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Exposure to environmental chemicals with estrogenic activity during the early stage of pregnancy can seriously affect embryonic development and the maintenance of pregnancy. To estimate the metabolism and pharmacodynamics of a xenoestrogen, bisphenol A, in a reproductive organ, the metabolite of bisphenol A was analyzed after incubating a rat uterine sac in buffer solutions containing the chemical. When the inner or the outer side of the uterine sac was exposed to bisphenol A, the concentration of the parent chemical was decreased in buffer solution and then, only one metabolite, bisphenol A-glucuronide, was observed only in the outer, that is, the maternal, side. A small amount of the parent chemical could pass through the uterine sac without being modified. Uridine diphosphate (UDP)-glucuronosyltransferase (UGT) was shown by immunohistochemical staining analysis to be distributed in epithelial cells of the endometrium, oviduct, and uterine glands. Based on measurements of enzyme activity and on Western blot analysis, UGT activity toward bisphenol A and UGT protein were identified in the microsomal fractions prepared from rat uterus. UGT isoforms, such as UGT1A1, 1A2, 1A5, 1A6, and 1A7, were expressed, and MRP-1 (multidrug resistance-associated protein) and MRP-3, which are well-known to be transporters of various drug-glucuronides, were detected in the rat uterus by reverse transcription-PCR. These results elucidate the rat uterine barrier system by showing that most bisphenol A perfused into the uterus was glucuronidated in the epithelium, resulting in transport of glucuronides to the maternal side. [ABSTRACT FROM AUTHOR]

Background: Cytogenomic mutations and chromosomal abnormality are implicated in the neuropathology of several brain diseases. Cell heterogeneity of brain tissues makes their detection and validation difficult, however. In the present study, we analyzed gene dosage alterations in brain DNA of schizophrenia patients and compared those with the copy number variations (CNVs) identified in schizophrenia patients as well as with those in Asian lymphocyte DNA and attempted to obtain hints at the pathological contribution of cytogenomic instability to schizophrenia. Results: Brain DNA was extracted from postmortem striatum of schizophrenia patients and control subjects (n = 48 each) and subjected to the direct two color microarray analysis that limits technical data variations. Disease-associated biases of relative DNA doses were statistically analyzed with Bonferroni's compensation on the premise of brain cell mosaicism. We found that the relative gene dosage of 85 regions significantly varied among a million of probe sites. In the candidate CNV regions, 26 regions had no overlaps with the common CNVs found in Asian populations and included the genes (i.e., ANTXRL, CHST9, DNM3, NDST3, SDK1, STRC, SKY) that are associated with schizophrenia and/or other psychiatric diseases. The majority of these candidate CNVs exhibited high statistical probabilities but their signal differences in gene dosage were less than 1.5-fold. For test evaluation, we rather selected the 10 candidate CNV regions that exhibited higher aberration scores or larger global effects and were thus confirmable by PCR. Quantitative PCR verified the loss of gene dosage at two loci (1p36.21 and 1p13.3) and confirmed the global variation of the copy number distributions at two loci (11p15.4 and 13q21.1), both indicating the utility of the present strategy. These test loci, however, exhibited the same somatic CNV patterns in the other brain region. Conclusions: The present study lists the candidate regions potentially representing cytogenomic CNVs in the brain of schizophrenia patients, although the significant but modest alterations in their brain genome doses largely remain to be characterized further. [ABSTRACT FROM AUTHOR]