Genotoxicity of inorganic mercury salts based on disturbed microtubule function

This study investigated the hypothesis that the chromosomal genotoxicity of inorganic mercury results from interaction(s) with cytoskeletal proteins. Effects of Hg2+ salts on functional activities of tubulin and kinesin were investigated by determining tubulin assembly and kinesin-driven motility in cell-free systems. Hg2+ inhibits microtubule assembly at concentrations above 1 μM, and inhibition is complete at about 10 μM. In this range, the tubulin assembly is fully (up to 6 μM) or partially (∼6-10 μM) reversible. The inhibition of tubulin assembly by mercury is independent of the anion, chloride or nitrate. The no-observed-effect- concentration for inhibition of microtubule assembly in vitro was 1 μM Hg2+, the IC50 5.8 μM. Mercury(II) salts at the IC 50 concentrations partly inhibiting tubulin assembly did not cause the formation of aberrant microtubule structures. Effects of mercury salts on the functionality of the microtubule motility apparatus were studied with the motor protein kinesin. By using a "gliding assay" mimicking intracellular movement and transport processes in vitro, HgCl2 affected the gliding velocity of paclitaxel-stabilised microtubules in a clear dose-dependent manner. An apparent effect is detected at a concentration of 0.1 μM and a complete inhibition is reached at 1 μM. Cytotoxicity of mercury chloride was studied in V79 cells using neutral red uptake, showing an influence above 17 μM HgCl2. Between 15 and 20 μM HgCl2 there was a steep increase in cell toxicity. Both mercury chloride and mercury nitrate induced micronuclei concentration-dependently, starting at concentrations above 0.01 μM. CREST analyses on micronuclei formation in V79 cells demonstrated both clastogenic (CREST-negative) and aneugenic effects of Hg2+, with some preponderance of aneugenicity. A morphological effect of high Hg2+ concentrations (100 μM HgCl2) on the microtubule cytoskeleton was verified in V79 cells by immuno-fluorescence staining. The overall data are consistent with the concept that the chromosomal genotoxicity could be due to interaction of Hg2+ with the motor protein kinesin mediating cellular transport processes. Interactions of Hg 2+ with the tubulin shown by in vitro investigations could also partly influence intracellular microtubule functions leading, together with the effects on the kinesin, to an impaired chromosome distribution as shown by the micronucleus test.

Small molecule inhibitors of HCV replication from Pomegranate

Hepatitis C virus (HCV) is the causative agent of end-stage liver disease. Recent advances in the last decade in anti HCV treatment strategies have dramatically increased the viral clearance rate. However, several limitations are still associated, which warrant a great need of novel, safe and selective drugs against HCV infection. Towards this objective, we explored highly potent and selective small molecule inhibitors, the ellagitannins, from the crude extract of Pomegranate (Punica granatum) fruit peel. The pure compounds, punicalagin, punicalin, and ellagic acid isolated from the extract specifically blocked the HCV NS3/4A protease activity in vitro. Structural analysis using computational approach also showed that ligand molecules interact with the catalytic and substrate binding residues of NS3/4A protease, leading to inhibition of the enzyme activity. Further, punicalagin and punicalin significantly reduced the HCV replication in cell culture system. More importantly, these compounds are well tolerated ex vivo and `no observed adverse effect level' (NOAEL) was established upto an acute dose of 5000 mg/kg in BALB/c mice. Additionally, pharmacokinetics study showed that the compounds are bioavailable. Taken together, our study provides a proof-of-concept approach for the potential use of antiviral and non-toxic principle ellagitannins from pomegranate in prevention and control of HCV induced complications.

Biomarker responses and reproductive toxicity of the effluent from a Chinese large sewage treatment plant in Japanese medaka (Oryzias latipes)

The present study was conducted to assess the potential toxicity of the effluent from a large sewage treatment plant (GBD-STP) in Beijing. Japanese medakas (Oryzias latipes) at reproduction active period were exposed to a serial of graded concentrations of the effluent or 100 ng l(-1) of 17-alpha-ethinylestradiol (EE2, positive control). Growth, gonadosomatic index (GSI), hepatosomatic index (HSI), reproductive success, induction potency of vitellogenin (VTG) in male fish and that of 7-ethoxyresorufin-o-deethylase activity (EROD) in male fish liver were used as test endpoints. The growth suppression of fish was observed in a dose-dependent manner, resulting in significant differences in both body length and body weight of medaka above 5% effluent. This effluent can inhibit the growth of gonad of medakas and are more sensitive to male than to female. At exposure concentration of 40% and higher, there was an unexpected decrease of HSI values, which may be resulted from sub-lethal toxicity of effluent to fish liver. VTG of plasma in males were induced in all exposure concentration levels, but not in a dose-dependent manner. The concentration of 5% effluent would be the lowest observed adverse effect level (LOAEL) affecting reproductive success when examining fertile individuals, fecundity and fertilization rate. The overt CYP1A response and higher reproductive toxicity may be indicative of low process efficiency of this STP. (c) 2004 Elsevier Ltd. All rights reserved.

