Neurotoxicology and Teratology : Environmental Influences and Emerging Mechanisms in the Etiology of Autism

jeudi 2 mai 2013

La revue Neurotoxicology and Teratology consacre son numéro de mars-avril 2013 sur le thème de l’étiologie de l’autisme et les facteurs environnementaux.

1. Bushnell PJ. Special issue : Environmental influences and emerging mechanisms in the etiology of autism. Neurotoxicology and Teratology ;2013 ;36(0):1-2.

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2. Stamou M, Streifel KM, Goines PE, Lein PJ. Neuronal connectivity as a convergent target of gene × environment interactions that confer risk for Autism Spectrum Disorders. Neurotoxicology and Teratology ;2013 ;36(0):3-16.

Abstract Evidence implicates environmental factors in the pathogenesis of Autism Spectrum Disorders (ASD). However, the identity of specific environmental chemicals that influence ASD risk, severity or treatment outcome remains elusive. The impact of any given environmental exposure likely varies across a population according to individual genetic substrates, and this increases the difficulty of identifying clear associations between exposure and ASD diagnoses. Heritable genetic vulnerabilities may amplify adverse effects triggered by environmental exposures if genetic and environmental factors converge to dysregulate the same signaling systems at critical times of development. Thus, one strategy for identifying environmental risk factors for ASD is to screen for environmental factors that modulate the same signaling pathways as ASD susceptibility genes. Recent advances in defining the molecular and cellular pathology of ASD point to altered patterns of neuronal connectivity in the developing brain as the neurobiological basis of these disorders. Studies of syndromic ASD and rare highly penetrant mutations or CNVs in ASD suggest that ASD risk genes converge on several major signaling pathways linked to altered neuronal connectivity in the developing brain. This review briefly summarizes the evidence implicating dysfunctional signaling via Ca2 +-dependent mechanisms, extracellular signal-regulated kinases (ERK)/phosphatidylinositol-3-kinases (PI3K) and neuroligin–neurexin–SHANK as convergent molecular mechanisms in ASD, and then discusses examples of environmental chemicals for which there is emerging evidence of their potential to interfere with normal neuronal connectivity via perturbation of these signaling pathways.

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3. Schwartzer JJ, Koenig CM, Berman RF. Using mouse models of autism spectrum disorders to study the neurotoxicology of gene–environment interactions. Neurotoxicology and Teratology ;2013 ;36(0):17-35.

To better study the role of genetics in autism, mouse models have been developed which mimic the genetics of specific autism spectrum and related disorders. These models have facilitated research on the role genetic susceptibility factors in the pathogenesis of autism in the absence of environmental factors. Inbred mouse strains have been similarly studied to assess the role of environmental agents on neurodevelopment, typically without the complications of genetic heterogeneity of the human population. What has not been as actively pursued, however, is the methodical study of the interaction between these factors (e.g., gene and environmental interactions in neurodevelopment). This review suggests that a genetic predisposition paired with exposure to environmental toxicants plays an important role in the etiology of neurodevelopmental disorders including autism, and may contribute to the largely unexplained rise in the number of children diagnosed with autism worldwide. Specifically, descriptions of the major mouse models of autism and toxic mechanisms of prevalent environmental chemicals are provided followed by a discussion of current and future research strategies to evaluate the role of gene and environment interactions in neurodevelopmental disorders.

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4. Moy SS, Nonneman RJ, Shafer GO, Nikolova VD, Riddick NV, Agster KL, Baker LK, Knapp DJ. Disruption of social approach by MK-801, amphetamine, and fluoxetine in adolescent C57BL/6J mice. Neurotoxicology and Teratology ;2013 ;36(0):36-46.

