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2002 Progress Report: Environmental Factors in the Etiology of Autism; Animal Models of Autism
EPA Grant Number: R829388C005Subproject: this is subproject number 005 , established and managed by the Center Director under grant R829388
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: CECEHDPR - University of California at Davis Center for the Study of Environmental Factors in the Etiology of Autism
Center Director: Pessah, Isaac N.
Title: Environmental Factors in the Etiology of Autism; Animal Models of Autism
Investigators: Amaral, David G. , Berman, Robert F. , Capitanio, John , Matsumura, Fumio
Current Investigators: Amaral, David G. , Berman, Robert F.
Institution: University of California - Davis
EPA Project Officer: Saint, Chris
Project Period: September 30, 2001 through September 29, 2002
Project Period Covered by this Report: September 30, 2001 through September 29, 2002
RFA: Centers for Children's Environmental Health and Disease Prevention Research (2001)
Research Category: Children's Health , Health Effects
Description:
Objective:The goals of this project are to establish in vivo exposure models in mice and primates with which to study how relevant xenobiotics of concern to childhood autism influence the development of social behavior. The specific aims of the mouse studies were to: (1) develop a battery of behavioral probes to assess social behavior in developing and mature mice, (2) to evaluate the effects of prenatal and early postnatal exposure to thimerosal, methyl mercury and congeners of PCB on the emergence and quality of social behavior in mice, (3) to determine whether the expected toxicity of exposure to xenobiotics is altered in mice whose immune systems have been activated early in postnatal development by administration of bacterial endotoxin lipopolysaccaride (LPS), and (4) to examine selected brain regions (e.g., amygdala) in xenobiotic treated mice for morphological alterations that may be similar to those observed in neuropathological studies of autism.
The aim of the monkey studies were to use a battery of social testing to evaluate potential alterations of conspecific social behavior following early postnatal exposure of realistic levels of thimerosal, methyl mercury and congeners of PCB.
Progress Summary:For the mouse studies, we have made good progress on the development of the battery of tests to be used to assess social behavior in developing and mature mice. Under Specific Aim 1, we have purchased and built equipment to measure ultrasonic vocalization in infant mice (i.e., postnatal days 3-14), anxiety and fear using the Plus-maze, dyadic social interaction, acoustic startle, and somatic growth. We will put in place the equipment and procedures for measurement of social transfer of food preference, sleep, nesting and whisker trimming, resident intruder interaction and contextual fear conditioning during the next 3-4 months.
Under Specific Aim 2, timed-pregnant mice have been purchased from Jackson Laboratories. The offspring, both male and female, have been exposed to thimerosal by s.c. injection on postnatal days 1, 12, 24 and 36. For these initial studies, a cumulative dosing schedule was used (i.e., animals received a thimerosal injection on each of these postnatal days). Animals were tested for general growth and development, as well as for the emergence of social behaviors. Half of the animals at each time point were sacrificed and their brains are being analyzed stereologically for possible morphological changes in the amygdala (Specific Aim 4). We have also developed analytical procedures for determining mercury levels in mouse tissue (e.g., brain, liver, blood, kidney, muscle) after injection with thimerosal, using inductively coupled plasma mass spectrometry (ICP-MS). Current sensitivity is 2 ppb, and tissue samples are being analyzed to establish tissue mercury levels in exposed mice.
For the primate studies, a very intensive analysis of the development of normal nonhuman primate social behavior has been carried out. Animals with early neonatal lesions of the amygdala and of the hippocampus have also been studied using a comprehensive battery of tasks to probe socioemotional development. These studies have provided the behavioral benchmarks with which to evaluate the effects of xenobiotics. It is important to point out, that these studies have employed a novel behavioral design in which infants are raised with their natural mother (all previous studies have used nursery reared animals) and all animals receive daily 3 hour periods of social interaction with conspecifics. These strategies of normal upbringing are designed so that rearing conditions themselves do not alter the animals social behavior and produce a confound on the effects of lesions or xenobiotic exposure. These studies have now set the stage for exposure studies that will take place in year 02 of the program.
Future Activities:Mouse Project (1) establishment of the remaining battery of behavioral tests, including resident-intruder aggression, social learning, social transfer of food preference, nest building and sleep behavior. (2) tissue levels of mercury following thimerosal exposure will be firmly established. (3) histopathological effects of thimerosal exposure will be determined for brain (e.g., amygdala, hippocampus) and other organ systems. Monkey Project (1) Postnatal exposure of 9 rhesus monkeys to environmental levels of thimerosal and comparison with 9 age matched controls on a variety of socioemotional tasks. (2) tissue levels of mercury following thimerosal exposure will be firmly established (3) histopathological effects of thimerosal exposure will be determined for brain (e.g., amygdala, hippocampus) and other organ systems.
Journal Articles:No journal articles submitted with this report: View all 3 publications for this subproject
Supplemental Keywords:Autism, thimerosal, amygdala, hippocampus, neurodevelopmental toxicity, animal models,
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ENVIRONMENTAL MANAGEMENT, Scientific Discipline, Health, RFA, PHYSICAL ASPECTS, Susceptibility/Sensitive Population/Genetic Susceptibility, Toxicology, Risk Assessment, Biology, Risk Assessments, Disease & Cumulative Effects, genetic susceptability, Health Risk Assessment, Physical Processes, Chemistry, Children's Health, biomarkers, exposure assessment, xenobiotics, neurological development, autism, synergistic interactions, mechanisms, human health risk, susceptibility, halogenated aromatics, etiology, gene-environment interaction, neurotoxic, biological markers, children, neurobehavioral, pesticides, chemical exposure, exposure, biomarker, neurobehavioral effects, neurodevelopmental, neurotoxicity
Progress and Final Reports:
Original Abstract
2003 Progress Report
2005 Progress Report
Main Center Abstract and Reports:
R829388 CECEHDPR - University of California at Davis Center for the Study of Environmental Factors in the Etiology of Autism
Subprojects under this Center:
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R829388C001 Environmental Factors in the Etiology of Autism; Analytic Biomakers (xenobiotic) Core
R829388C002 Environmental Factors in the Etiology of Autism; Cell Activation/Signaling Core
R829388C003 Environmental Factors in the Etiology of Autism; Molecular Biomakers Core
R829388C004 Environmental Factors in the Etiology of Autism; Childhood Autism Risks from Genetics and the Environment (The CHARGE Study)
R829388C005 Environmental Factors in the Etiology of Autism; Animal Models of Autism
R829388C006 Environmental Factors in the Etiology of Autism; Molecular and Cellular Mechanisms of Autism