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N-Acetylgalactosamine 4-sulfate 6-O-sulfotransferase (GalNAc4S-6ST) is the sulfotransferase responsible for biosynthesis of highly sulfated chondroitin sulfate CS-E. Although involvements of CS-E in neuronal cell functions have been extensively analyzed, the role of GalNAc4S-6ST in astrocytic tumor progression remains unknown. Here, we reveal that GalNAc4S-6ST transcripts were detected in astrocytic tumors derived from all 30 patients examined using quantitative reverse transcription-PCR analysis. Patients with high GalNAc4S-6ST mRNA expression had significantly worse outcome compared with patients with low expression, and multivariate survival analysis disclosed that GalNAc4S-6ST is an independent poor prognostic factor for astrocytic tumors. We then tested whether CS-E enhanced haptotaxic migration of glioblastoma U251- MG cells that endogenously express both the CS-E's scaffold tyrosine phosphatase ζ (PTPζ) and GalNAc4S-6ST, in the presence of CS-E's preferred ligands, pleiotrophin (PTN) or midkine (MK), using a modified Boyden chamber method. Haptotaxic stimulation of cell migration by PTN was most robust on control siRNA-transfected U251-MG cells, while that enhancing effect was cancelled following transduction of GalNAc4S-6ST siRNA. Similar results were obtained using MK, suggesting that both PTN and MK enhance migration of U251-MG cells by binding to CS-E. We also found that PTPζ as well as PTN and MK were frequently expressed in astrocytic tumor cells. Thus, our findings indicate that GalNAc4S-6ST mRNA expressed by astrocytic tumor cells is associated with poor patient prognosis likely by enhancing CS-E-mediated tumor cell motility in the presence of PTN and/or MK. [ABSTRACT FROM AUTHOR]

Background: Nanoparticle-rich diesel exhaust (NR-DE) has potentially adverse effects on testicular steroidogenesis. However, it is unclear whether NR-DE influences steroidogenic systems in the brain. Objective: To investigate the effect of NR-DE on hippocampal steroidogenesis of adult male rats in comparison with its effect on the testis. Methods: F344 male rats (8-week-old) were randomly divided into four groups ( n = 8 or 9 per group) and exposed to clean air with 4.6 ± 3.2 μg/m3 in mass concentration, NR-DE with 38 ± 3 μg/m3 (a level nearly equivalent to the environmental standard in Japan (low NR-DE)), NR-DE with 149 ± 8 μg/m3 (high NR-DE), or filtered diesel exhaust with 3.1 ± 1.9 μg/m3 (F-DE), for 5 hours/day, 5 days/week, for 1, 2 or 3 months. F-DE was prepared by removing only particulate matters from high NR-DE with an HEPA filter. Results: Exposures to the high NR-DE for 1 month, and low NR-DE for 2 months, significantly increased or tended to increase plasma and testicular testosterone levels compared to clean air exposure, which might have resulted from the increased expression of mRNA of steroidogenic acute regulatory protein and its protein in the testes of rats. In the hippocampus, high NR-DE exposure for 1 month significantly increased the androstendione level compared to the clean air exposure, while no significant difference was observed in the steroidogenesis between fresh air exposure and any exposure to NR-DE or F-DE. Conclusion: NR-DE may influence steroidogenic enzymes in the testis, but not those in the hippocampus. [ABSTRACT FROM AUTHOR]

