Effects of endocrine disruptors on developing brain, with special reference to gene expression.

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To investigate the effects of in utero exposure to bisphenol A(BPA) on developing brain, we have studied fetal mouse brains that were exposed to BPA during embryonic period with molecular biological as well as immunohistochemical methods. BPA was given so to pregnant ICR mice, from the beginning of gestation to embryonic day 12.5, 14.5, 16.5, 18.5, respectively. Fetal telencephalons were processed for global gene analysis with microarrays containing more than 30,000 mouse gene fragments. Pregnant mice that were treated as mentioned above were given 5-bromo-2'-deoxyuridine (BrdU, 12.5mg.kg) ip, at E12.5, 14.5, 16.5, and 18.5. Fetuses were obtained by caesarean section, 1h after BrdU injection or 2-3days after. The brains were fixed and embedded in wax, followed by immunohistochemical staining for BrdU as well as protein disulfide isomerase(PDI) and other cell-differentiation markers. cDNA microarray analyses revealed up-regulation (2-fold difference in BPA-treated mice was regarded as being significant) of approximately 2% of genes, which included developmentally regulated genes such as Numb, and Lnx family. PDI immunoreactivity was discernible in the cortical plate, subplate, intermediate zone of dorsal neocortex and CA of hippocampus, from E12.5 to 16.5. PDI immunoreactivity was prominent in the cortical plate as radial distribution. BrdU-positive cell density in telencephalic wall was increased in all zones of developing cortex, from E12.5 to 14.5, which suggests accelerated stem cell proliferation and premature neuronal migration by BPA. TUJ1-positive projecting fibers showed more prominent fasciculation in BPA-treated mice. Our observation indicates that exposure to BPA at early to mid-embryonic period affects brain development in mice.