Use of in vitro models to elucidate mechanisms of developmental neurotoxicity.

摘要

Exposure to polychlorinated biphenyls is associated with decreased cognitive function in humans and experimental animals; however, the mechanism(s) by which this occurs are unknown. In this work, PCBs were investigated for their ability to induce apoptosis in two primary neuronal cell types from regions of the brain that are critical to learning and memory, the cortex and the hippocampus. Cortical and hippocampal neurons were exposed to varying concentrations of Aroclor 1254, a commercial mixture of PCBs and to individual congeners. We observed that noneoplanar PCBs induce apoptosis in hippocampal neurons through disruption of the RyR. This work is important because it is the first to identify a possible link between altered Ca2+ homeostasis and an actual functional outcome for the cell, apoptosis. This alteration in regional patterns of apoptosis could be an important mechanism underlying the developmental neurotoxicity of PCBs.; There is increasing evidence that cognitive and behavioral problems may also be linked to perinatal exposure to organophosphorus containing pesticides (OPs) such as chlorpyrifos (CPF). Determining the mechanism(s) by which CPF induces changes in neuronal function is difficult because there is limited information regarding the stage(s) of neuronal development that are targeted by this pesticide. We found that both CPF and CPFO inhibit axon outgrowth in primary peripheral neurons at concentrations that do not inhibit the catalytic activity of acetylcholinesterase (AChE). ACNE is a known target of CPF and is also believed to play a role in axon outgrowth. To determine if ACNE is the target in CPF induced inhibition of axon outgrowth, we examined the effects of CPF/CPFO in cultured dorsal root ganglia (DRG) neurons in which ACNE expression was genetically altered. Interestingly, CPF inhibits axon outgrowth in DRG from AChE +/+ mice, but not from AChE −/− mice. These data strongly suggest that the target molecule is AChE. We confirmed this conclusion by demonstrating that AChE −/− DRG transfected with AChE responded as wild type neurons with decreased axon outgrowth in the presence of 1 nM CPFO. Taken together, these data suggest that AChE is in fact a critical target in the developmental neurotoxicity of CPF/CPFO and that the morphogenic activity of AChE is inhibited by CPF. (Abstract shortened by UMI.)