Decreased Sperm Motility in Rats Orally Exposed to Single or Mixed Pesticides

The Brazilian Agency of Sanitary Vigilance (ANVISA) conducted a study that demonstrated the presence of residues of several pesticides in fresh fruits and vegetables that were available for purchase by the general populace. In order to evaluate potential adverse health effects of low-level exposure to agrochemicals, the reproductive toxicity of the pesticides dicofol, dichlorvos, permethrin, endosulfan, and dieldrin was evaluated in rats dosed with these chemicals individually or as mixtures. Sixty male Lewis rats (6 wk old, 200 x g) were randomly allocated to 8 groups: (1) control group, received basal diet; (2) 5 groups designated a to e received the diet containing each pesticide individually, at the respective effective doses: lowest-observed-adverse-effect level (LOAEL) for dieldrin and endosulfan, lowest-observed-effect level (LOEL) for dicofol, and lowest effect level (LEL) for dichlorvos and permethrin, respectively, depending on the published data; (3) effective dose group, which received a mixture of pesticides added to basal diet at the respective doses reported to produce adverse effects; and (4) low dose group, which received a pesticide mixture added to the basal diet, where each pesticide was at its no-observed-effect level (NOEL). After 8 wk of treatment, reproductive parameters were evaluated. Sperm morphology, daily sperm production (DSP), sperm transit time through the epididymis, hormonal levels, and histopathological evaluation of testis and epididymis did not differ significantly among the groups. However, sperm motility was significantly decreased in animals that received a mixture of dieldrin, endosulfan, dicofol, dichlorvos, and permethrin, as well as in the group receiving dicofol alone. Exposure to the individual pesticides endosulfan, dichlorvos, and permethrin did not markedly affect sperm motility. The impairment of sperm motility in the mixture of pesticides at the NOEL level indicates that reproductive effects not seen with individual pesticides may occur in presence of several pesticides due to an additive effect. However, the pesticide mixtures did not appear to affect DSP or spermatogenesis despite reduced sperm motility.

Proliferação e Morte Celular (Apoptose) avaliadas em ratos Lewis após tratamento com mistura de praguicidas em baixas doses

The use of pesticides in Brazil has intensified over the years. And since 2009 it was ranked as the largest market for pesticides worldwide. The consequential diffuse contamination of the environment is therefore due to the increasing number of chemicals of different classes, origins and modes of action. Little is known about the action of pesticides on human health in situations of co-exposure. Possible toxic effects are not restricted to agricultural and industrial workers, but also the general population that may be exposed continuously to its residues in food and water. Although these pesticides are mostly present in the environment at low doses, it must be considered that possible cumulative or synergistic effects may occur when there are concurrent or sustained exposure for two or more of these agents, which can lead to late manifestation of subclinical damages, sometimes irreversible. Thus, the specific objective of this study was to assess the effect of carcinogenesis promotion of a mixture of pesticides at low doses and analyze the phenomena of cell proliferation and apoptosis in rat liver. A total of 50 male Lewis rats was separated into 5 groups for 8 weeks in a medium term hepatocarcinogenesis model. The three different classes of pesticides (dieldrin, dicofol, endosulfan, dichlorvos and permethrin), whose residues were detected by ANVISA during the period from 2001 to 2005 in tomatoes cultures, were added to the feed of rats initiated to hepatocarcinogenesis with diethylnitrosamine (DEN- 200mg/kg ip). We used two different mixtures, one with no toxic effects at doses (MEX1) referring to the NOEL (no-observed-effect level) and another at doses LOEL / LEL / LOAEL (Lowest-observed-effect level / Lowest-effect level / Lowest -observed-adverse-effect level), to the installation of adverse effects (MEX2), derived from chronic studies. All animals ...(Complete abstract click electronic access below)

Effects of a Mixture of Pesticides on the Adult Female Reproductive System of Sprague-Dawley, Wistar, and Lewis Rats

