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Archives of Toxicology (v.79, #5)
Disposition of low doses of 14C-bisphenol A in male, female, pregnant, fetal, and neonatal rats by Hideo Kurebayashi; Shin-Ichiro Nagatsuka; Hiroyuki Nemoto; Hideyo Noguchi; Yasuo Ohno (pp. 243-252).
Bisphenol A (BPA) is a weak xenestrogen (ADI=50 μg kg−1, US EPA) which is mass-produced, with potential for human exposure. To study absorption, distribution, excretion, and metabolism of BPA, BPA labeled with carbon-14 was administered p.o. to male and female Fischer (F344) rats at relatively low doses (20, 100, and 500 μg kg−1), and i.v. injected at 100 and 500 μg kg−1. 14C-BPA (500 μg kg−1) was also administered orally to pregnant and lactating rats to examine the transfer of radioactivity to fetuses, neonatal rats, and milk. Radioluminographic determination using phosphor imaging plates was employed to achieve highly sensitive determination of radioactivity. Absorption ratios of radioactivity after three oral doses were high (35–82%); parent 14C-BPA in the circulating blood was quite low, however, suggesting considerable first-pass effect. After an oral dose of 100 μg kg−1 14C-BPA, the radioactivity was distributed and eliminated rapidly, but remained in the intestinal contents, liver, and kidney for 72 h. The major metabolite in the plasma and urine was BPA glucuronide, whereas most of the BPA was excreted with the feces as free BPA. A second peak in the time-course of plasma radioactivity suggested enterohepatic recirculation of BPA glucuronide. There was limited distribution of 14C-BPA to the fetus and neonate after oral administration to the dam. Significant radioactivity was not detected in fetuses on gestation days 12 and 15. On day 18, however, radioactivity was detected in the fetal intestine and urinary bladder 24 h after oral dosing of 14C-BPA to the pregnant rats. Part of radioactivity was transferred to neonatal rats from the milk of the treated lactating dam and remained in the intestine of the neonates after 24-h nursing by an untreated dam.
Keywords: Bisphenol-A; Distribution; Pregnant rat; Fetus; Neonate
Purification and characterization of recombinant human liver prolidase expressed in Saccharomyces cerevisiae by Shu-Hao Wang; Qing-Wen Zhi; Man-Ji Sun (pp. 253-259).
The recombinant human liver prolidase (rh-prolidase, EC 3.4.13.9) from the lysate supernatant of engineering yeast Saccharomyces cerevisiae was purified in two steps employing anion-exchange gradient chromatography (DEAE-Sepharose fast flow) and gel filtration chromatography (Sephacryl S-200 high resolution). The purified recombinant protein furnished a single band with a molecular weight of 56 kD. Intensity scanning of the SDS-PAGE gel revealed that the prolidase accounted for more than 90% of total protein. The optimum pH of the catalytic reaction was 8.0. The enzyme was stimulated by Mn2+, but strongly inhibited by Cu2+ and Zn2+. The rh-prolidase expressed in S. cerevisiae had both dipeptidase and organophosphorus acid anhydrolase activity. It catalyzed the hydrolysis of soman and the dipeptide Gly–Pro. In a detoxification test in vitro, purified rh-prolidase was remarkably efficient at eliminating the toxicity of a lethal dose of soman, with the result that mice survived injection of such a dose.
Keywords: Rh-prolidase; Purification; Characterization; Soman
Altered thyroxin and retinoid metabolic response to 2,3,7,8-tetrachlorodibenzo-p-dioxin in aryl hydrocarbon receptor-null mice by Noriko Nishimura; Junzo Yonemoto; Yuichi Miyabara; Yoshiaki Fujii-Kuriyama; Chiharu Tohyama (pp. 260-267).
To determine whether the disruption of thyroid hormone and retinoid homeostasis that occurs after exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can be mediated by the arylhydrocarbon receptor (AhR), pregnant AhR-heterozygous (AhR+/−) mice were administered a single oral dose of 10 μg kg−1 TCDD at gestation day 12.5. Serum and liver were collected on postnatal day 21 from vehicle-treated control or TCDD-treated AhR+/− and AhR-null (AhR−/−) mouse pups. Whereas TCDD exposure resulted in a marked reduction of total thyroxin (TT4) and free T4 (FT4) levels in the serum of AhR+/− mice, TCDD had no effects on AhR−/− mice. Gene expression of UDP-glucuronosyltransferase (UGT)1A6, cytochrome P450 (CYP)1A1, and CYP1A2 in the liver was induced markedly by TCDD in AhR+/− but not AhR−/− mice. Induction of CYP1A1 in response to TCDD was confirmed by immunohistochemical evidence in that CYP1A1 protein was conspicuously localized in the cytoplasm of hepatocytes in the centrilobular region. Levels of retinyl palmitate were greatly reduced in the liver of TCDD-exposed AhR+/− mice, but not in vehicle-treated AhR+/− mice. No effects of TCDD on retinoid levels in the liver were found in AhR−/− mice. We conclude that disruption of thyroid hormone and retinoid homeostasis is mediated entirely via AhR. Induction of UGT1A6 is thought to be responsible at least partly for reduced serum thyroid hormone levels in TCDD-exposed mice.
