INHIBITION OF SYNAPSE FORMATION BY PCB METABOLITES ACCUMULATED IN THE HUMAN BRAIN; A POSSIBLE ENVIRONMENTAL CAUSE OF AUTISM SPECTRUM DISORDER

Background: Deficits of function in autism spectrum disorder are explained by abnormal neural connectivity as a consequence of alternations in synapse formation during development. Thyroid hormones (THs) are essential for functional brain development through TH-dependent gene expressions which are disrupted by polychlorinated biphenyls (PCBs) at pM order concentrations (Miyazaki et al.J.B.C.279:18195,2004). PCBs and their metabolites hydroxy-PCBs (OH-PCBs), which have similar chemical structure to THs, have accumulated in almost all human blood examined, even in their brain by global environmental contamination. 4- OH-PCB 187 is found as the major OH-PCB in human cerebrospinal fluid (Takasuga et al.Org.Halogen Comp.66:2529,2004). These toxic chemicals pass easily through placenta to fetal brain where the blood-brain barrier has not yet developed. We reported two other OH-PCB congeners inhibited TH-dependent dendrite arborization of Purkinje cells in culture (Kimura-Kuroda et al.Dev.Brain Res.154:259,2005). Monkey experiments showed maternal PCBs exposure caused some difficulties in the development of social communications of their offspring (Nakagami et al., 2007). Objectives: Effects of OH-PCB congeners on synapse formation and dendrite extension were investigated using cultured Purkinje cells of fetal mice. Methods: Dissociated cerebellar culture was prepared as previously described (Kimura-Kuroda et al.,Dev.Brain Res.137:55,2002).After OH-PCB treatments, Purkinje cells and synapses were immunostained , observed by confocal laser microscope and quantified using CCD - MetaMorph imaging system. Results: Addition of 4-OH-PCB 187 significantly inhibited synapse formation on Purkinje cells at pM order concentrations. 4-OH-PCB 187 also caused abnormal dendrite extension in the Purkinje cells. Conclusions: These data further support the hypothesis that interaction with genetic backgrounds, PCBs (and probably other neurotoxic chemicals) contaminated in perinatal brain cause abnormal synaptic connections during development, result in heterogeneous symptoms of autism spectrum disorders and/or other comorbid disorders like LD, ADHD, depending on spatio-temporal difference in sensitive synaptogenesis and in chemical exposure doses (Kuroda, Environ. Sci.,10:23,2003).