The Brazilian federal government Agency for Health Surveillance detected pesticide residues in fresh food available for consumers all over the country. The current study investigated the effects of a mixture of some of those pesticides (dichlorvos, dicofol, dieldrin, endosulfan, and permethrin) on the reproductive system of Sprague-Dawley (SD), Wistar (WT), and Lewis (LEW) rats. Female rats from each strain were randomized into three experimental groups and were fed a control diet or diets added with pesticides mixture at their respective no-observed-effect level (NOEL)/no-observed-adverse-effect level (NOAEL) (low dose) (mg/kg/d): dichlorvos (0.23), dicofol (0.5), dieldrin (0.025), endosulfan (0.7), permethrin (5), or lowest-observed-effect level (LOEL)/lowest-effect level (LEL)/ lowest-observed-adverse-effect level (LOAEL) (toxically effective dose) (mg/kg/d): dichlorvos (2.3), dicofol (2.1), dieldrin (0.05), endosulfan (3.8), and permethrin (25) as reported in the literature. Euthanasia was performed between wk 10 and 12, during the estrous stage. Decreased body weights gain (SD and WT) and increased liver weights (SD, WT, and LEW) were observed in each strain fed the pesticides mixture at the higher levels. At that dose level, rat strains also varied in their responses regarding the estrous cycle, hormonal levels, and number of developing ovarian follicles. The studied mixture of pesticides was found to interfere with the female reproductive system when individual pesticides were mixed above a certain level, indicating a threshold exists for each of the strains studied.

Avaliação toxicológica da ayahuasca em ratos Wistar : comportamento e toxicidade reprodutiva em machos

Dissertação (mestrado)—Universidade de Brasília, Faculdade de Ciências da Saúde, Programa de Pós-Graduação em Ciências da Saúde, 2016.

The adverse effect of a high energy dense diet on cardiac tissue

Purpose: To determine whether a high energy dense diet intake increases oxidative stress and alters antioxidant enzymes in cardiac tissue. Design: A randomized, controlled study. Ninety-day-old female rats were randomly divided into two groups: one fed with a low energy dense diet (LE; 3.0 kcal g-1) and one with a high energy dense diet (HE; 4.5 kcal g-1). Materials and Methods: After 8 weeks of treatment, the animals were fasted overnight and sacrificed by decapitation. The serum was used for glucose, triacylglycerol, cholesterol, low-density lipoprotein (LDL)-cholesterol and high-density lipoprotein (HDL)-cholesterol determinations. The glycogen, lipoperoxide, lipid hydroperoxide, superoxide dismutase, glutathione peroxidase, lactate dehydrogenase, citrate synthase, total and non-protein sulphhydryl groups were determined in cardiac tissue. Results: HE decreased the myocardial glycogen content and increased the lactate dehydrogenase/citrate synthase ratio, indicating an increased glycolytic pathway and a shift from myocardial aerobic metabolism. HE-treated female rats showed increased lipoperoxide and hydroperoxide levels in cardiac tissue. Although no alterations were observed in the total sulphhydryl group and superoxide dismutase activities, glutathione peroxidase and the non-protein sulphhydryl group were significantly decreased in HE-treated animals. Conclusions: Although no alterations were observed in energy intake, HE induced an increased intake of fat and carbohydrate and an increased rate of weight gain. HE intake induced alterations in markers of oxidative stress in cardiac tissue. Hydrogen peroxide is an important toxic intermediate in the development of cardiac oxidative stress by HE. The specific nutrient content, such as fat and carbohydrate, rather than caloric intake, appears to be the main process inducing oxidative stress in HE-treated female rats.

Adverse effect of noise in the operating theatre on surgical-site infection

The aim of this pilot study was to evaluate the noise level in an operating theatre as a possible surrogate marker for intraoperative behaviour, and to detect any correlation between sound level and subsequent surgical-site infection (SSI).

How is leflunomide prescribed and used in Australia? analysis of prescribing and adverse effect reporting

Purpose To evaluate the use of leflunomide in the Australian community since introduction in 2000. Trends in adverse drug reaction (ADR) reporting were also studied. Methods Annual Australian prescription and dispensing statistics were analysed. Drug utilisation was estimated as defined daily doses (DDD)/1000 inhabitants/day. ADR data from the Therapeutic Goods Administration's Adverse Drug Reactions Advisory Committee (ADRAC) national monitoring system were compared with the World Health Organisation (WHO) Vigibase records. Results Leflunomide use in Australia (dispensing data) increased from 0.2 in 2000 to 0.4 DDD/1000 inhabitants/day in 2002. The same overall pattern was observed in the 'authority to prescribe' data. From 2000-2002, prescribing of the starter pack (3 x 100 mg loading dose plus 30 x 20 mg tablets) declined (down 74%); likewise for the 20mg (30 tablets) pack. Gradual increases were noted for the 10 mg (30 tablets) pack (up 40%). Approximately 135 reports, detailing about 370 individual ADR, were generated annually. Gastro-intestinal disorders predominated, accounting for 24% of reactions reported to ADRAC. Skin and appendages disorders constituted 14% of reported reactions. Deaths in leflunomide users were attributed to a combination of haematological and gastro-intestinal complications, but it was not possible to ascertain other medication usage or contributing factors. Trends observed with the ADRAC reports were consistent with the WHO database. Conclusions Leflunomide was the first registered DMARD in Australia in over a decade and its use has increased within the community. The ADR reports might have contributed to Australian rheumatologists gradually abandoning loading patients with high doses of leflunomide in favour of starting therapy at lower doses. Copyright (c) 2006 John Wiley & Sons, Ltd.

