By using a yeast detection system for androgenic and antiandrogenic effects of chemicals, we identified bisphenol A (BPA) and nonylphenol (NP) as antiandrogens. In this study, we report molecular mechanisms for the antiandrogenic action of BPA and NP. In the ARhLBD-activating signal cointegrator 1 (ASC1) yeast two-hybrid system, which reflects the androgen-dependent interaction between androgen receptor (AR) and its coactivator, ASC1, BPA and NP acted as potent AR antagonists comparable to a known strong antagonist, cyproterone acetate. Ligand competition assays revealed that [3H]5alpha-dihydroxytestosterone (DHT) binding to AR is inhibited a maximum of 30 and 40% at approximately 5 nM of NP and 50 nM of BPA, respectively. In addition, the nuclear translocation of green fluorescent protein (GFP)-AR fusion protein in the presence of testosterone was affected by the addition of BPA and NP, which cause rather dispersed distribution of GFP-AR between the nuclear and the cytoplasmic compartments. Furthermore, in transient transfection assays, BPA and NP inhibited androgen-induced AR transcriptional activity. Taken together, the results suggest that BPA and NP affect multiple steps of the activation and function of AR, thereby inhibiting the binding of native androgens to AR, AR nuclear localization, AR interaction with its coregulator, and its subsequent transactivation. These data may help us better understand the biological alterations induced by these environmental compounds.

Purpose To examine relationships following adjuvant chemotherapy between circulating proinflammatory cytokines, regional cerebral metabolism, and cognitive complaints in early stage breast cancer patients. Patients and Methods 33 breast cancer patients who had completed initial treatment (surgery, ± radiation, 23 chemotherapy, 10 no chemotherapy) obtained resting (18)F-FDG PET/CT brain imaging at baseline and one year later. Pro-inflammatory cytokine markers (IL-1ra, sTNF-RII, CRP, and IL-6) and cognitive complaints were also assessed at both time points. Results At baseline, consistent correlations were seen between the left medial frontal and right inferior lateral anterior temporal cortices and inflammatory markers within the chemotherapy group, and not in the group who did not receive chemotherapy. After one year, correlations persisted in the medial frontal cortex and the temporal cortex, the latter shifting superiorly. Both of these regional correlations demonstrated the highest levels of significance when looking across the one year time frame (IL-1ra: peak voxel p<0.0005; cluster size p<0.0005, p=0.001 after correction (medial prefrontal), p<0.0005; cluster size p=0.001, p=0.029 corr. (anterior temporal), sTNF-RII: p<0.0005; cluster size p=0.001, p=0.040 corr. (medial prefrontal)). Positive correlations were also seen within the chemotherapy group between baseline memory complaints and the medial frontal (p<0.0005; cluster size p<0.0005, p<0.0005 corr.) and anterior temporal (p<0.0005; cluster size p<0.0005, p=0.002 corr.) cortices at baseline and one year later. Conclusion Metabolism in the medial prefrontal cortex and anterior temporal cortex was found to correlate with both memory complaints and cytokine marker levels in chemotherapy patients.

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Background: High insulin in T2D is associated with low testosterone, but the role of insulin has not been fully studied in testis. Results: Insulin directly inhibits testicular steroidogenesis via induction of DAX-1 in Leydig cells. Conclusion: Insulin induces DAX-1 in Leydig cells, and DAX-1 inhibits LRH-1-mediated testicular steroidogenesis. Significance: Elevated insulin level in insulin-resistant states such as T2D suppresses the synthesis of testicular steroidogenesis.

Arginine vasotocin (VT) is the ortholog in all nonmammalian vertebrates of arginine vasopressin (AVP) in mammals.We have previously cloned an amphibian V1a-type vasotocin receptor (VT1R) that exhibited higher sensitivity for VT than AVP, while the mammalian V1a type receptor (V1aR) responded better to AVP than VT. In the present study, we identified the amino acid residues that confer differential ligand selectivity for AVP and VT between rat V1aR and bullfrog VT1R (bfVT1R). A chimeric rat V1aR having transmembrane domain (TMD) VI to the carboxyl-terminal tail (C-tail) of bfVT1R showed a reverse ligand preference for AVP and VT, whereas a chimeric VT1R with TMD VI to the C-tail of rat V1aR showed a great increase in sensitivity for AVP.