Autism is a severe neurodevelopmental disorder, diagnosed on the basis of core behavioral symptoms. Although the mechanistic basis for the disorder is not yet known, genetic analyses have suggested a role for abnormal excitatory/inhibitory signaling systems in brain, including dysregulation of glutamatergic neurotransmission. In mice, the constitutive knockdown of NMDA receptors leads to social deficits, repetitive behavior, and self-injurious responses that reflect aspects of the autism clinical profile. However, social phenotypes differ with age : mice with reduced NMDA-receptor function exhibit hypersociability in adolescence, but markedly deficient sociability in adulthood. The present studies determined whether acute disruption of NMDA neurotransmission leads to exaggerated social approach, similar to that observed with constitutive disruption, in adolescent C57BL/6J mice. The effects of MK-801, an NMDA receptor antagonist, were compared with amphetamine, a dopamine agonist, and fluoxetine, a selective serotonin reuptake inhibitor, on performance in a three-chamber choice task. Results showed that acute treatment with MK-801 led to social approach deficits at doses without effects on entry numbers. Amphetamine also decreased social preference, but increased number of entries at every dose. Fluoxetine (10 mg/kg) had selective effects on social novelty preference. Withdrawal from a chronic ethanol regimen decreased activity, but did not attenuate sociability. Low doses of MK-801 and amphetamine were also evaluated in a marble-burying assay for repetitive behavior. MK-801, at a dose that did not disrupt sociability or alter entries, led to a profound reduction in marble-burying. Overall, these findings demonstrate that moderate alteration of NMDA, dopamine, or serotonin function can attenuate social preference in wild type mice.

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5. Roullet FI, Lai JKY, Foster JA. In utero exposure to valproic acid and autism — A current review of clinical and animal studies. Neurotoxicology and Teratology ;2013 ;36(0):47-56.

Abstract Valproic acid (VPA) is both an anti-convulsant and a mood stabilizer. Clinical studies over the past 40 years have shown that exposure to VPA in utero is associated with birth defects, cognitive deficits, and increased risk of autism. Two recent FDA warnings related to use of VPA in pregnancy emphasize the need to reevaluate its use clinically during child-bearing years. The emerging clinical evidence showing a link between VPA exposure and both cognitive function and risk of autism brings to the forefront the importance of understanding how VPA exposure influences neurodevelopment. In the past 10 years, animal studies have investigated anatomical, behavioral, molecular, and physiological outcomes related to in utero VPA exposure. Behavioral studies show that VPA exposure in both rats and mice leads to autistic-like behaviors in the offspring, including social behavior deficits, increased repetitive behaviors, and deficits in communication. Based on this work VPA maternal challenge in rodents has been proposed as an animal model to study autism. This model has both face and construct validity ; however, like all animal models there are limitations to its translation to the clinical setting. Here we provide a review of clinical studies that examined pregnancy outcomes of VPA use as well as the related animal studies.

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6. Chomiak T, Hu B. Alterations of neocortical development and maturation in autism : Insight from valproic acid exposure and animal models of autism. Neurotoxicology and Teratology ;2013 ;36(0):57-66.

Autism spectrum disorder (ASD) is a behaviourally defined brain disorder affecting approximately 1 in 88 children. Many pathological studies have shown that ASD is frequently associated with grey and white matter changes that can be described by their deviations from the normal trajectory of cortical maturation. For example, during the early (i.e. < 2 years) postnatal period there is marked and selective tissue overgrowth in the higher-order temporal and frontal networks involved in emotional, social, and communication functions. In this focused review we first summarize some basic principles of neocortical neural organization and how they are disrupted in ASD. We will then highlight some of the potential mechanisms by which the normal developmental trajectory and organization of neocortical networks can be altered based on animal studies of valproic acid, a teratogen widely used in animal models of ASD. We argue that the trajectory of postnatal cerebral neocortex development may be influenced by several cellular and molecular mechanisms that may all converge to produce a neuropathology characterized by premature or accelerated neuronal growth.

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7. Goines PE, Ashwood P. Cytokine dysregulation in autism spectrum disorders (ASD) : Possible role of the environment. Neurotoxicology and Teratology ;2013 ;36(0):67-81.

