DESCRIPTION (provided by applicant): There is increasing evidence that perinatal exposure to relatively low levels of polychlorinated biphenyls (PCBs) may cause cognitive and behavioral problems in children. However, assessment of this risk is complicated by large gaps in our understanding of critical exposure periods and mechanisms of PCB developmental neurotoxicity. Filling these gaps is dependent upon the development and characterization of appropriate model systems. In light of the human data, it is surprising that most experimental studies have employed model systems that analyze the effects of developmental PCB exposure on cognition in adult rather than juvenile animals. Therefore, the first specific aim of this application is to determine the feasibility of using juvenile rats to examine the effect of PCBs on cognitive function. The investigators will use the Morris swim task to test spatial learning and memory in rats beginning on postnatal day 24 (P24). To identify critical exposure periods, cross-fostering studies will be used to generate animals exposed to Aroclor 1254 (10 or 100 ppm in the maternal diet) during gestation only or lactation only. Another group of rats will be exposed continuously throughout gestation and lactation. The second specific aim is to generate pilot data regarding the hypothesis that PCBs impair cognitive function by disrupting dendritic growth. Dendritic morphology is a primary determinant of neuronal connectivity; disruption of dendritic growth or maturation is associated with neural deficits of various etiologies. Developing neurons use specific environmental cues to regulate the growth of dendrites in time and space. Several cues known to regulate dendritic morphogenesis in central neurons - thyroid hormone, cholinergic activity, and estrogen - are also known or suspected targets of PCBs. These observations suggest that PCBs may impair cognition via effects on dendritic growth. To assess the feasibility of this hypothesis, the investigators will determine if PCBs induce changes in dendritic morphology that correlate with cognitive deficits. Dendritic morphology will be analyzed in the brains of animals immediately following the conclusion of behavioral studies. Various morphometric techniques will be used including immunohistochemical localization and western blot analyses of MAP2 and PSD95, and image analysis of dendritic growth in individual neurons labeled with the Golgi-Cox stain. The long-term objectives of these studies are to delineate the cell and molecular mechanisms of PCB developmental neurotoxicity.
|Effective start/end date||3/15/02 → 8/31/04|
- National Institutes of Health: $25,961.00
- National Institutes of Health: $76,670.00
- National Institutes of Health: $51,524.00