Developmental Toxicity by Exposure to Bisphenol A Diglycidyl Ether during Gestation and Lactation Period in Sprague-dawley Male Rats / 예방의학회지

OBJECTIVES: Bisphenol A diglycidyl ether (BADGE) is the major component in commercial liquid epoxy resins, which are manufactured by co-reacting bisphenol A with epichlorohydrin. This study was performed to show the developmental effects of prenatal and postnatal exposures to BADGE in male rat offspring. METHODS: Mated female rats were divided into four groups, each containing 12 rats. The dosing solutions were prepared by thoroughly mixing BADGE in corn oil at the 0, 375, 1500 and 3000 mg/kg/day concentrations. Mated females were dosed once daily by oral gavage on gestation day (GD) 6 - 20 and postnatal day (PND) 0 - 21. Pregnant female dams were observed general symptoms and body weight. Also, male pups were observed the general symptoms, body weight, developmental parameters (e.g. anogenital distance, pina detachment, incisor eruption, nipple retention, eye opening, testis descent), organ pathologic changes and hormone levels of plasma. RESULTS: Pregnant rats treated with BADGE died at a rate of about 70% in the 1500 mg/kg/day group and all rats treated with 3000 mg/kg/day died. Body weight, for male pups treated with doses of 375 mg/kg/day, was significantly lower than in the control group at PND 42, 56, and 63 (p<0.05). Evaluation of body characteristics including; separation of auricle, eruption of incisor, separation of eyelid, nipple retention, descent of testis, and separation of the prepuce in the BADGE treated group showed no difference in comparisons with the control group. AGD and adjusted AGD (mm/kg) for general developmental items in BADGE 375 mg/kg/day treated pups tended to be longer than in controls, however, these differences were not statistically significant. Relative weights of adrenal gland, lung (p<0.05), brain, epididymis, prostate, and testis (p<0.01) were heavier than in control in measures at PND 9 weeks. There were no significant changes in comparisons of histological findings of these organs. Loss of spermatids was observed in the seminiferous tubule at PND 9 weeks, but no weight changes were observed. The plasma estrogen levels were similar in the control and treatment groups at PND 3, 6 and 9 weeks. The plasma testosterone levels in the control group tended to increase with age. However, in the BADGE 375 mg/kg/day treated male pups it did not tend to increase. CONCLUSIONS: These findings suggest that BADGE is a chemical that has developmental effects consistent with it being an endocrine disruptor.

The Inhibition of Human Telomerase Reverse Transcriptase Expression by Peroxiredoxin I and c-Myc in Prostatic Cancer Cells / 대한비뇨기과학회지

PURPOSE: We evaluated the hypothesis that the telomerase expression is associated with c-Myc and peroxiredoxin I (Prx I) in patients with prostate cancer. The study determined the link between Prx I, c-Myc and human telomerase reverse transcriptase (hTERT) in prostate cancer cells. MATERIALS AND METHODS: The cDNA of the Prx I gene was obtained by reverse-transcriptase polymerase chain reaction (RT-PCR) amplification. Cotransfections were performed by using a hTERT luciferase reporter plasmid and each expression vector as indicated (c-Myc or Prx I). Empty vectors were used as controls for determining the basal promoter activity. RT-PCR was performed to evaluate the effect of the DEM-induced Prx I mRNA expression. Luciferase assay was performed to evaluate the inhibitory effect of transfected Prx I and the DEM induced Prx I on the transcriptional activity of hTERT in the human prostatic cancer cell lines PC-3 and DU-145. RESULTS: In this study, we found that Prx I could inhibit hTERT expression through direct interaction with c-Myc protein in the prostate cancer cell lines. In addition, it was obvious that Prx I could interact with c-Myc protein. We also found that DEM could induce upregulation of the Prx I mRNA expression and that the increased expression of Prx I could downregulate the expression of hTERT. CONCLUSIONS: Our results demonstrated a direct link between Prx I, c-Myc and hTERT, and we suggest that Prx I regulates cellular immortalization through c-Myc and hTERT, which is activation step in carcinogenesis.

