Topical glucocorticoids are commonly applied for treatment of atopic dermatitis, and are often administered over a long period. However, itching often occurs as a rebound phenomenon after cessation of long-term glucocorticoid application. The present study was an initial trial designed to establish an animal model of glucocorticoid-induced pruritus by topical application of dexamethasone over a long period in mice with contact dermatitis. BALB/c mice with chronic allergic contact dermatitis induced by 5 weeks of repeated application of 2,4,6-trinitro-1-chlorobenzene (TNCB) were treated topically with dexamethasone for 3 weeks from 2 weeks after the elicitation of dermatitis. The effects of dexamethasone on inflammation and pruritus were evaluated by measurement of ear-swelling and scratching behavior, respectively. Significant enhancement of pruritus was confirmed after chronic application of dexamethasone. The increased frequency of scratching behavior was reduced by withdrawal of dexamethasone. On the other hand, ear-swelling was markedly ameliorated by dexamethasone treatment, but rapidly relapsed after dexamethasone withdrawal. The level of interleukin (IL)-4 mRNA in ear skin and that of IgE in serum were increased in the mice with dermatitis and reduced by dexamethasone treatment. On the other hand, the level of nerve growth factor (NGF) mRNA was slightly increased by dexamethasone treatment and remained high even after its discontinuation. It is anticipated that this novel animal model of glucocorticoid-induced pruritus will be useful for clarifying the mechanisms of the rebound phenomenon induced by chronic treatment with topical glucocorticoids, and for developing a new form of therapy.
Perfluorocarbons from common household products such as food containers, stain- resistant protection for clothing, furniture and carpets, paints, and fire-fighting foams are found in soil, water, plants, animal and human serum worldwide. Previous research has shown a significant association between these chemicals and thyroid disease in women. The present data from the C8 Health Project assessed thyroid function in a cross-sectional analysis of 52,296 adults with a year or more of exposure to perfluorooctanoate (PFOA) from drinking water. Outcomes were: thyroxine, T3 uptake, and thyroid stimulating hormone (TSH). Analyses were stratified by gender and age group (< 20 - < 50 years and > 50). Both PFOA and perfluorooctane sulfonate (PFOS) were associated with significant elevations in serum thyroxine and a significant reduction in T3 uptake in all participants. There were also significant gender/PFOS interactions for T3uptake and thyroxine, as well as gender/PFOA interactions for T3 uptake. Results provide evidence for disruption of thyroid function related to these common chemicals and possible mechanisms are discussed.
Capecitabine is an oral anticancer prodrug which is converted to 5-fluorouracil (5-FU) via 3 enzymatic steps, these being 5’-deoxy-5-fluorocytidine (5’-DFCR), 5’-deoxy-5-fluorouridine (5’-DFUR), and finally 5-FU by carboxylesterase (CES), cytidine deaminase (CDA), and thymidine phosphorylase (TP), respectively. Because rats, mice and monkeys are used for preclinical safety studies, we investigated the in vitro conversion from capecitabine to 5-FU by hepatic and intestinal mucosal microsomes and cytosols, to compare their metabolic activity to that of humans. Capecitabine was hydrolyzed to 5’-DFCR in hepatic and intestinal mucosal microsomes in these animal species. In humans and monkeys, CLint (Vmax/Km) for the hydrolysis of capecitabine in intestine (expressed as µl/min/g tissue) was much lower than that in hepatic microsomes but, in rats and mice, CLint was higher in intestine than in liver. In humans and monkeys, similar Km values and inhibition patterns by tetrahydrouridine (THU) a CDA inhibitor, were observed in CDA activity of hepatic and intestinal cytosols. However, rats showed very low CDA activity and mice showed non-Michaelis-Menten kinetics and a different inhibition pattern by THU. Km values for TP activity were almost similar in rats, mice, monkeys and humans. In conclusion, it was confirmed that monkeys are a suitable animal model for the safety assessment of capecitabine in terms of metabolic enzymes and it was suggested that higher toxic incidences in mouse small intestine were related to high hydrolytic activity of capecitabine in the small intestine.