Keywords: Aryl hydrocarbon receptor-null mice; Retinoid; Thyroxin; 2,3,7,8-Tetrachlorodibenzo-p-dioxin; Vitamin A
Absence of cardiotoxicity of the experimental cytotoxic drug cyclopentenyl cytosine (CPEC) in rats by Kirsten Schimmel; Roel Bennink; Kora de Bruin; Rene Leen; Karsten Sand; Maurice van den Hoff; André van Kuilenburg; Jean-Luc Vanderheyden; Neil Steinmetz; Martin Pfaffendorf; Arnauld Verschuur; Henk-Jan Guchelaar (pp. 268-276).
The experimental anticancer drug cyclopentenyl cytosine (CPEC) was associated with cardiotoxicity in a phase I study. The aim of the present study was twofold; first we investigated whether the observed effects could be reproduced in in-vitro and in-vivo rat models. Second, we intended to investigate the underlying mechanism of the possible cardiotoxicity of CPEC. Effects on frequency and contractility were studied on the isolated atria of 18 male Wistar rats. Atria were incubated with 0.1 mmol L−1 (n=6) or 1 mmol L−1 (n=6) CPEC for 1.5 h and compared with control atria (incubation with buffer solution, n=6). The cardiac apoptosis-inducing potential was studied in-vivo on 66 rats by 99mTc-Annexin V scintigraphy, followed by postmortem determination of radioactivity in tissues, histological confirmation with the TUNEL assay (late-phase apoptosis), and immunohistochemical staining for cleaved caspase 3 and cytochrome C (early-phase apoptosis). Serum levels of the necrotic cardiomyopathy marker troponin T were also determined. No effect on heart frequency was found in the isolated atria after CPEC treatment. A trend towards a decrease of contraction force was observed. However, the differences were not statistically significant. 99mTc-Annexin V scintigraphy showed no increase in cardiac uptake ratio upon CPEC treatment in the in-vivo rat model, which was confirmed by determination of radioactivity in heart versus blood ratios. At each section a few individual isolated late apoptotic cells (<5) could be identified by the TUNEL assay in the highest CPEC dose group (90 mg kg−1) but not in controls or in rats treated with 60 mg kg−1 CPEC. Staining for the early apoptosis markers cleaved caspase 3 and cytochrome C did not reveal any significant differences between treated and control rats. Cardiac troponin T levels were not increased after CPEC treatment. CPEC does not affect heart frequency or contraction force in our cardiotoxicity models. Moreover, we did not find an indication of CPEC-induced apoptosis in heart tissue.
Keywords: Cyclopentenyl cytosine; CPEC99mTc-Annexine; Rat; Cardiotoxicity; Apoptosis
Weakness in the mechanical properties of the femur of growing female rats exposed to cadmium by Małgorzata M. Brzóska; Katarzyna Majewska; Janina Moniuszko-Jakoniuk (pp. 277-288).
This study was aimed at assessing the effect of cadmium (Cd) intoxication on the risk of deformities and fractures of the growing bone on a female rat model of human exposure to this metal. For this purpose, bone mineral density (BMD) and mechanical properties of the proximal and distal ends and diaphysis of the femur were investigated in female Wistar rats exposed to 1, 5, and 50 mg Cd L−1 in drinking water for 3, 6, 9, and 12 months since weaning. Daily Cd doses received from the drinking water during the treatment period were in the ranges 0.059–0.219, 0.236–1.005, and 2.247–9.649 mg kg−1 body weight at 1, 5, and 50 mg Cd L−1, respectively. Biomechanical properties of the femoral proximal and distal ends were evaluated in a compression test and those of the femoral diaphysis in a cutting test with loading perpendicular to the bone longitudinal axis in all tests. Cd dose- and exposure duration-dependently affected the mineralization and mechanical properties of the bone tissue at various locations of the femur. Exposure to 1 mg Cd L−1 (corresponding to low human exposure) during skeletal development weakened the fracture strength of the femoral neck and of the trabecular bone at the level of the distal end of the femur and affected the elastic properties of the cortical bone at the femoral diaphysis. At the higher levels of Cd treatment, the adverse action generally occurred after shorter exposure than at 1 mg Cd L−1 and was more seriously advanced. The Cd-induced weakening in the bone biomechanical properties at particular sites of the femur correlated with the decreased bone mineralization. The results indicate that even low exposure to Cd may affect the mineralization and biomechanical properties of growing bone, thus increasing the risk of fractures.