Autism spectrum disorders (ASD) are neurodevelopmental diseases that affect an alarming number of individuals. The etiological basis of ASD is unclear, and evidence suggests it involves both genetic and environmental factors. There are many reports of cytokine imbalances in ASD. These imbalances could have a pathogenic role, or they may be markers of underlying genetic and environmental influences. Cytokines act primarily as mediators of immunological activity but they also have significant interactions with the nervous system. They participate in normal neural development and function, and inappropriate activity can have a variety of neurological implications. It is therefore possible that cytokine dysregulation contributes directly to neural dysfunction in ASD. Further, cytokine profiles change dramatically in the face of infection, disease, and toxic exposures. Imbalances in cytokines may represent an immune response to environmental contributors to ASD. The following review is presented in two main parts. First, we discuss select cytokines implicated in ASD, including IL-1Β, IL-6, IL-4, IFN-γ, and TGF-Β, and focus on their role in the nervous system. Second, we explore several neurotoxic environmental factors that may be involved in the disorders, and focus on their immunological impacts. This review represents an emerging model that recognizes the importance of both genetic and environmental factors in ASD etiology. We propose that the immune system provides critical clues regarding the nature of the gene by environment interactions that underlie ASD pathophysiology.

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8. Persico AM, Napolioni V. Urinary p-cresol in autism spectrum disorder. Neurotoxicology and Teratology ;2013 ;36(0):82-90.

Autism spectrum disorder (ASD) is a neuropsychiatric disorder with onset during early childhood and life-long consequences in most cases. It is characterized by impairment in social interaction and communication, as well as by restricted patterns of interest and stereotyped behaviors. The etiology of autism is highly heterogeneous, encompassing a large range of genetic and environmental factors. Several lines of evidence suggest that, in addition to broader diagnostic criteria and increased awareness, also a real increase in incidence primarily due to greater gene–environment interactions may also be occurring. Environmental exposure to the organic aromatic compound p-cresol (4-methylphenol) is relatively common and occurs through the skin, as well as the gastrointestinal and respiratory systems. However, the largest and most widespread source of this compound is represented by some gut bacteria which express p-cresol synthesizing enzymes not found in human cells. Urinary p-cresol and its conjugated derivative p-cresylsulfate have been found elevated in an initial sample and recently in a replica sample of autistic children below 8 years of age, where it is associated with female sex, greater clinical severity regardless of sex, and history of behavioral regression. Potential sources of p-cresol excess in ASD, such as gut infection, chronic constipation, antibiotics, abnormal intestinal permeability, and environmental exposure, are being investigated. P-cresol may contribute to worsen autism severity and gut dysfunction, often present in autistic children. It may also contribute to a multibiomarker diagnostic panel useful in small autistic children.

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9. Slotkin TA, Seidler FJ. Terbutaline impairs the development of peripheral noradrenergic projections : Potential implications for autism spectrum disorders and pharmacotherapy of preterm labor. Neurotoxicology and Teratology ;2013 ;36(0):91-96.

Terbutaline, a β2-adrenoceptor agonist, is used off-label for long-term management of preterm labor ; such use is associated with increased risk of neurodevelopmental disorders, including autism spectrum disorders. We explored the mechanisms underlying terbutaline’s effects on development of peripheral sympathetic projections in developing rats. Terbutaline administration on postnatal days 2–5 led to immediate and persistent deficiencies in cardiac norepinephrine levels, with greater effects in males than in females. The liver showed a lesser effect ; we reasoned that the tissue differences could represent participation of retrograde trophic signaling from the postsynaptic site to the developing neuronal projection, since hepatic β2-adrenoceptors decline in the perinatal period. Accordingly, when we gave terbutaline earlier, on gestational days 17–20, we saw the same deficiencies in hepatic norepinephrine that had been seen in the heart with the later administration paradigm. Administration of isoproterenol, which stimulates both β1- and β2-subtypes, also had trophic effects that differed in direction and critical period from those elicited by terbutaline ; methoxamine, which stimulates α1-adrenoceptors, was without effect. Thus, terbutaline, operating through trophic interactions with β2-adrenoceptors, impairs development of noradrenergic projections in a manner similar to that previously reported for its effects on the same neurotransmitter systems in the immature cerebellum. Our results point to the likelihood of autonomic dysfunction in individuals exposed prenatally to terbutaline ; in light of the connection between terbutaline and autism, these results could also contribute to autonomic dysregulation seen in children with this disorder.

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