2004 Progress Report: Disruption of Ontogenic Development of Cognitive and Sensory Motor Skills

EPA Grant Number: R829391C003
Subproject: this is subproject number 003 , established and managed by the Center Director under grant R829391
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: CECEHDPR - University of Medicine and Dentistry of New Jersey Center for Childhood Neurotoxicology and Assessment
Center Director: Lambert, George H.
Title: Disruption of Ontogenic Development of Cognitive and Sensory Motor Skills
Investigators: Wagner, George
Institution: University of Medicine and Dentistry of New Jersey , University of Medicine and Dentistry of New Jersey
Current Institution: University of Medicine and Dentistry of New Jersey
EPA Project Officer: Louie, Nica
Project Period: November 1, 2001 through October 31, 2006
Project Period Covered by this Report: November 1, 2003 through October 31, 2004
RFA: Centers for Children's Environmental Health and Disease Prevention Research (2001) RFA Text |  Recipients Lists
Research Category: Children's Health , Health Effects , Health


Behavioral manifestations of developmental disorders may be characterized as “retardation” (a behavior fails to develop during a critical period), “regression” (a behavior develops at the right time but then is lost or exhibits a stunted rate of progression), or “intrusion” (appearance of behaviors aberrant in form or frequency). The period when symptoms appear may represent a time when environmental toxicants have accumulated in the brain to critical levels or the deleterious effects of early exposure become manifest through perturbation of normal development of brain pathways. Furthermore, certain individuals may be more sensitive to toxicants because of a genetic (perhaps immune-related) predisposition. Within this framework, the hypothesis that toxicants are causally involved in developmental disorders lends itself well to testing. In this proposal, a new paradigm for the study of toxicant-induced developmental disorders incorporating systematic assessment of retardation, regression, and/or intrusions in male and female mice of three strains will be developed. This will include a characterization of the ontogeny of key behaviors under normal conditions: (1) mid-air righting reflex and balance beam performance; (2) water maze (hidden platform) and passive avoidance behavior; and (3) water maze (visible platform), active avoidance, and stereotypic and self-injurious behavior. These behaviors have been linked to cerebellum, hippocampus, and striatum, brain areas known to be involved in developmental disorders and are known to be targets of lead and methylmercury (MeHg). The behavioral ontogeny will be linked to neural circuitry and synapse formation and the disruptive effects of low- dose exposure to each toxicant on the development of each behavior will be assessed at three time points over full dose-response curves. Thus, the specific objectives of this research project are to: (1) characterize the normal development of these behaviors in these three strains of mice; (2) evaluate the effects of acute and chronic low- dose exposure to lead and MeHg on these behaviors in each strain at each of three time points; (3) correlate the normal development with maturation of neural circuitry and synaptogenesis and the magnitude of toxicant-induced disruption of neurobehavioral development to morphological, neural circuitry, and neurochemical measures; and (4) evaluate the outcome in the context of this new paradigm in the form of the following question: Did toxicant exposure result in retardation,regression and/or intrusions in the neurobehavioral development of male or female mice of these strains?

Progress Summary:

The initial studies focused on intrusive behaviors, defined as behaviors that are aberrant in form or frequency to such a degree that they overshadow normal development. For autism, often-observed intrusive behaviors include stereotypic and self-injurious behaviors. The underlying mechanism for these behaviors initially was thought to be over activation of brain dopaminergic neurons. In our studies, we observed that, in fact, two systems are involved, dopaminergic and serotonergic over activation. Fu rthermore, pharmacological antagonism of these systems leads to potent and highly efficacious treatment of these debilitating symptoms. This work is now accepted for publication ( Wagner, et al., 2004).

This observation was followed by a full characterization of neurodevelopmental deficits following toxicant exposure, first using sodium valproate and then with MeHg . We used sodium valproate because this compound has been associated with increased risk for autism and has been an accepted animal model of autism. Mice receiving pre- or early post natal exposure to sodium valproate exhibited a range of behavioral deficits that we were able to characterize as retardation, regression, or intrusions ( Wagner, et al., 2006). Specifically, the pre-natal treated mice showed retardation in their acquisition of surface and mid-air righting, negative geotaxis, and water maze performance. More important, there was a significant sex difference (akin to that apparent in autism), with males far more sensitive than females. In addition, in other studies, post natal treatment caused a regression in that mid-air righting, once acquired, was lost following exposure. These observations were apparent long after the exposure and substantially validated our behavior model.