Ioannis A. Zervos, Efstathios Nikolaidis, Sophia N. Lavrentiadou, Maria P. Tsantarliotou, Eleni K. Eleftheriadou, Elias P. Papapanagiotou, Dimitrios J. Fletouris, Marios Georgiadis, Ioannis A. Taitzoglou
Endosulfan provokes systemic toxicity in mammals and induces reactive oxygen species (ROS) and lipid peroxidation (LPO). The brain is susceptible to LPO and several studies implicate ROS and LPO in CNS diseases. Tissue plasminogen activator (t-PA) has been accredited with plasminogen-dependent roles in the CNS, as well as plasminogen-independent functions. The aim of this study was to investigate the activities of t-PA and its inhibitor, plasminogen activator inhibitor-1 (PAI-1) in the adult rat brain, after subchronic endosulfan treatment. Furthermore, the potency of vitamins C and E to attenuate these effects was explored. Endosulfan was administered in Wistar rats either alone or with vitamin C and/or vitamin E. The induced oxidative stress was manifested by induction of LPO as determined by higher malondialdehyde levels. This was accompanied by elevation of t-PA and PAI-1 activities. Vitamins E and C, both well-known for their antioxidant properties, substantially acted in a preventive way and protected the brain from these effects.
To evaluate the effects of a variety of chemical, biological and physiological stimuli on erythropoiesis, in vitro assays using erythroid progenitor cells from humans or laboratory animals are well-known methods. On the other hand, little has been reported on in vitro assays using mature erythroblasts such as polychromatic erythroblasts. In the present study, we established a convenient method for enrichment of polychromatic erythroblasts from rat bone marrow and confirmed their development in vitro. To establish a method for the enrichment of polychromatic erythroblasts, bone marrow cells from 3- and 10-week-old rats were separated by discontinuous density gradient centrifugation using Percoll. As a result, polychromatic erythroblasts were most highly enriched in the bone marrow fraction from 3-week old rats at the density interface between 1.040 and 1.058 g/ml. The enriched polychromatic erythroblasts were then cultured in growth medium supplemented with 20% fetal bovine serum in the presence or absence of erythropoietin for 48 hr. During the culture period, cell proliferation and maturation to orthochromatic erythroblasts were observed, and intracellular heme contents were also increased. In particular, the culture in the presence of erythropoietin revealed higher proliferation of erythroid cells, and therefore might be more appropriate for in vitro experiments on the effects of various stimuli on late-stage erythropoiesis.
3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are associated with adverse skeletal muscle toxicity, but the underlying mechanism remains unclear. To investigate the pathological mechanism of statin-induced myotoxicity, cerivastatin (20 ppm; corresponding to 2 mg/kg/day) was dietarily administered to young male F344 rats for 10 days, and time-course clinical observations, measurement of plasma creatine kinase activity, and light and electron microscopy of type I fiber-predominant skeletal muscle (soleus) or type II fiber-predominant skeletal muscles (extensor digitorum longus and tibialis anterior), were performed. Clinical symptoms including weakness of hind limbs, staggering gait and body weight loss, accompanied by marked plasma creatinine kinase elevation in rats fed cerivastatin at around Day 6 to 8. Interestingly, microscopic examination revealed that cerivastatin-induced muscle damages characterized by hypercontraction (opaque) and necrosis of the fibers were of particular abundance in the soleus muscle at Day 8, whereas these histological lesions in the extensor digitorum longus and tibialis anterior were negligible, even at Day 9. Prior to manifestation of muscle damage, swollen mitochondria and autophagic vacuoles in the soleus were observed as the earliest ultra structural changes at Day 6; then activated lysosomes, disarray of myofibril and dilated sarcoplasmic reticulum vesicles became ubiquitous at Day 8. These results demonstrate that cerivastatin induces type I fiber-predominant muscles injury, which is associated with mitochondrial damage, in young male F344 rats. Since the rat exhibiting type I fiber-targeted injury is a unique animal model for statin-induced myotoxicity, it will be useful for gaining insight into mechanisms of statin-induced myotoxicity.
