Autism symptoms, including impairments in language development, social interactions, and motor skills, have been difficult to model in rodents. Since children exposed in utero to sodium valproate (VPA) demonstrate behavioral and neuroanatomical abnormalities similar to those seen in autism, the neurodevelopmental effects of this antiepileptic agent were examined in mice following its pre- or postnatal administration. Exposed pups were evaluated in a battery of neurodevelopmental procedures designed to assess VPA-induced retardation (wherein a behavior fails to mature on schedule), regression (wherein a behavior does mature on time but then deteriorates), or intrusions (wherein normal behaviors are overshadowed by stereotypic or self-injurious behaviors). The resulting observations were interpreted in the context of this new strategy to model autism.

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BackgroundEpidemiological studies suggest that physical activity reduces the risk of colon cancer in humans. Results from animal studies, however, are inconclusive. The present study investigated the effects of voluntary exercise on intestinal tumor formation in two different animal models, ApcMin/+ mice and azoxymethane (AOM)/dextran sulfate sodium (DSS)-treated mice.MethodsIn Experiments 1 and 2, five-week old female ApcMin/+ mice were either housed in regular cages or cages equipped with a running wheel for 6 weeks (for mice maintained on the AIN93G diet; Experiment 1) or 9 weeks (for mice on a high-fat diet; Experiment 2). In Experiment 3, male CF-1 mice at 6 weeks of age were given a dose of AOM (10 mg/kg body weight, i.p.) and, 12 days later, 1.5% DSS in drinking fluid for 1 week. The mice were then maintained on a high-fat diet and housed in regular cages or cages equipped with a running wheel for 16 weeks.ResultsIn the ApcMin/+ mice maintained on either the AIN93G or the high-fat diet, voluntary exercise decreased the number of small intestinal tumors. In the AOM/DSS-treated mice maintained on a high-fat diet, voluntary exercise also decreased the number of colon tumors. In ApcMin/+ mice, voluntary exercise decreased the ratio of serum insulin like growth factor (IGF)-1 to IGF binding protein (BP)-3 levels. It also decreased prostaglandin E2 and nuclear β-catenin levels, but increased E-cadherin levels in the tumors.ConclusionThese results indicate hat voluntary exercise inhibited intestinal tumorigenesis in ApcMin/+ mice and AOM/DSS-treated mice, and the inhibitory effect is associated with decreased IGF-1/IGFBP-3 ratio, aberrant β-catenin signaling, and arachidonic acid metabolism.

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Autism is a pervasive neurodevelopmental disorder that leads to deficits in social interaction, communication and restricted, repetitive motor movements. Autism is a highly heritable disorder, however, there is mounting evidence to suggest that toxicant-induced oxidative stress may play a role. The focus of this article will be to review our animal model of autism and discuss our evidence that oxidative stress may be a common underlying mechanism of neurodevelopmental damage. We have shown that mice exposed to either methylmercury (MeHg) or valproic acid (VPA) in early postnatal life display aberrant social, cognitive and motor behavior. Interestingly, early exposure to both compounds has been clinically implicated in the development of autism. We recently found that Trolox, a water-soluble vitamin E derivative, is capable of attenuating a number of neurobehavioral alterations observed in mice postnatally exposed to MeHg. In addition, a number of other investigators have shown that oxidative stress plays a role in neural injury following MeHg exposure both in vitro and in vivo. New data presented here will show that VPA-induced neurobehavioral deficits are attenuated by vitamin E as well and that the level of glial fibrillary acidic protein (GFAP), a marker of astrocytic neural injury, is altered following VPA exposure. Collectively, these data indicate that vitamin E and its derivative are capable of protecting against neurobehavioral deficits induced by both MeHg and VPA. This antioxidant protection suggests that oxidative stress may be a common mechanism of injury leading to aberrant behavior in both our animal model as well as in the human disease state

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