Validation of High Performance Liquid Chromatographic Method with UV Detector for the Determination of Di(2-ethylhexyl)Phthalate in Plasma in some Korean Male Workers / 대한산업의학회지

OBJECTIVES: This study was conducted to validate a simple, rapid and sensitive reverse-phase high-performance liquid chromatographic method with UV detector (HPLC-UV) and present the plasma level of di(2-ethylhexyl)phthalate (DEHP) in some Korean male workers. METHODS: HPLC-UV for quantification of plasma DEHP was validated by the following guideline from the Center for Drug Evaluation and Research (CDER)-calibration/standard curve, precision, accuracy and recovery. Plasma DEHP from 255 healthy Korean male workers aged from 30 to 60 years was analyzed by validated HPLC-UV method. RESULTS: The calibration curve over the range 0~150 microgram/liter for the plasma DEHP standard solution showed linearity(r2=0.999). The limit of detection (LOD) and limit of quantification (LOQ) of plasma DEHP were 5.22 microgram/liter and 15.81 microgram/liter, respectively. The accuracy and precision for 2.5 microgram/liter of DEHP were acceptable in CDER guideline on the second and third day but not first day, and those for 50 microgram/liter and 150 microgram/liter of DEHP were acceptable on all three days(Ed-confirm this addition). The distribution of plasma DEHP level was skewed to the left and ranged from 0 to 18.9 microgram/liter. The plasma DEHP level was lower than 10 microgram/liter for 98 % of subjects and lower than 5 microgram/liter for 85 %. The geometric mean and standard deviation of plasma DEHP were 0.4 +/- 1.5 microgram/liter. CONCLUSIONS: The HPLC-UV method for quantification of plasma DEHP was acceptable by CDER guideline. The plasma DEHP of 255 Korean male workers ranged from 0 to 18.9 microgram/liter and the distribution was skewed to the left.

Prostagladin E Receptor II and IV Increase the Expression of Martrix Metalloproteinase-7 in PC (Prostate Cancer)-3 Cells / 대한비뇨기과학회지

PURPOSE: The effects of PGE2 receptors (EP1, 2, 3, 4) on the proliferation of prostate cancer cells are still unclear. The degradation of the basement membrane by MMP-2, 7, 9 and TIMP-1, 2 is a critical point in tumor invasion and metastasis. We investigated the effects of PGE2 receptors concerning MMP and TIMP after the treatment of COX-2 inhibitors on prostate cancer cell-lines. MATERIALS AND METHODS: Two prostate cancer cell-lines, PC-3 and DU-145 cells were used in this study. RT-PCR were performed to detect the mRNA expression of EP1, 2, 3, 4, MMP-2, 7, 9 and TIMP-1, 2, MMP-7 was measured by ELISA after being treated with the selective EP2 agonist and EP4 agonist 10(-10), 10(-8), 10(-6) microM respectively. RESULTS: EP2, 3 and 4 mRNA were expressed in both cell-lines. After the NS-398 treatment, EP2 and EP4 mRNA expressions decreased in PC-3 cells. While only the MMP-7 mRNA expression decreased in PC-3 cells after NS-398 treatment, after NS-398 with selective EP2 agonist and EP4 agonist, MMP-7 mRNA expression increased. In PC-3 cells, selective EP2 agonist and EP4 agonist induced a significant dose-dependent increase in MMP-7 production in comparison to the NS-398 treatment group (control) in the conditioned ELISA medium. CONCLUSIONS: These results strongly suggest that COX-2, to some extent, contribute to prostate carcinogenesis at the EP2 and EP4 receptor, which could also be explained by increments of MMP-7 in PC-3 cells. Therefore, these findings show that selective EP inhibitor is useful in preventing specific disease progression in prostate cancer.

Effect of Selective Cyclooxygenase-2 Inhibitor on Apoptosis of the Human Prostate Cancer Cell Xenografted in Nude Mice / 대한비뇨기과학회지

PURPOSE: Cyclooxygenase (COX)-2, an inducible enzyme that catalyzes the formation of prostaglandins from arachidonic acid, is overexpressed in various cancers, including prostate cancer, and cell lines. COX-2 has been reported to play an important role in carcinogenesis. The aim of this study was to evaluate the effects of a selective COX-2 inhibitor (meloxicam) on the cell proliferation, apoptosis, Bcl-2, and Bcl-xL expression in prostate cancer. MATERIALS AND METHODS: 20 male nude mice were subcutaneously inoculated with 1 million PC-3 cells expressing COX-2. After 1 week, the mice were divided into two groups of 10 mice. Group 1 was left untreated, which served as a control. Group 2 was treated with meloxicam (40mg/kg) four times a week for 3 weeks. After the 4 weeks experimental period, the tumors were immunohistochemically assayed for apoptosis (TUNEL) and proliferation (Ki-67). The COX-2, Bcl-2 and Bcl-xL mRNA expression levels in the tumors were evaluated by RT-PCR. RESULTS: The meloxicam had no effect on the tumor cell proliferation, but induced inhibition of PC-3 tumor cell growth and apoptosis. The Bcl-2 expression decreased in the meloxicam-treated group, but there was no significant difference between the two groups. The Bcl-xL expression was significantly down regulated in the meloxicam-treated group (p<0.01). CONCLUSIONS: Our results suggest that a selective COX-2 inhibitor suppresses PC-3 cell tumor growth in vivo. Tumor growth suppression was achieved by the induction of tumor cell apoptosis, and was associated with a decreased Bcl-xL expression, which is one of the Bcl-2 related genes.