Abstract: We previously reported that exposure to low (22.5±0.2nm in diameter, 15.4±1.0μg/m3 in mass weight, 2.27×105/cm3 in mean number concentration), and medium (26.1±0.5nm, 36.4±1.2μg/m3, 5.11×105/cm3) concentrations of nanoparticle-rich diesel exhaust (NR-DE) for 1 and 2 months (5h/day, 5 days/week) significantly increased plasma testosterone in male Fischer 344 rats, whereas exposure to a high concentration (27.1±0.5nm, 168.8±2.7μg/m3, 1.36×106/cm3) did not. The present study attempts to clarify the mechanism of this elevation. Low and medium exposures to NR-DE for 1 and 2 months significantly increased steroidogenic acute regulatory protein (StAR)- and cytochrome P450 side-chain cleavage (P450scc)-mRNA and their protein expressions in the testis of rats, in which the elevation pattern was very similar to that of plasma testosterone levels. Interestingly, both exposure levels for 1 month significantly increased growth hormone (GH) receptor expression in the testis, and low exposure also increased testicular insulin-like growth factor I-mRNA levels and hepatic microsomal cytochrome P450 2C11-mRNA and their protein levels in rats. These two factors are thought to be related to growth hormone secretion. Disruption of testosterone biosynthesis by NR-DE exposure may be a mode of action for reproductive toxicity, which may, in part, be regulated by increasing StAR and P450scc expressions via GH signalling. [Copyright &y& Elsevier]

Abstract: Perfluorooctanoic acid (PFOA) is a ligand for peroxisome proliferator-activated receptor (PPAR) α, which exhibits marked species differences in expression and function, especially between rodents and humans. We investigated the functional difference in PFOA response between mice and humans, using a humanized PPARα transgenic mouse line. Three genotyped mice, 129/Sv wild-type (mPPARα), Pparα-null mice and humanized PPARα (hPPARα) mice (8-week-old males) were divided into three groups: the first was treated with water daily for 2 weeks by gavage (control group), and the remaining two groups were treated with 0.1 and 0.3mg/kg ammonium perflurooctanate (APFO), respectively, for 2 weeks by gavage. The APFO dosages used did not influence the plasma triglyceride or total cholesterol levels in any mouse line, but the high dose increased both hepatic lipid levels only in mPPARα mice. APFO increased mRNA and/or protein levels of PPARα target genes cytochrome P450 Cyp4a10, peroxisomal thiolase and bifunctional protein only in the liver of mPPARα mice, but not in Pparα-null or hPPARα mice. This chemical also increased expression of mitochondrial very long chain acyl-CoA dehydrogenase only in the liver of mPPARα mice. Taken together, human PPARα may be less responsive to PFOA than that of mice when a relatively low dose is applied. This information may be very valuable in considering whether PFOA influences the lipid metabolism in humans. [Copyright &y& Elsevier]

Abstract: Aryl hydrocarbon receptor (AhR) plays important roles in the regulation and induction of xenobiotic-metabolizing enzymes including the cytochromes P450 1 family (CYP1) and UDP-glucuronosyltransferases 1A (UGT1As) by polycyclic aromatic hydrocarbons as well as chlorinated aromatic hydrocarbons. To determine whether pyrene-induced xenobiotic-metabolizing enzymes are regulated by AhR, male AhR (+/+) and (−/−) mice were used. Both genotyped mice were exposed to 0, 205, 300 or 410mg/(kgday pyrene), once daily, for four consecutive days by gavage. Exposure to pyrene did not influence hepatic CYP1A1-mRNA in mice of both genotypes, whereas it induced hepatic CYP1A2 protein and mRNA expression and associated 7-ethoxyresorufin O-deethylase and pyrene 1-hydroxylation activities in both AhR (+/+) and (−/−) mice. Similar effects were also found with sulfotransferase 1A1 expression and the associated 1-hydroxypyrene sulfation activity. In contrast, pyrene exposure increased expression of the UGT1A1 and 1A6, and glucuronidation activities associated with 1-hydroxypyrene and 1-naphthol in the liver only in AhR (−/−) mice, although pyrene treatment dose-dependently decreased the latter activity. Pyrene exposure did not increase AhR-mRNA expression in AhR (+/+) mice. In contrast, pyrene-induced expression of the hepatic constitutive androstane receptor (CAR) and one of its target genes, CYP2B10, in both AhR (+/+) and (−/−) mice. These results strongly suggest that pyrene-induced CYP1A2 and SULT1A1 are regulated by CAR, not by AhR. However, the mechanisms of UGT1A1 and 1A6 induction by pyrene were not elucidated in this study. [Copyright &y& Elsevier]

