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: 2.58). 04/2005; 23(2-3):189-99. DOI: 10.1016/j.ijdevneu.2004.11.001
Source: PubMed


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 · 2.15 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; 50. DOI:10.1016/j.neuro.2015.07.008 · 3.38 Impact Factor
    • "Retrospective studies on human participants have shown that in-utero exposure to valproic acid (VPA) – a teratogenic anticonvulsant – during the first trimester of pregnancy leads to an increased incidence (4.42% absolute risk) of autism and intellectual disability (Christianson et al., 1994; Moore et al., 2000; Rasalam et al., 2005; Christensen et al., 2013). Owing to this correlation between in-utero VPA exposure and the increased risk of autism, the VPA rodent model was developed (Rodier et al., 1996; Arndt et al., 2005; Bromley et al., 2009, 2013; Bath and Scharfman, 2013). Pregnant dams exposed to a single dose of VPA on gestational day 12.5 produce progeny that show behavioral and neuroanatomical anomalies that are similar to those present in humans with autism (Rodier et al., 1996, 1997; Schneider and Przewlocki, 2005; Rinaldi et al., 2008; Snow et al., 2008; Mychasiuk et al., 2012; Chomiak et al., 2013). "
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    ABSTRACT: Autism is a severe neurodevelopmental disorder characterized by qualitative impairments in social behavior, communication, and aberrant repetitive behaviors. A major focus of animal models of autism has been to mimic the social deficits of the disorder. The present study assessed whether rats exposed prenatally to valproic acid (VPA) show deficits in social play as juveniles that are consistent with the social deficits observed in autism. Dams were exposed to an acute dose of VPA on gestational day 12.5. Later, the playful interactions and associated ultrasonic vocalizations of the juveniles were examined. It was predicted that VPA-treated rats should play less than the controls. Characteristic of neurobehavioral insult at this early age, the VPA-treated juveniles showed significant increases in the frequency of body shakes and sexual mounting, but played at the same frequency as the controls. However, when playing, they were less likely to use tactics that facilitated bodily contact and vocalized less. These data suggest that prenatal VPA exposure disrupts some aspects of being able to communicate effectively and engage partners in dynamic interactions - deficits that are consistent with those observed in autism.
    Behavioural pharmacology 07/2015; DOI:10.1097/FBP.0000000000000169 · 2.15 Impact Factor
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