This study aimed to determine the cardiac and autonomic nervous effects of deoxynivalenol (DON), a representative mycotoxin which frequently contaminates cereal grains, in conscious rats that had been implanted with telemetric transmitters. Four groups of rats given subcutaneous injections of 0.5, 1.0, or 2.0 mg/kg of DON or propylene glycol (vehicle solution) were used in the experiments. Telemetric electrocardiogram (ECG) recordings were performed for 2 weeks or longer during the pre- and post-DON injection period. The present study demonstrated that DON caused marked arrhythmias, such as second-degree atrioventricular block, atrial bradycardia, supraventricular extrasystole, and ventricular extrasystole, at 3 hr or later (mostly at 10-20 hr) after the DON-injection, which were accompanied by a significant increase in heart rate (HR) and a significant decrease in total power and low- and high-frequency power during the period from 90 to 180 min after the injection. In conclusion, it was elucidated that DON produces significant cardiac dysfunction and transient inhibition of the autonomic nervous function in conscious rats at a dose of 0.5 mg/kg s.c. or more.
The potential health risks of inhaling nanomaterials are of great concern because of their high specific activity and their unique property of translocation. Earlier studies showed that exposure to nanoparticles through the airway affects both respiratory and extrapulmonary organs. When pregnant mice were exposed to nanoparticles, the respiratory system, the central nervous system and the reproductive system of their offspring were affected. The aim of this study was to assess the effect of maternal exposure to nanoparticles on the offspring, particularly on the kidney. Pregnant ICR mice were exposed to a total of 100 µg of carbon black nanoparticle on the fifth and the ninth days of pregnancy. Samples of blood and kidney tissue were collected from 3-week-old and 12-week-old male offspring mice. Collagen expression was examined by quantitative RT-PCR and immunohistochemistry. Serum levels of creatinine and blood urea nitrogen were examined. Exposure of pregnant ICR mice to carbon black resulted in increased expression of Collagen, type VIII, a1 (Col8a1) in the tubular cells in the kidney of 12-week-old offspring mice but not in 3-week-old ones. The levels of serum creatinine and blood urea nitrogen, indices of renal function, were not different between the groups. These observations were similar to those of tubulointerstitial fibrosis in diabetic nephropathy. These results suggest that maternal exposure to carbon black nanoparticle induces renal abnormalities similar to tubulointerstitial fibrosis in diabetic nephropathy are induced in the kidney of offspring.
This study was conducted to determine the presence of phthalates in 10 different brands of bottled water available in Saudi markets and stored under different conditions. Dimethyl phthalate (DMP), diethylphthalate (DEP), di-n-butyl phthalate (DBP), benzyl butyl phthalate (BBP) and diethyl hexyl phthalate (DEHP) were measured by headspace solid-phase microextraction followed by gas chromatography- mass spectrometer detector. Most of these phthalates were detected in the selected bottled water sample that might be either leached from the plastic packaging materials or contamination during bottling processes. Bottled waters stored at 4°C contained higher levels of DMP, DEP, BBP and DEHP than those stored at room temperature and outdoors. On the other hand, the levels of DMP, DEP and BBP were significantly lower in bottled waters stored at room temperature than those outdoor. It seems that temperature and sunlight play a role in the degradation of phthalates within time. The levels of BBP were the highest at 4°C storage (4.592 ± 3.081 µg/l; range: 1.194-21.128 µg/l) and approximately 76% of the bottled waters had BBP above the limit of quantification (LOQ) of 0.994 µg/l. Apart from DEHP (< 6 µg/l), there are not current legislations for other phthalates. Regardless of storage conditions, all our samples did not exceed the maximum established limit of DEHP. Although, the levels of phthalates in tested bottled waters were low, one should not dismiss that these chemicals may cause endocrine disruption through several mechanisms, especially to potentially vulnerable populations such as infants and pregnant women. Saudi Arabia ranks 12 in bottled water consumption (88 L per capita in 2004) among the 71 reported countries. With this high consumption, a quality assurance scheme for residue monitoring in water is quite important. Although, one cannot avoid phthalates contamination in bottled waters due to manufacturing process but at least special care should be taken regarding their storage conditions.
