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12 results on '"Kugathas, Subramaniam"'

1. Synthetic glucocorticoids in the aquatic environment : their potential impacts on fish

Author

Kugathas, Subramaniam, Sumpter, J., and Routledge, E.

Subjects
577.27, Pharmaceuticals, Endocrine disruptors, Steriods, Emerging contaminants, Gene expression
Abstract

Human pharmaceuticals have been shown to be entering the aquatic environment in quantities sufficient to produce adverse effects to aquatic organisms, particularly fish. The impacts of synthetic oestrogens have been well documented, but other groups of steroidal pharmaceuticals have not yet been studied. Hence, the present research was designed to study synthetic glucocorticoids (GCs), which are used in large amounts as immunosuppressive and anti-inflammatory drugs. This study involved different approaches, including in silico, in vitro, in vivo and genomics, to assess the effects of GCs on fish. Using reliable data on consumption of GCs in the UK and the LF2000-WQX hydrological model, mean concentrations of GCs in the river Thames were predicted to be in the range from 30 ng/L to 850 ng/L. Mammalian cell lines were transiently transfected with trout corticosteroid receptors (GR1, GR2 and MR) and the transactivation abilities of ten of the most prescribed GCs in the UK were measured in vitro. All tested GCs showed significantly higher activity with GR2 than with GR1. In order to assess the impact of low concentrations of GCs in vivo, two chronic exposure experiments were conducted with adult fathead minnows (Pimephales promelas). Both experiments showed potency-related and concentration-related impacts on various endpoints. There was a concentration-related increase in plasma glucose concentrations and a decrease in blood lymphocyte count. Induction of secondary sexual characters in females suggests a concentration-related masculinisation of fathead minnows. There was a decreasing trend in plasma vitellogenin concentrations in female fish with increasing exposure concentration of GCs. Expression profiles of selected genes (PEPCK, GR and Vtg) in liver also demonstrated concentration-related effects at all three tested concentrations. Hence, it was not possible to define a no effect concentration for the tested GCs. This study probably provides reliable estimates of the likely range of concentrations of GCs in a typical river, impacted by effluent from many sewage treatment plants. The in vitro results indicate that all tested GCs bind to fish GR in a similar manner to that reported for mammalian receptors. The in vivo results suggest that GCs could cause effects at very low (as low as 100 ng/L) concentrations that could be environmentally-relevant. The immunosuppresive effects could make fish susceptible to disease and the reproductive effects may have population-level impacts. It is very likely that the effects of different GCs will be additive, as has been shown for oestrogenic chemicals. Therefore, this study warrants further environmental risk assessment of GCs, especially in mixture scenarios.

Published
2011

3. Effects of common pesticides on prostaglandin D2 (PGD2) inhibition in SC5 mouse Sertoli cells, evidence of binding at the COX-2 active site, and implications for endocrine disruption

Author

Kugathas, Subramaniam, Audouze, Karine, Ermler, Sibylle, Orton, Frances, Rosivatz, Erika, Scholze, Martin, and Kortenkamp, Andreas

Subjects
Genetic disorders -- Chemical properties -- Analysis, Endocrine disruptors -- Chemical properties -- Analysis -- Health aspects, Pesticides -- Chemical properties -- Analysis -- Health aspects, Birth defects -- Risk factors -- Analysis, COX-2 inhibitors -- Health aspects -- Analysis, Environmental issues, Health
Abstract

Background: There are concerns that diminished prostaglandin action in fetal life could increase the risk of congenital malformations. Many endocrine-disrupting chemicals have been found to suppress prostaglandin synthesis, but to our knowledge, pesticides have never been tested for these effects. Objectives: We assessed the ability of pesticides that are commonly used in the European Union to suppress prostaglandin D2 (PGD2) synthesis. Methods: Changes in PGD2 secretion in juvenile mouse Sertoli cells (SC5 cells) were measured using an ELISA. Coincubation with arachidonic acid (AA) was conducted to determine the site of action in the PGD2 synthetic pathway. Molecular modeling studies were performed to assess whether pesticides identified as PGD2-active could serve as ligands of the cyclooxygenase-2 (COX-2) binding pocket. RESULTS: The pesticides boscalid, chlorpropham, cypermethrin, cyprodinil, fenhexamid, fludioxonil, imazalil (enilconazole), imidacloprid, iprodione, linuron, methiocarb, o-phenylphenol, pirimiphos-methyl, pyrimethanil, and tebuconazole suppressed PGD2 production. Strikingly, some of these substances--o-phenylphenol, cypermethrin, cyprodinil, linuron, and imazalil (enilconazole)--showed potencies (IC50) in the range between 175 and 1,500 nM, similar to those of analgesics intended to block COX enzymes. Supplementation with AA failed to reverse this effect, suggesting that the sites of action of these pesticides are COX enzymes. The molecular modeling studies revealed that the COX-2 binding pocket can accommodate most of the pesticides shown to suppress PGD2 synthesis. Some of these pesticides are also capable of antagonizing the androgen receptor. CONCLUSIONS: Chemicals with structural features more varied than previously thought can suppress PGD2 synthesis. Our findings signal a need for in vivo studies to establish the extent of endocrinedisrupting effects that might arise from simultaneous interference with PGD2 signaling and androgen action. http://dx.doi.org/10.1289/ehp.1409544, Introduction Although the importance of androgens as drivers of male sexual differentiation in fetal life is widely recognized (Sharpe 2006), the involvement of prostaglandins in these processes has received comparatively [...]