Toxicological evaluation of fucoidan extracted from Laminaria japonica in Wistar rats

Fucoidans, the sulfated polysacchrides extracted from brown algae, have been extensively studied for their diverse biological activities. However, there is no detailed report investigating the toxicity of fucoidan. In this study, the acute and subchronic (6 months) toxicity of varying levels of fucoidan extracted from Laminaria japonica was investigated in Wistar rats after oral administration. The results showed that no significant toxicological changes were observed when 300 mg/kg body weight per day fucoidan was administered to rats. But when the dose was increased to 900 and 2500 mg/kg body weight per day, the clotting time was significantly prolonged. Besides this, no other signs of toxicity were observed. Based on these results, it can be concluded that the no adverse effect level of fucoidan from L. japonica is 300 mg/kg body weight per day. (C) 2004 Elsevier Ltd. All rights reserved.

Effects of early life permethrin exposure on spatial working memory and on monoamine levels in different brain areas of pre-senescent rats

Pesticide exposure during brain development could represent an important risk factor for the onset of neurodegenerative diseases. Previous studies investigated the effect of permethrin (PERM) administered at 34 mg/kg, a dose close to the no observable adverse effect level (NOAEL) from post natal day (PND) 6 to PND 21 in rats. Despite the PERM dose did not elicited overt signs of toxicity (i.e. normal body weight gain curve), it was able to induce striatal neurodegeneration (dopamine and Nurr1 reduction, and lipid peroxidation increase). The present study was designed to characterize the cognitive deficits in the current animal model. When during late adulthood PERM treated rats were tested for spatial working memory performances in a T-maze-rewarded alternation task they took longer to choose for the correct arm in comparison to age matched controls. No differences between groups were found in anxiety-like state, locomotor activity, feeding behavior and spatial orientation task. Our findings showing a selective effect of PERM treatment on the T-maze task point to an involvement of frontal cortico-striatal circuitry rather than to a role for the hippocampus. The predominant disturbances concern the dopamine (DA) depletion in the striatum and, the serotonin (5-HT) and noradrenaline (NE) unbalance together with a hypometabolic state in the medial prefrontal cortex area. In the hippocampus, an increase of NE and a decrease of DA were observed in PERM treated rats as compared to controls. The concentration of the most representative marker for pyrethroid exposure (3-phenoxybenzoic acid) measured in the urine of rodents 12 h after the last treatment was 41.50 µ/L and it was completely eliminated after 96 h.

The adverse effect of dummy auction bids on market value

The popularity of an auction as a means of selling residential real estate has increased markedly in recent years. The effectiveness of an auction program is heavily promoted by most real estate agents, claiming it to be the best means of attracting the best price from the highest bidder, It is based on the theory of gathering all buyers together at a publicised time, and then offering the property for sale to the open market.

In theory, the person most willing to buy the property will have the highest bid, supposedly agreeing at market value with the vendor (although above the vendor's reserve I. Unfortunately, the practice of dummy bidding has recently resurfaced and highlights serious flaws in the auction system, with hundreds of residential auctions conducted across Australia every weekend.

Clearly, it is in the vendor's best interests land the auctioneer's best interests, who is paid even more by the vendor if the price is higherl to achieve the highest offer from the last bidder. The tactic of dummy bids is designed to deceive genuine purchasers into a false sense of perception, where there appears to be more competition for the property than there actually exists.

This paper examines the auction process with the emphasis placed on the practice of dummy biding, It considers the broad implications for the definition of market value and also the overall residential market. Useful advice is also included for real estate valuers relying upon auction sale properties in their market analysis. As well as strongly supporting the auction concept, the authors suggest improvements to the overall auction process to ensure relevance to the definition of market value is maintained.

Do Different Casein Concentrations Increase the Adverse Effect of Rutin on the Biology of Anticarsia gemmatalis Hubner (Lepidoptera: Noctuidae)?

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)