Teratology of autism

Department of Obstetrics and Gynecology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.
International Journal of Developmental Neuroscience (Impact Factor: 2.92). 04/2005; 23(2-3):189-99. DOI: 10.1016/j.ijdevneu.2004.11.001
Source: PubMed

ABSTRACT Autism spectrum disorders affect behaviors that emerge at ages when typically developing children become increasingly social and communicative, but many lines of evidence suggest that the underlying alterations in the brain occur long before the period when symptoms become obvious. Studies of the behavior of children in the first year of life demonstrate that symptoms are often detectable in the first 6 months. The environmental factors known to increase the risk of autism have critical periods of action during embryogenesis. Minor malformations that occur frequently in people with autism are known to arise in the same stages of development. Anomalies reported from histological studies of the brain are consistent with an early alteration of development. Congenital syndromes with high rates of autism include somatic that originate early in the first trimester. In addition, it is possible to duplicate a number of anatomic and behavioral features characteristic of human cases by exposing rat embryos to a teratogenic dose of valproic acid at the time of neural tube closure.

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    • "It is generally assumed that the effects of environmental factors on offspring development are strongly related to the gestational stages at which the exposure occurs, with the first trimester of pregnancy being the most susceptible period (Copp and Greene, 2010). In particular, several birth defects and central nervous system abnormalities in humans are related to insults that occur around the time of formation of the neural tube, which may result not only in neural tube defects, but also in neuropsychiatric disorders, including ASD (Rodier et al., 1996; Arndt et al., 2005). The neural tube is the embryo's precursor of the central nervous system, the formation of which starts on the 17th day of gestation and ends after 25–26 days, whereas the closure of the vertebral arches is completed at 11 weeks of gestation (Copp and Greene, 2010). "
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    ABSTRACT: Autism spectrum disorders (ASD) are among the most severe developmental psychiatric disorders known today, characterized by impairments in communication and social interaction and stereotyped behaviors. However, no specific treatments for ASD are as yet available. By enabling selective genetic, neural, and pharmacological manipulations, animal studies are essential in ASD research. They make it possible to dissect the role of genetic and environmental factors in the pathogenesis of the disease, circumventing the many confounding variables present in human studies. Furthermore, they make it possible to unravel the relationships between altered brain function in ASD and behavior, and are essential to test new pharmacological options and their side-effects. Here, we first discuss the concepts of construct, face, and predictive validity in rodent models of ASD. Then, we discuss how ASD-relevant behavioral phenotypes can be mimicked in rodents. Finally, we provide examples of environmental and genetic rodent models widely used and validated in ASD research. We conclude that, although no animal model can capture, at once, all the molecular, cellular, and behavioral features of ASD, a useful approach is to focus on specific autism-relevant behavioral features to study their neural underpinnings. This approach has greatly contributed to our understanding of this disease, and is useful in identifying new therapeutic targets.
    Behavioural pharmacology 09/2015; 26(6):522-540. DOI:10.1097/FBP.0000000000000163 · 2.19 Impact Factor
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    • "); d NCC give rise to rib cage (Henderson et al., 1999); (1) (Grandjean et al., 1997); (2) (Grandjean and Landrigan, 2006); (3) (Opler et al., 2008); (4) (Ha et al., 2009); (5) (Tian et al., 2009); (6) (Kippler et al., 2012); (7) (Hamadani et al., 2011); (8) (Saha et al., 2012); (9) (Eubig et al., 2010); (10) (Patandin et al., 1999); (11) (Valvi et al., 2012); (12) (Lai et al., 2002); (13) (Chen et al., 1992); (14) (Zarn et al., 2004); (15) (Di Renzo et al., 2007); (16) (Machera, 1995); (17) (Giavini and Menegola, 2010); (18) (Krieger, 2004); (19) (Dean et al., 2002); (20) (Arndt et al., 2005); (21) (Meador et al., 2006); (22) (Rasalam et al., 2005); (23) (Menegola et al., 2005b); (24) (Verbois, 2006); (25) (Valenzuela-Fernandez et al., 2008). "