The Expressions of iNOS and the Effects of iNOS Inhibitor in the Rats of Cisplatin Induced Nephrotoxicity / 대한비뇨기과학회지

PURPOSE: This study was designed to investigate the role of NO in cisplatin induced nephrotoxicity of rats, especially in association with expressions of inducible nitric oxide synthase(iNOS) and the effects of iNOS inhibitor. MATERIALS AND METHODS: Male, Sprague-Dawley rats weighing 170-190gm were used. Nephrotoxicity was induced by single intraperitoneal administration of cisplatin(10mg/kg). Aminoguanidine sulfate (300mg/kg), a relatively specific iNOS inhibitor, was administrated 30 minutes prior to cisplatin administration. Individual kidneys were obtained from control, cisplatin single treated and cisplatin combined with aminoguanidine treated rats at 6, 12, 24, 48, 72hours and 7days after cisplatin administration. Serum BUN/creatinine(mg/dl), the unit weight of rat kidney (kidney wet weight/body weight) were estimated. HE stain was performed for histologic evaluation of nephrotoxicity. The expressions of iNOS were assessed by Western blotting and RT-PCR. RESULTS: Serum BUN/creatinine levels in aminoguanidine treated groups were suppressed its increment significantly at 12, 24 and 48 hours compared with cisplatin single treated groups (p<0.05). The unit weight of kidneys in aminoguanidine treated groups were decreased significantly at 24 and 48hours compared with cisplatin single treated groups (p<0.05). Western blotting represents intense iNOS protein bands (117KDa) at 24,48 and 72hours in cisplatin single treated groups. RT-PCR assay for iNOS mRNA (429bp) were weakly expressed in control groups and intense expressions were identified cisplatin single treated and cisplatin combined with aminoguanidine treated groups at 6, 12, 24 and 72hours. CONCLUSIONS: From these results, it is suggested that cisplatin induced nephrotoxicity may be partly mediated by NO. Aminoguanidine may delay or suppress the cisplatin induced nephrotoxicity of rat kidney.

Clinical Significance of Basic Fibroblast Growth Factor Expression in Bladder Cancer / 대한비뇨기과학회지

Basic fibroblast growth factor (bFGF) is a potent mitogen and angiogenic protein that may function as an autocrine growth regulator in a variety of malignancies. However, the prognostic value of bFGF expression in bladder cancer has not been adequately studied. We examined tumor tissues of 22 superficial and 25 invasive bladder cancers to define the prognostic value of bFGF expression. We performed immunohistochemical staining of bFGF in formalin-fixed and paraffin-embedded bladder tissue sections using rabbit polyclonal antibody. Microvessels were identified by immunohistochemistry using antibodies to endothelial marker, factor VIII-related antigen. The staining of bFGF were significantly correlated with grade and T stage (p<0.05). The elevated expression of bFGF in patients with invasive bladder cancer was significant correlated with recurrence and 2 year survival (p<0.05). However, no significantly correlation was observed between level of bFGF and vascular counts in frozen sections derived from bladder cancers. These results suggest that the bFGF expression has an important prognostic value in patients with bladder cancer. Immunohistochemical study for bFGF may become a valuable method to predict long-term survival and necessity for adjuvant therapy in patients with bladder cancer.

A Case of Cystic Pheochromocytoma / 대한비뇨기과학회지

Pheochromocytoma is a rare, but an important cause of surgically curable hypertension. Pheochromocytoma is a highly vascular tumor and not infrequently undergoes hemorrhagic necrosis and pseudocyst formation. Such cystic pheochromocytoma may be accompanied by shock and sepsis and commonly invade adjacent organs, in which cases its diagnosis and management may be difficult. Herein we present a case of adrenal cystic pheochromocytoma which was accompanied by sepsis and hypertension and mimicked pararenal abscess with a review of literatures.