Effects of synthesized glucocorticoid, dexamethasone (DEX, dose = 1.0 mg/kg body weight/day for 10 days) on the expressions of β2-adrenoceptor (AR) and glucocorticoid receptor (GR) were studied in fast-twitch (extensor digitorum longus (EDL)) and slow-twitch fiber-rich (soleus(SOL)) muscles of rats. DEX decreased the expression of β2-AR mRNA in SOL muscle without changing that in EDL muscle. The expression of β2-AR protein in EDL and SOL muscles was not affected by DEX. DEX-induced decreased action of the expression of GR mRNA was much greater in SOL muscle than in EDL muscle. However, there were no differences in the expression of GR protein in EDL and SOL muscles. DEX also decreased mRNA expression of cAMP response element binding protein (CREB, transcription factor of β2-AR mRNA) in SOL muscle, whereas increased that in EDL muscle. Further, DEX tended to increase mRNA expressions of post-transcription factors of β2-AR mRNA in EDL muscle without changing those in SOL muscle. These results demonstrated that the expressions of β2-AR and GR are regulated at mRNA levels but not protein levels by DEX. Further, these results also suggest that DEX-induced decrease in the expression of β2-AR mRNA in slow-twitch fiber-rich SOL muscle is associated with the transcriptional regulations.
Heavy oil is one of the most serious pollutants in marine ecosystem. The poisonous influences of the chemical substances contained in heavy oil on many kinds of marine organisms are widely studied. However, the influence of the chemical compounds in heavy oil on our health has not been cleared yet. In order to reveal the poisonous influences of these chemical compounds on mammalian reproductive system, water-soluble fraction (WSF) extracted from heavy oil was administrated to mice for 2 weeks. WSF-administrated mice were crossed with either WSF- or distilled water-administrated group for mating experiment. When WSF-administrated male mice were used as a father, it reduced not only mating ratio, but also neonatal male ratio. The numbers of sperms of WSF-administrated male mice were decreased. In addition, abnormality of sperms such as bent or twisted tail was increased approximately 6-fold by WSF intake. The level of testosterone in serum from WSF-administrated mice was lower than that from control mice. Testosterone is the most important for the spermatogenesis in vertebrate. It is supposed from these findings, the decrease in the number of sperms may relate with the reduction of sex hormone level in serum. It is suggested from these results that the chemical substances in WSF affected the sperm function in reproductive system of male mice.
Previous studies have shown that prenatal and postnatal exposure to diesel exhaust (DE), which is known to be one of the main constituents of air pollution, enhances the persistence of endometriosis in a rat model. The aim of this study is to investigate the pathological changes induced by DE exposure in a rat model of endometriosis. Pregnant Sprague-Dawley rats were exposed to DE or clean air beginning on gestational day 2 and neonatal rats were persistently exposed to DE or clean air. Endometriosis was induced by autotransplantation of endometrium onto the peritoneum of eight-week-old female offspring. Endometriotic lesions were examined at 7 and 14 days post-transplantation. As a result, infiltration of activated mast cells remained in deeper area of peritoneal tissue around the endometriosis model compared to the control group at 14 days post-autotransplantation. In the DE exposure group, 14 days post-transplant, the remaining lesions contained fibroblasts and activated mast cells, which were surrounded by collagen fibers. The data showed that prenatal and postnatal DE exposure enhances the activation of mast cells and prolongs the persistence of collagen fibers in the induced rat model of endometriosis.
The potential genotoxicity of the rodent liver carcinogen 2,6-dinitrotoluene (2,6-DNT) was evaluated in compliance with the guidelines for genotoxicity studies of drugs (Notification No. 1604, Nov. 1, 1999, Ministry of Health and Welfare, Japan) and the OECD guidelines for the testing of chemicals by performing the bacterial reverse mutation (Ames) assay, the in vitro chromosomal aberration assay, and the in vivo comet assay (alkaline single cell gel electrophoresis) in rat liver. In the Ames assay, 2,6-DNT was moderately positive irrespective of metabolic activation. In the in vitro chromosomal aberration assay, under conditions where the test substance would precipitate out, weak structural aberrations were observed with or without S9 mix at each dose at which the cell growth rate was about 40 to 50%. The in vivo comet assay yielded positive results in rat liver; that is to say, the increases in % tail DNA in liver in the 25 and 50 mg/kg groups were observed statistically significantly and dose-dependent. Our findings are in accordance with previous findings in the in vivo/in vitro unscheduled DNA synthesis (UDS) assay in rat liver and in a young rat liver micronucleus assay, although the rat bone marrow micronucleus assay gave negative results. These results suggest that test systems using liver are a useful method for the in vivo genotoxicity assessment of chemicals that require metabolic activation.
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