Having established the utility of this model, we next tried MeHg. Using post natal exposure regimens, we again found neurodevelopmental deficits classified as retardation, regression, or intrusions. Alterations in behavior following MeHg were dose-dependent, that is, lower doses of MeHg (2 mg/kg, administered on alternate days from postnatal day [PND] 3-15) produced no deficits in early developing behaviors (mid- air righting, surface righting, negative geotaxis) whereas higher doses (4-8 mg/kg sc) resulted in a 1-5 day delay in the ontogenesis of these behaviors. Grip strength and cliff avoidance were not affected. Furthermore, these animals exhibited intrusive behaviors, being more susceptible to amphetamine-induced self-injurious behavior (at 7.5 mg/kg) at PND 120. Both 2 and 4 mg/kg MeHg resulted in self-injurious behavior, self- biting, and taffy pulling following a dose of amphetamine that had no effect in control-treated animals. This effect was not seen when a higher dose of MeHg (8 mg/kg) was administered on PNDs 13 and 15 only, suggesting that the behavioral consequences of MeHg are both dose- and time- dependent, with a critical period prior to PND 13. As in our Year 1 Annual Report, this induction of self-injurious behavior was accompanied by an enhanced serotonin release and increased hyperthermia. These data reveal that a later challenge may “unmask” behavioral impairments following early MeHg exposure that are not seen under normal conditions. Finally, the effect of MeHg when administered during discrete critical periods extends to spatial learning and habituation of exploratory activity as well. Animals treated on PNDs 3-13, but not PND 24, demonstrate deficits in water maze behavior and hypoactivity and slower habituation rates. Animals treated with MeHg from PNDs 3-13 show a slower acquisition curve; however, they were able to find the hidden platform in the same speed as control-treated mice.


The major effort this year was the validation of the model in the context of current autism research. We developed a battery of neurodevelopmental tests and characterized the appearance of key behaviors over the early life of mice. We further showed that pre- and/or post natal exposure to sodium valproate or MeHg disrupted the normal development of these key behaviors in a manner that could be classified as retardation, regression, or intrusion. Together with Dr. Reuhl, we now are examining similarly treated mice for biological markers of these behavioral deficits.

Future Activities:

Major studies currently underway are designed to examine the effects of early exposure to trimethyl tin, pesticides, or plasticizers. As above, we predict that such exposure will cause neurobehavioral deficits in these key behaviors and will heighten the sensitivity of these mice to later challenges with methamphetamine response as well.

Journal Articles on this Report : 3 Displayed | Download in RIS Format

Other subproject views: All 21 publications 9 publications in selected types All 9 journal articles
Other center views: All 86 publications 50 publications in selected types All 49 journal articles
Type Citation Sub Project Document Sources
Journal Article Halladay AK, Kusnecov A, Michna L, Kita T, Hara C, Wagner GC. Relationship between methamphetamine-induced dopamine release, hyperthermia, self-injurious behaviour and long term dopamine depletion in BALB/c and C57BL/6 mice. Pharmacology & Toxicology 2003;93(1):33-41. R829391 (2004)
R829391 (2005)
R829391 (2006)
R829391C003 (2004)
  • Abstract from PubMed
  • Full-text: Wiley-Full Text HTML
  • Other: Wiley-Full Text PDF
  • Journal Article Wagner GC, Avena N, Kita T, Nakashima T, Fisher H, Halladay AK. Risperidone reduction of amphetamine-induced self-injurious behavior in mice. Neuropharmacology 2004;46(5):700-708. R829391 (2004)
    R829391 (2005)
    R829391 (2006)
    R829391C003 (2004)
  • Abstract from PubMed
  • Abstract: ScienceDirect-Abstract
  • Journal Article Wagner GC, Reuhl KR, Cheh M, McRae P, Halladay AK. A new neurobehavioral model of autism in mice: pre- and postnatal exposure to sodium valproate. Journal of Autism and Developmental Disorders 2006;36(6):779-793. R829391 (2004)
    R829391 (2005)
    R829391 (2006)
    R829391C002 (2006)
    R829391C003 (2004)
  • Abstract from PubMed
  • Abstract: Springer-Abstract
  • Supplemental Keywords:

    children’s health, disease and cumulative effects, ecological risk assessment, environmental chemistry, health risk assessment, risk assessments, susceptibility/sensitive population/genetic susceptibility, toxicology, genetic susceptibility, assessment of exposure, assessment technology, autism, behavioral assessment, behavioral deficits, childhood learning, children, developmental disorders, developmental effects, environmental health hazard, environmental toxicant, exposure assessment, gene-environment interaction, neurodevelopmental, neurological development, neuropathological damage, neurotoxic, neurotoxicity, outreach and education, public health,, RFA, Health, Scientific Discipline, Health Risk Assessment, Biochemistry, Children's Health, developmental neurotoxicity, biological response, motor development, neurodevelopmental toxicity, cognitive development, children's environmental health, environmental health hazard, environmental toxicant, growth & development

    Progress and Final Reports:

    Original Abstract
  • 2002
  • 2003
  • 2005 Progress Report
  • Final

  • Main Center Abstract and Reports:

    R829391    CECEHDPR - University of Medicine and Dentistry of New Jersey Center for Childhood Neurotoxicology and Assessment

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R829391C001 Neurotoxicant Effects on Cell Cycle Regulation of Neurogenesis
    R829391C002 Adhesion and Repulsion Molecules in Developmental Neurotoxic Injury
    R829391C003 Disruption of Ontogenic Development of Cognitive and Sensory Motor Skills
    R829391C004 Exposure Assessment and Intervention Project (EAIP)
    R829391C005 Clinical Sciences Project