Chlorinated polycyclic aromatic hydrocarbons (ClPAHs) with 3-5 rings are ubiquitous environmental contaminants. However, toxicities of ClPAHs remain unclear. In this study, aryl hydrocarbon receptor (AhR)-mediated activities of ClPAHs were investigated by using a yeast assay system. All environmentally relevant 18 ClPAHs showed the AhR activities in the test; the activities were elevated with the number of chlorine atoms on the lower molecular weight PAH ( approximately three-ring and fluoranthene derivatives) but not for higher molecular weight ClPAHs (>four-ring). The similar trends were also observed in certain ClPAHs-induced cytochrome P450 1A1 expression in MCF-7 cells. The structure-activity relationship between the AhR activity and the corresponding solvent accessible surface area of ClPAHs revealed a parabolic relationship, with approximately 350 A (2)/molecule as the optimal dimensions as the ligand for binding to AhR. These findings indicate that the spatial dimensions of ClPAHs apparently influence their ability to activate the AhR. Finally, we discussed the toxicity of exposure to ClPAHs based on the AhR activities, estimated that it would be approximately 30-50 times higher than that of dioxins.

No abstract

Despite our ever-changing environment, animals are remarkably adept at selecting courses of action that are predictive of optimal outcomes. While requiring the contribution of a number of brain regions, a vast body of evidence implicates striatal mechanisms of associative learning and action selection to be critical to this ability. While numerous models of striatal-based decision-making have been developed, it is only recently that we have begun to understand the precise contributions of specific subpopulations of striatal neurons. Studies utilizing contemporary cell-type-specific technologies indicate that striatal output pathways play distinct roles in controlling goal-directed and social behaviors. Here we review current models of striatal-based decision-making, discuss recent developments in defining the functional roles of striatal output pathways, and assess how striatal dysfunction may contribute to the etiology of various neuropathologies.

Abstract.To evaluate the effects of bisphenol A (BPA), a candidate endocrine disruptor (ED), on embryonic development, we examined the mRNA expression levels of the arylhydrocarbon receptor (AhR), which binds with many EDs and plays crucial roles in xenobiotic metabolism, and of the retinoic acid receptor (RAR) α and retinoid X receptor (RXR) α, key factors in nuclear receptordependent retinoid signal transduction, in murine embryos exposed in utero to BPA (0.02, 2, 200, and 20,000 µg/kg/day) at 6.5-13.5 or 6.5-17.5 days post coitum (dpc), using the real-time reverse transcription-polymerase chain reaction (RT-PCR) method. Extremely low-dose BPA (0.02 µg/kg/ day; 1/100 the dose of environmental exposure) remarkably increased AhR mRNA expression in the cerebra, cerebella, and gonads (testes and ovaries) of male and female 14.5-and 18.5-dpc-embryos. In utero exposure to BPA at 2, 200, and 20,000 µg/kg/day also increased levels of AhR mRNA. In gonads of 14.5-dpc-embryos, AhR mRNA levels were elevated and showed diphasic (U) dose-response curves following exposure to BPA, but inverted U dose-response curves were obtained for 18.5-dpcembryos. Exposure to BPA increased expression levels of RARα and RXRα mRNAs in the cerebra, cerebella, and gonads of male and female 14.5-and 18.5-dpc-embryos. Extremely low-dose BPA (0.02 µg/kg/day) increased RARα mRNA expression in the cerebella of male and female 14.5-and 18.5-dpc-embryos and in the gonads of female 14.5-dpc-embryos, and significantly increased RXRα mRNA expression in the cerebra and cerebella of male and female 14.5-dpc-embryos. The present findings confirm that in utero exposure to an extremely low dose of BPA up-regulates the mRNA expression of AhR, RARα, and RXRα in murine embryos and disrupts the receptor-dependent signal transducing systems, and will contribute to the assessment of the toxic effects of BPA on xenobiotic metabolism and retinoid signals in embryogenesis. Key words: Arylhydrocarbon receptor (AhR), Bisphenol A, Murine embryo, Retinoic acid receptor (RAR) α, Retinoid X receptor (RXR) α (J. Reprod. Dev. 51: [315][316][317][318][319][320][321][322][323][324] 2005) isphenol A [BPA; 2,2-bis (4-hydroxyphenyl) p r o p a n e ] , a c o m m o n p l a s t i c i z e r a n d a candidate environmental endocrine disruptor (ED), has toxicological effects on the reproductive, immunological, and nervous systems of mammals [1][2][3][4]. BPA binds to estrogen receptor-α (ERα; NR3A1) and -β (ERβ; NR3A2), and induces

No abstract

No abstract

In acute lymphoblastic leukemia (ALL) patients, the bone marrow niche is widely known to be an important element of treatment response and relapse. Furthermore, a characteristic liver pathology observed in ALL patients implies that the hepatic microenvironment provides an extramedullary niche for leukemic cells. However, it remains unclear whether the liver actually provides a specific niche. The mechanism underlying this pathology is also poorly understood. Here, to answer these questions, we reconstituted the histopathology of leukemic liver by using patients-derived primary ALL cells into NOD/SCID/Yc null mice. The liver pathology in this model was similar to that observed in the patients. By using this model, we clearly demonstrated that bile duct epithelial cells form a hepatic niche that supports infiltration and proliferation of ALL cells in the liver. Furthermore, we showed that functions of the niche are maintained by the SDF-1/CXCR4 axis, proposing a novel therapeutic approach targeting the extramedullary niche by inhibition of the SDF-1/CXCR4 axis. In conclusion, we demonstrated that the liver dissemination of leukemia is not due to nonselective infiltration, but rather systematic invasion and proliferation of leukemic cells in hepatic niche. Although the contribution of SDF-1/CXCR4 axis is reported in some cancer cells or leukemic niches such as bone marrow, we demonstrated that this axis works even in the extramedullary niche of leukemic cells. Our findings form the basis for therapeutic approaches that target the extramedullary niche by inhibiting the SDF-1/CXCR4 axis.

Bisphenol A (BPA), a candidate endocrine disruptor (ED), is considered to bind to estrogen receptors and to regulate expressions of estrogen responsive genes. It has also shown evidence of affecting the reproductive, immunological and nervous systems of mammalian embryos. However, the effects of BPA on placentae, a central organ of feto-maternal interlocution, are still unclear. To reveal the mechanisms of BPA effects on placentae in mammals, we compared the mRNA expression of 20 nuclear receptors between placentae of vehicle controls and those of orally BPA exposed pregnant mice by a DNA microarray technique. In murine placentae, mRNAs of 11 nuclear receptors were not detected. However, greater than 1.5 fold changes in mRNA expression of nine nuclear receptors between vehicle control and BPA treated mice were noted. Moreover, remarkable changes in mRNA expression of six non-nuclear receptor proteins were induced by BPA exposure. There were various differences in the effects of BPA on the expression of these mRNAs between the placentae with male embryos and those with female embryos. Such embryo-sex dependent differences are interesting and important pointers to understanding of the endocrine disrupting effect of BPA. The present data indicate that BPA affects the expression of nuclear receptor mRNAs in placentae and may disrupt the physiological functions of placentae.