Keywords: Cadmium; Bone mineral density; Biomechanical testing; Femur; Rats
Investigation of the role of hyperbaric oxygen therapy in cisplatin-induced nephrotoxicity in rats by Enes Murat Atasoyu; Senol Yildiz; Oguz Bilgi; Hakan Cermik; Rıfkı Evrenkaya; Samil Aktas; Mustafa Gültepe; E Gökhan Kandemir (pp. 289-293).
Cisplatin (CP) is an effective chemotherapeutic agent used in the treatment of a variety of solid tumours. The most frequently observed side-effect of the use of CP is nephrotoxicity. Recently, evidence has been demonstrated that reactive oxygen species forming in the tubular epithelium play an important role in CP-linked nephrotoxicity. The aim of the study was to observe the effect of hyperbaric oxygen (HBO) therapy on CP nephrotoxicity, a subject which has not been studied previously. Wistar rats were treated with CP (a single intraperitoneal (IP) dose of 0.6 mg/100 g) alone and in combination with HBO (60 min every day for seven days at 2.5×atmospheric pressure). Effects of the treatment on renal function and histology were determined. In analyses at the end of the study it was observed that serum urea, creatinine, and daily urinary protein excretion levels of the CP group were higher than at the start of the study, and that the creatinine clearance level had fallen (P<0.05). There was no significant difference between the CP+HBO group and HBO group serum urea, creatinine, creatinine clearance, and daily urinary protein excretion levels at the beginning and end of the study (P>0.05). Histopathological examination showed that the necrosis score in the proximal tubule epithelial cells and average apoptitic cell numbers in the CP group were higher than those in the CP+HBO and HBO groups (P<0.05). There was no statistical difference between the CP+HBO group and the HBO group in terms of necrosis score in the proximal tubule epithelial cells and the percentage of distal tubules containing hyaline casts in the lumen. In conclusion, in this study it was observed that in experimental study of CP nephrotoxicity the synchronous application of HBO therapy with CP prevents kidney damage.
Keywords: Cisplatin-induced nephrotoxicity; Hyperbaric oxygen therapy; Acute tubuler necrosis
The effect of occlusive and unocclusive exposure to xylene and benzene on skin irritation and molecular responses in hairless rats by A. Chatterjee; R. J. Babu; E. Ahaghotu; M. Singh (pp. 294-301).
Aromatic hydrocarbons readily penetrate the skin on dermal exposure, leading to irritation, inflammation and cytotoxicity. The effects of short-term occlusive and long-term unocclusive dermal exposure to benzene and xylene on the skin irritation response (transepidermal water loss (TEWL), skin moisture content and erythema) and cytokine/chemokine expression (interleukin-1α (IL-1α), tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1)) were investigated in hairless rats. Occlusive dermal exposure was carried out with 230 μL of the chemicals for 1 h using Hill top chambers. In unocclusive dermal exposure, 15 μL of the chemicals were applied to the skin every 2 h, for 8 h a day, for 4 days. The occlusive dermal exposure revealed a clear difference in the TEWL and erythema response of these chemicals (xylene>benzene) whereas unocclusive exposure revealed similar TEWL and erythema scores for both benzene and xylene. The expression of IL-1α was elevated 2.5- and 3.8-fold in response to occlusive and unocclusive exposure, respectively, vs control (P<0.01) for both the chemicals (benzene and xylene). Similarly, TNF-α levels were elevated about 2.4- and 6.0-fold as a result of occlusive and unocclusive exposure, respectively, vs control (P<0.01). These results show that unocclusive exposure induced significantly higher TNF-α expression than occlusive exposure (P<0.05). The MCP-1 expression in blood was slightly elevated compared with the control group, but this increase was not statistically significant (P>0.05). Similarly, MCP levels in skin were increased approximately 1.7- and 1.8-fold by occlusive and unocclusive exposure, respectively, compared with the control group (P<0.05). Our study demonstrates that the skin irritation profiles of benzene and xylene are similar and unocclusive long-term exposure to small amounts of these chemicals can induce more skin irritation and cytokine response than occlusive exposure.
Keywords: Skin irritation; Benzene; Xylene; Dermal exposure
Glucuronidation patterns of common urinary and serum monoester phthalate metabolites
by Manori J. Silva; Dana B. Barr; John A. Reidy; Kayoko Kato; Nicole A. Malek; Carolyn C. Hodge; Donald Hurtz III; Antonia M. Calafat; Larry L. Needham; John W. Brock (pp. 302-302).