aR). In another rodent model, monogamous prairie voles are highly social and form strong pair bonds with their mates. Pair bonds can be facilitated or disrupted by perturbing the oxytocin and vasopressin systems. Non-monogamous vole species that do not pair bond have different oxytocin and V1aR distribution patterns in the brain than monogamous vole species. Potential ties from these rodent models to the human autistic condition are then discussed. Given the hallmark disturbances in social function, the study of animal models of social behavior may provide novel therapeutic targets for the treatment of autism.     

Autism, the superior temporal sulcus and social perception

The most common clinical sign of autism spectrum disorders (ASD) is social interaction impairment, which is associated with communication deficits and stereotyped behaviors. Based on recent brain-imaging results, our hypothesis is that abnormalities in the superior temporal sulcus (STS) are highly implicated in ASD. STS abnormalities are characterized by decreased gray matter concentration, rest hypoperfusion and abnormal activation during social tasks. STS anatomical and functional anomalies occurring during early brain development could constitute the first step in the cascade of neural dysfunction underlying ASD. We will focus this review on the STS, which has been highly implicated in social cognition. We will review recent data on the contribution of the STS to normal social cognition and review brain-imaging data implicating this area in ASD. This review is part of the INMED/TINS special issue "Nature and nurture in brain development and neurological disorders", based on presentations at the annual INMED/TINS symposium (http://inmednet.com/).     

Psychiatric and Psychosocial Correlates of Sexual Risk Behavior among Adults with Severe Mental Illness

Persons with severe mental illness (SMI) are disproportionately affected by HIV/AIDS. This study examined multivariate correlates of sexual risk among 152 adults with SMI receiving outpatient psychiatric treatment. Structured interviews assessed psychiatric, psychosocial, and behavioral risk factors. The majority was sexually active (65%), and many reported unprotected intercourse (73%), multiple partners (45%), and sex trading (21%) in the past year. Logistic regression models found that sexual behaviors were differentially associated with non-psychotic disorder, psychiatric symptoms, substance abuse, childhood sexual abuse, romantic partnership, and social support (all ps < .05). Findings underscore the need for targeted HIV prevention interventions that address psychiatric and psychosocial risk factors. Christina S. Meade is a Research Fellow at Harvard Medical School, McLean Hospital, Belmont, MA. Kathleen J. Sikkema is an Associate Professor in the Department of Epidemiology and Public Health, Yale University, New Haven, CT.     

The social deficits of the oxytocin knockout mouse

Numerous studies have implicated oxytocin (OT) and oxytocin receptors in the central mediation of social cognition and social behavior. Much of our understanding of OT's central effects depends on pharmacological studies with OT agonists and antagonists. Recently, our knowledge of OT's effects has been extended by the development of oxytocin knockout (OTKO) mice. Mice with a null mutation of the OT gene manifest several interesting cognitive and behavioral changes, only some of which were predicted by pharmacological studies. Contrary to studies in rats, mice do not appear to require OT for normal sexual or maternal behavior, though OT is necessary for the milk ejection reflex during lactation. OTKO pups thrive if raised by a lactating female, but OTKO pups emit fewer ultrasonic vocalizations with maternal separation and OTKO adults are more aggressive than WT mice. Remarkably, OTKO mice fail to recognize familiar conspecifics after repeated social encounters, though olfactory and non-social memory functions appear to be intact. Central OT administration into the amygdala restores social recognition. The development of transgenic mice with specific deficits in social memory represents a promising approach to examine the cellular and neural systems of social cognition. These studies may provide valuable new perspectives on diseases characterized by social deficits, such as autism or reactive attachment disorder.     

Immune dysfunction in autism: A pathway to treatment

Autism is a complex and clinically heterogeneous disorder with a spectrum of symptoms. Clinicians, schools, and service agencies worldwide have reported a dramatic increase in the number of children identified with autism. Despite expanding research, the etiology and underlying biological processes of autism remain poorly understood, and the relative contribution from genetic, epigenetic, and environmental factors remains unclear. Although autism affects primarily brain function (especially affect, social functioning, and cognition), it is unknown to what extent other organs and systems are disrupted. Published findings have identified widespread changes in the immune systems of children with autism, at both systemic and cellular levels. Brain specimens from autism subjects exhibit signs of active, ongoing inflammation, as well as alterations in gene pathways associated with immune signaling and immune function. Moreover, many genetic studies have indicated a link between autism and genes that are relevant to both the nervous system and the immune system. Alterations in these pathways can affect function in both systems. Together, these reports suggest that autism may in fact be a systemic disorder with connections to abnormal immune responses. Such immune system dysfunction may represent novel targets for treatment. A better understanding of the involvement of the immune response in autism, and of how early brain development is altered, may have important therapeutic implications.     

Dopamine and Oxytocin Interactions Underlying Behaviors: Potential Contributions to Behavioral Disorders

Dopamine is an important neuromodulator that exerts widespread effects on the central nervous system (CNS) function. Disruption in dopaminergic neurotransmission can have profound effects on mood and behavior and as such is known to be implicated in various neuropsychiatric behavioral disorders including autism and depression. The subsequent effects on other neurocircuitries due to dysregulated dopamine function have yet to be fully explored. Due to the marked social deficits observed in psychiatric patients, the neuropeptide, oxytocin is emerging as one particular neural substrate that may be influenced by the altered dopamine levels subserving neuropathologic‐related behavioral diseases. Oxytocin has a substantial role in social attachment, affiliation and sexual behavior. More recently, it has emerged that disturbances in peripheral and central oxytocin levels have been detected in some patients with dopamine‐dependent disorders. Thus, oxytocin is proposed to be a key neural substrate that interacts with central dopamine systems. In addition to psychosocial improvement, oxytocin has recently been implicated in mediating mesolimbic dopamine pathways during drug addiction and withdrawal. This bi‐directional role of dopamine has also been implicated during some components of sexual behavior. This review will discuss evidence for the existence dopamine/oxytocin positive interaction in social behavioral paradigms and associated disorders such as sexual dysfunction, autism, addiction, anorexia/bulimia, and depression. Preliminary findings suggest that whilst further rigorous testing has to be conducted to establish a dopamine/oxytocin link in human disorders, animal models seem to indicate the existence of broad and integrated brain circuits where dopamine and oxytocin interactions at least in part mediate socio‐affiliative behaviors. A profound disruption to these pathways is likely to underpin associated behavioral disorders. Central oxytocin pathways may serve as a potential therapeutic target to improve mood and socio‐affiliative behaviors in patients with profound social deficits and/or drug addiction.