To clarify species differences in the induction of peroxisome proliferator-activated receptor alpha (PPARα)-related enzymes by di(2-ethylhexyl)phthalate (DEHP) exposure, we investigated the inductions of PPARα and its target genes (mitochondrial medium-chain acyl-CoA dehydrogenase (MCAD) and peroxisomal keto-acyl-CoA thiolase (PT) in liver from mice (CD-1), rats (Sprague–Dawley), and marmosets ( Callithrix jacchus) exposed to DEHP. Male mice and rats were treated with 0, 1.25 and 2.5 mmol/kg DEHP for 2 weeks, and marmosets with 0, 0.25, 1.25 and 6.25 mmol/kg DEHP for 15 months by gavage. Hepatic mono(2-ethylhexyl)phthalate (MEHP) levels were significantly higher in mice and rats than in marmosets. The constitutive expression of hepatic PPARα was 5–7 times greater in rats and mice than in marmosets, but DEHP treatment did not induce PPARα-mRNA in all animals. The treatment-induced PT expression detected either by anti-PT antibody or PT-mRNA levels in the liver only from mice and rats, and the induction of the mRNA was greater in the latter than in the former. Thus, DEHP used in this experiment influenced the peroxisomal enzymes in mice and rats, but did not affect the mitochondrial enzymes in any animals or the peroxisomal enzymes in marmosets. These results suggest that there are species differences in the induction of PPARα-related enzymes, especially in peroxisomal enzymes by DEHP treatment, and their underlying mechanism may in part reside in the different constitutive levels of PPARα and different forming levels of MEHP. [ABSTRACT FROM AUTHOR]

Abstract: Permethrin, the most popular insecticide among the synthetic pyrethroids, has been used worldwide to control a wide range of insects in agriculture, forestry, public health, and homes. Humans may have suffered potential exposure to this compound. The commercial formulation of permethrin contains trans and cis isomers. Here, at the same dosage, we made a comparison of the reproductive effects between these two isomers. Male adult ICR mice were orally administered trans- or cis-permethrin daily for 6 weeks at a dose of 0 or 70mg/(kgday). In the cis-permethrin exposure group, the caudal epididymal sperm count and sperm motility were significantly reduced, and testosterone levels in testes and plasma also fell. Moreover, cis-permethrin induced abnormal seminiferous tubules in testes and suppressed testicular mRNA expression levels of peripheral benzodiazepine receptor, steroidogenic acute regulatory protein, and the cytochrome P450 side-chain cleavage enzyme. Although such adverse effects were not observed in the trans-permethrin exposure group, testicular and urinary metabolite 3-phenoxybenzoic acid levels in trans-permethrin-exposed mice were about three- and sevenfold higher than those in cis-permethrin-exposed mice, respectively. Furthermore, in vitro, hepatic microsomal hydrolase activity for trans-permethrin was nearly 62-fold higher than that for cis-permethrin. Taken together, the difference in metabolic activity between cis- and trans-permethrin might contribute to the difference in the reproductive toxicity between both isomers. [Copyright &y& Elsevier]

Abstract: Two 3-phenyldihydroisocoumarins (hydrangenol and phyllodulcin), a 3-phenylisocoumarin (thunberginol A), and a stilbene (hydrangeaic acid) from the processed leaves of Hydrangea macrophylla var. thunbergii (Hydrangeae Dulcis Folium) promoted adipogenesis of 3T3-L1 cells. Hydrangenol, a principal constituent, significantly increased the amount of adiponectin released into the medium and mRNA levels of adiponectin, peroxisome proliferator-activated receptor γ2 (PPARγ2), and glucose transporter 4 (GLUT4), while it decreased the expression of interleukin 6 (IL-6) mRNA. Furthermore, hydrangenol significantly lowered blood glucose and free fatty acid levels 2 weeks after its administration at a dose of 200mg/kg/d in KK-Ay mice. [Copyright &y& Elsevier]