Progress 01/01/06 to 07/31/07
Outputs
OUTPUTS: In Specific Aim 1 a comprehensive battery of neurobehavioral tests, including measures of social behaviors, memory and learning, sensory and motor development, sensory gating and anxiety was used to assess in C57BL/6J mice neurodevelopmental toxicity of BDE47, PCB 95 and MeHg. Behavioral testing of the first cohort of 70 mice exposure to BDE 47 is completed and immune system function is also being analyzed in subsets of mice in the first cohort, and brains of mice used for behavioral studies were perfused and prepared for histological analysis. Specific Aim 2 examines the effects of perinatal exposure of mice to MeHg, PCB 95 or BDE47 on immune system function. B-cell proliferation was studied in splenocytes from the offspring of BDE 47 exposed mice (0.03 or 0.10 mg/kg/day versus untreated controls and vehicle controls) using lipopolysaccharide (LPS) and phytohaemagglutinin (PHA). Specific Aim 3 is to determine if exposure to environmental toxicants early in development contributes to the etiology of neurodevelopmental disorders associated with human autism and animal models of autism. Specific Aim 4 examines the effects of prenatal exposure of pregnant mice to immunoglobulin G (IgG) isolated from biological mothers of autistic children on brain development and behavior. The research aims/projects were integrated within a center framework that provided extensive facility core capabilities in xenobiotic/lipid analysis (Core I), cell activation biomarkers (Core II), and molecular biomarkers (Core III). PARTICIPANTS: Nothing significant to report during this reporting period. TARGET AUDIENCES: Researches and Public Health Professionals working on autism. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.
Impacts
Initial studies used perinatal exposure of C57BL/6 mice to BDE-47 at concentrations of 0.03, 0.10 and 1.0 mg/kg/day in Project 1. Litters were divided into subgroups, with male and female mice in each subgroup used for neurobehavioral studies, assessment of immune system function, or neurohistology, respectively. Behavioral and neurophysiological experiments with perinatal and lactational exposure to PCB-95 and PCB170 in the Sprague Dawley rat have shown an enhanced seizure susceptibility and excitotoxicity that is synergized by depression of GABAergic neurotransmission. In Project 2, the pattern of preliminary data suggests that perinatal to low levels of BDE-47 (i.e., 0.03 and 0.1 mg/kg/day) may have enhanced mitogen-stimulated proliferation of both T-cell and B-cell/macrophage monocytes. In collaboration with Core 3, we have also determined tissue levels of BDE 47 by GC-MS. Brain, blood, liver, muscle and adipose tissue levels of BDE 47 have been measured following perinatal. Results thus far demonstrate that at an exposure level of 1 mg/kg/day there is a marked accumulations of BDE 47 in all tissues examined, including the brain and blood. Furthermore, offspring of dams given BDE 47 through gestation and preweaning show tissue levels that are similar to those found in the dams, demonstrating transfer of BDE-47 to the mouse fetus (Project 3). We have carried out two initial IgG studies in C57BL/6 mice. These studies used 1 or 2 injections of IgG-A or IgG-C given on gestational days 12 and 16. Two injections were found to result in a high mortality rate in the offspring of both groups, while a single injection appears did not appear to increase mortality. This suggests that an immune complex reaction to the second injection of purified human IgG may have occurred. As a result we repeated these experiments using a single IgG-A or IgG-C injection on gestational day 12, and will carry out behavioral, histological and immunological studies as proposed. Blood samples from the initial IgG-injected dams and offspring have been collected and will be analyzed for the presence of mouse antibodies directed towards human IgG to determine if an immune reaction occurred in either the dams or pups. These studies are significant because they (1) examine the potential for environmental toxins to contribute to the risk for neurodevelopmental disorders, such as autism (2) explore the interactions between exposure to environmental toxins and immune system dysfunction, and (3) they are focused on the effects of chronic low-dose exposure. If early exposure to environmental agents can be shown to be a risk factor for neurodevelopmental disorders, then regulatory controls can be put in place to reduce the risk. In addition, such findings could help explain the apparent dramatic increase in the incidence of neurodevelopmental disorders that is occurring world wide.
Publications
- Berman, R.F., Lawler, C., Harry, G.J. Effects of neonatal thimerosal exposure on SJL mice on measures of sensory gating, anxiety and sociability. Birth Defects Research, 75(5), 360, 2006. (abstract and presentation at the 2006 Teratology Society Meeting, Tucson, Arizona).
- Harry, G.L., Mouton, P., Golub, M., Lawler, C., Berman, R.F. Hippocampal morphology - effects of litter and neonatal thimerosal exposure in SJl/J mice. Birth Defects Research, 76(5), 361, 2006. (abstract and presentation at the 2006 Teratology Society Meeting, Tucson, Arizona).
- Berman, R.F., Pessah, I.N., Mouton, P., Mav, D. & Harry, J. Examination of thimerosal effects on neonatal SJL/J mice at vaccination-associated exposure levels. Scheduled presentation at the 11th International Neurotoxicology Association Meeting, Pacific Grove, CA, June 10-15, 2007.
- Kenet, T., Froemcke, R., Schreiner, C., Pessah, I. N. and Merzenich, M.M. (2007) Abnormal auditory cortex development in PCB exposed rats. Proc. Natl. Acad. Sci. USA (In Press).
- Jaubert, P.J., Golub, M.S., Lo, Y.Y., German, S.L., Dehoff, M.H., Worley, P.F., Kang, S.H., Schwartz, M.K., Seeburg, P.H. & Berman, R.F. Complex, multimodal behavioral profile of the Homer1 knockout mouse. Genes, Brain & Behavior, (6):141-154, 2007.
- Berman, R.F., Pessah, I.N., Mouton, P., Mav, D. & Harry, J. Low-level thimerosal exposure: Further evaluation of altered neurotoxic potential in SJL mice. Submitted for publication, 2007.
- Burke, K., Cheng, Y., Li, B., Petrov, A., Joshi, P. Berman, R.F., Reuhl, K.R. & Dicicco-Bloom, E. Methylmercury elicits rapid inhibition of cell proliferation in the developing brain and decreases cell cycle regulator, cyclin E. Neurotoxicology, (6): 970-81, 2006.
- Goth, S. R., Chu, R., Gregg, P. J., Cherednichenko, G., and Pessah, I. N. (2006). Uncoupling of ATP-mediated calcium signaling and dysregulation of IL-6 secretion in dendritic cells by nanomolar thimerosal. Env. Health Perspect. 114, 1083-109.
- Goth, S. R., Chu, R. A., and Pessah, I. N. Oxygen tension regulates the in vitro maturation of GM-CSF expanded murine bone marrow dendritic cells by modulating class II MHC expression J. Immunol. Meth. 308, 179-191. 2006.
- Pessah, I. N., Hansen, L. G., Albertson, T. E., Garner, C. E., Ta, T. A., Do, Z., and Wong P. W. (2006). Structure-Activity relationship for noncoplanar polychlorinated biphenyl congeners toward the ryanodine receptor-Ca2+ channel complex type 1 (RyR1). Chem. Res. Toxicol. 19, 92-101.
- Ta, T. A., and Pessah, I. N. (2007). Ryanodine receptor type 1 (RyR1) possessing malignant hyperthermia mutation R615C exhibits heightened sensitivity to dysregulation by non-coplanar 2,2',3,5',6-pentachlorobiphenyl (PCB 95). NeuroToxicology (in press).
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