PCBによる脳機能発達の修飾作用

抄録

Polychlorinated biphenyl (PCB) is an environmental chemical that may cause adverse health effects. Previous studies have shown that developing central nervous system is one of the most vulnerable organs against its exposure. However, the molecular mechanisms of PCB action have not yet been fully understood. Since PCB exposure induces abnormal brain development similar to those seen in perinatal hypothyroid animal, we have been studied the effect of PCB/dioxin on thyroid hormone (TH) receptor (TR)-mediated transcription. We have previously identified that PCB may not competitively bind to TR ligand binding domain. Instead, it partially dissociated TR from TH-response element located on the promoter region of target gene. The mechanisms of such dissociation in not well known. However, our recent findings have indicated that PCB may bind to DNA binding domain of TR, which may alter the structural conformation of TR protein.In addition to PCB action on TR, we have also studies the effects of PCB on several other nuclear receptors. It may affect to estrogen receptor (ER)-, and steroid and xenobiotic receptor (SXR)-mediated transcription, but not to glucocorticoid or progesterone receptor action. Further, PCB may also act to neuronal membrane to induce an increase in intracellular calcium concentration, which then stimulate the expression of calcium-induced transcription factors such as c-Jun.These results indicate that PCB may act at multiple systems to alter the gene expression profile of neuronal cells that may affect the normal brain development. [J Physiol Sci. 2006;56 Suppl:S22]