Published
2016
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6. Prediction of environmental concentrations of glucocorticoids: the River Thames, UK, as an example

Author

Kugathas, Subramaniam, Williams, Richard J., Sumpter, John P., Kugathas, Subramaniam, Williams, Richard J., and Sumpter, John P.

Abstract

Synthetic glucocorticoids (GCs) are consumed in large amounts as anti-inflammatory and immunosuppressive drugs worldwide. Based on what has been learnt from studies of other human pharmaceuticals, they are likely to be present in the aquatic environment. However, to date, information on the environmental concentrations of GCs is very limited. The situation is complicated by the fact that a considerable number of GCs are in everyday use in most developed countries. Hence, obtaining a full picture of GC concentrations in the aquatic environment using the traditional analytical chemistry approach would be time-consuming and expensive. Thus, we took a modelling approach to predict the total environmental concentration of all synthetic GCs (consisting of 28 individual GCs) in the river Thames, as a first step in risk assessment of these drugs. Using reliable data on consumption, the LF2000-WQX model predicts mean concentrations up to 30 ng/L of total GCs in surface water as a best case scenario when the lowest excretion and highest removal rates in sewage treatment works were used, whereas mean concentrations up to 850 ng/L were predicted when the highest excretion and lowest removal rates are considered. We also present the 10th and 90th percentile concentrations (which indicate the likely range of concentrations seen from high flow to low flow conditions in the river) of the highest and lowest consumed GCs, to show the spatial and temporal variations of the concentrations of individual GCs. These data probably provide reliable estimates of the likely range of concentrations of GCs in a typical river impacted by effluent from many sewage treatment plants. Results also identify the hot spots where field studies on fish could be focused. To determine if aquatic organisms face any threat from GCs, laboratory toxicity studies should be conducted using concentrations similar to those reported here.

Published
2012

12. From single chemicals to mixtures—Reproductive effects of levonorgestrel and ethinylestradiol on the fathead minnow

Author

Runnalls, Tamsin J., Beresford, Nicola, Kugathas, Subramaniam, Margiotta-Casaluci, Luigi, Scholze, Martin, Scott, Alexander P., and Sumpter, John P.

Subjects
Fathead minnow, Mixtures toxicity, Health, Toxicology and Mutagenesis, Reproduction, Levonorgestrel, Aquatic Science, EE2, Read-Across
Abstract

This is an open access article under the CC BY license(http://creativecommons.org/licenses/by/4.0/). The aquatic environment is polluted with thousands of chemicals. It is currently unclear which of these pose a significant threat to aquatic biota. The typical exposure scenario is now represented by a widespread blanket of contamination composed of myriads of individual pollutants-each typically present at a low concentration. The synthetic steroids, 17α-ethinylestradiol and levonorgestrel, have been widely reported to be present in the aquatic environment in the low ng to sub-ng/l range. They are widely used in contraceptive formulations, both individually and in combination. Our research employed the fathead minnow (Pimephales promelas) 21 day 'pair-breeding' assay to assess reproductive output when pairs of fish were exposed to the single chemicals at low environmentally relevant concentrations, and then to a binary mixture of them. A variety of endpoints were assessed, including egg production, which was inhibited in a concentration-dependent manner by both the individual chemicals and the mixture. Significant, sex specific effects were also seen with both chemicals, at differing levels of biological organisation. Plasma concentrations of EE2 and levonorgestrel were predicted and in the case of levonorgestrel measured, and compared with the human therapeutic plasma concentrations (Read-Across approach) to support the interpretation of the results. A novel quantitative method was developed for the data analysis, which ensured a suitable endpoint for the comparative mixture assessment. This approach compares the reproductive performance from individual pairs of fish during chemical exposure to its pre-treatment performance. The responses from the empirical mixture study were compared to predictions derived from the single substance data. We hypothesised combined responses which were best described by the concept of concentration addition, and found no clear indications against this additivity expectation. However, the effect profiles support the current knowledge that both compounds act in different ways to reduce egg production in fish, and suggest that probably response addition (also called Independent action) is the more appropriate mixture model in this case. This research was conducted under Department of the Environment, Food and Rural affairs (DEFRA,UK) research contract. L.M.-C. was supported by a Biotechnology and Biological Sciences Research Council (BBSRC) Research Grant(BB/100646X/1) awarded to J.P.S.

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