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    ABSTRACT: Functional assays, such as the "migration inhibition of neural crest cells"(MINC) developmental toxicity test, can identify toxicants without requiring knowledge on their mode of action (MoA). Here, we were interested, whether (i) inhibition of migration by structurally diverse toxicants resulted in a unified signature of transcriptional changes; (ii) whether statistically-identified transcript patterns would inform on compound grouping even though individual genes were little regulated, and (iii) whether analysis of a small group of biologically-relevant transcripts would allow the grouping of compounds according to their MoA. We analysed transcripts of 35 'migration genes' after treatment with sixteen migration-inhibiting toxicants. Clustering, principal component analysis and correlation analyses of the data showed that mechanistically related compounds (e.g. histone deacetylase inhibitors (HDACi)), PCBs) triggered similar transcriptional changes, but groups of structurally diverse toxicants largely differed in their transcriptional effects. Linear discriminant analysis (LDA) confirmed the specific clustering of HDACi across multiple separate experiments. Similarity of the signatures of the HDACi trichostatin A and suberoylanilide hydroxamic acid to the one of valproic acid (VPA), suggested that the latter compound acts as HDACi when impairing neural crest migration. In conclusion, the data suggest that (i) a given functional effect (e.g. inhibition of migration) can be associated with highly diverse signatures of transcript changes; (ii) statistically significant grouping of mechanistically-related compounds can be achieved on the basis of few genes with small regulations. Thus, incorporation of mechanistic markers in functional in vitro tests may support read-across procedures, also for structurally un-related compounds. Copyright © 2015. Published by Elsevier B.V.
    NeuroToxicology 07/2015; DOI:10.1016/j.neuro.2015.07.008 · 3.05 Impact Factor
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    • "However; the recent upsurge of clinical cases of idiopathic ASD suggests that environmental teratogens could be an important factor in the development of ASD (Christianson et al., 1994; Moore et al., 2000; Rasalam et al., 2005) and, therefore , environmental models of ASD are an important tool for uncovering the neurobiological basis of ASD. One such model is the valproic acid (VPA) animal model of ASD (Rodier et al., 1997; Arndt et al., 2005; Kim et al., 2011). This model is based on the discovery that when the anticonvulsant drug, VPA, is administered to women during their first trimester of pregnancy, they "
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    ABSTRACT: Autism Spectrum Disorders (ASD) are complex neurodevelopmental disorders characterized by repetitive behavior and impaired social communication and interactions. Apart from these core symptoms, a significant number of ASD individuals display higher levels of anxiety and some ASD individuals exhibit impaired emotional learning. We therefore sought to further examine anxiety and emotional learning in an environmentally induced animal model of ASD that utilizes the administration of the known teratogen, valproic acid (VPA) during gestation. Specifically we exposed dams to one of two different doses of VPA (500 and 600 mg/kg) or vehicle on day 12.5 of gestation and examined the resultant progeny. Our data indicate that animals exposed to VPA in utero exhibit enhanced anxiety in the open field test and normal object recognition memory compared to control animals. Animals exposed to 500 mg/kg of VPA displayed normal acquisition of auditory fear conditioning, and exhibited reduced extinction of fear memory and normal litter survival rates as compared to control animals. We observed that animals exposed to 600 mg/kg of VPA exhibited a significant reduction in the acquisition of fear conditioning, a significant reduction in social interaction and a significant reduction in litter survival rates as compared to control animals. VPA (600 mg/kg) exposed animals exhibited similar shock sensitivity and hearing as compared to control animals indicating the fear conditioning deficit observed in these animals was not likely due to sensory deficits, but rather due to deficits in learning or memory retrieval. In conclusion, considering that progeny from dams exposed to rather similar doses of VPA exhibit striking differences in emotional learning, the VPA model may serve as a useful tool to explore the molecular and cellular mechanisms that contribute to not only ASD, but also emotional learning.
    Frontiers in Behavioral Neuroscience 11/2014; 8:387. DOI:10.3389/fnbeh.2014.00387 · 4.16 Impact Factor
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