Inter-population variability in the reproductive morphology of the shore crab (Carcinus maenas): Evidence of endocrine disruption in a marine crustacean?

Environmental contaminants that are capable of causing endocrine disrupting effects are currently a major cause for concern. These chemicals are known to influence the reproductive development of vertebrates by mimicking or antagonising the actions of endogenous hormones. However, little is known regarding their potential effects on invertebrates. Here we examine variations in the reproductive morphology of the shore crab (Carcinus maenas) for evidence of endocrine disruption. Crabs were collected from a number of sites comprising a putative gradient of exposure to endocrine disrupting chemicals. Patterns of inter-population variability in the expression of sexually dimorphic traits were then examined for evidence of hormone disruption. Extensive variability was detected and patterns of chelal morphology were consistent with the gradient of endocrine disruption. However, overall, the patterns of morphological variability were not consistent with hormonally-mediated effects. This suggests that shore crabs are not susceptible to the same type of endocrine disrupting effects that have been detected in vertebrates, which are most commonly mediated via the oestrogen receptor. However, the potential for androgenic effects on crustacean morphology are discussed

Mixtures of Chemicals in Water: Implications of chemical legislation and environmental policy

Scientists have shown that mixtures of chemicals can act together to reduce the reproductive capacity of fish even if each individual chemical in the mixture is present at a concentration that does not cause an adverse effect. This evidence demonstrates that legislation based on the assessment of single chemicals may not be sufficiently protective and suggest that there is a need for a review of existing environmental policy

Preliminary data on the influence of rearing temperature on the growth and reproductive status of fathead minnows Pimephales promelas

This article has been made available through the Brunel Open Access Publishing Fund and is available from the specified link - Copyright @ 2011 Brian JV et al.An investigation into the influence of temperature on the growth and reproductive status of the fathead minnow Pimephales promelas revealed that, while there was no clear effect of treatment on sex differentiation, ovarian tissue from female fish reared under the highest temperature regime contained large amounts of undefined tissue containing no germ cells. Furthermore, both male and female fish exhibited differences in length mass, condition and somatic indices, and in the expression of secondary sexual characteristics. The patterns observed are discussed in the context of climate change

Benzotriazole is antiestrogenic in vitro but not in vivo

Copyright © 2007 SETAC. This is the accepted version of the following article: Harris et al (2007), "Benzotriazole is antiestrogenic in vitro but not in vivo", Environmental Toxicology and Chemistry, 26(11), 2367–2372, which has been published in final form at the link below.Benzotriazole (BT) is an anticorrosive agent well known for its use in aircraft deicing and antifreeze fluids but also used in dishwasher detergents. It is highly persistent in the environment; therefore, BT is frequently found in runoff emanating from large airports as well as in the surrounding groundwater. In addition, BT has recently been found to be ubiquitous in Swiss wastewater treatment plant effluents and their receiving waters; however, very little chronic toxicity data is available on which to base a sound ecological risk assessment of this chemical. In vitro assays conducted using a recombinant yeast (anti-) estrogen assay indicated that BT possessed clear antiestrogenic properties. This chemical was approximately 100-fold less potent than Tamoxifen, which was used as a positive control. A subsequent in vivo study, however, involving analysis of vitellogenin induction and somatic indices in adult fathead minnows (Pimephales promelas) exposed to BT at concentrations of 10, 100, and 1,000 μg/L for two weeks showed no evidence of antiestrogenic activity by this compound. The possibility exists that higher concentrations of BT may yet induce the type of activity observed in vitro, although the concentrations used here already far exceed those reported in surface-water samples. Furthermore, adverse effects may be observed in fish or other organisms exposed to BT for a longer period than employed here, although such studies are costly and unlikely to be included in standard risk assessment procedures. A rigorous investigation of the chronic toxicity of BT is imperative

Hypoxia does not influence the response of fish to a mixture of estrogenic chemicals

The official published version can be obtained from the link below - Copyright @ 2009 American Chemical SocietyChemical risk assessment procedures assign a major role to standardized toxicity tests, in which the response of a particular organism to a single test substance is determined under otherwise constant and favorable conditions in the laboratory. This approach fails to consider the potential for chemical interactions, as well as failing to consider how the toxicological response varies, depending on the conditions of exposure. As yet, the issue of confounding factors on chemically mediated effects in wildlife has received little attention, despite the fact that a range of physicochemical parameters, including temperature, water quality, and pH, are known to modify chemical toxicity. Here, we consider how the estrogenic response of fish varies with regard to hypoxia. Fathead minnows (Pimephales promelas) were exposed to a mixture of estrogenic chemicals under hypoxic or normoxic conditions. Their estrogenic response was characterized using an in vivo assay, involving the analysis of the egg yolk protein, vitellogenin (VTG). The results revealed that there was no effect of hypoxia on the VTG response in either treatment group at the end of the exposure period. This suggests that this end point is robust and relatively insensitive to the effects of any physiological changes that arise as a result of hypoxia. The implications of these negative findings are discussed in terms of their relevance with regard to the development of risk assessment policy.This work was funded by a grant from the Natural Environment Research Council(NE/D00389X/1)

The influence of a surfactant, linear alkylbenzene sulfonate, on the estrogenic response to a mixture of (xeno)estrogens in vitro and in vivo

This is the post-print version of the final paper published in Aquatic Toxicology. The published article is available from the link below. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. Copyright © 2008 Elsevier B.V. All rights reserved.The effect of the presence of a surfactant on the activity of a mixture of environmental estrogens was assessed. In their natural habitat, fish are subject not only to exposure to mixtures of estrogenic compounds, as has been addressed in previous publications, but also to other confounding factors (chemical, physical and biological), which may, in theory, affect their responses to such compounds. To assess the potential for such interference, the commonly occurring surfactant, linear alkylbenzene sulfonate (LAS), was applied to the yeast estrogen screen at various concentrations, independently and together with a mixture of estrogens at constant concentrations. LAS enhanced the estrogenic activity of the mixture, an effect which became less pronounced over the course of time. This information was used to design an in vivo study to assess induction of vitellogenin in fathead minnows exposed to the same mixture of estrogens plus LAS. A similar trend was observed, that is, the response was enhanced, but the effect became less pronounced as the study progressed. However, the enhanced response in vivo occurred only at the highest concentration of LAS tested (362 μg/L), and was transient because it was no longer apparent by the end of the study. Although LAS is a significant contaminant in terms of both concentration and frequency of detection in the aquatic environment, these data do not suggest that it will have a significant impact on the response of fish to environmental estrogens

A computational model of the hypothalamic - pituitary - gonadal axis in female fathead minnows (Pimephales promelas) exposed to 17α-ethynylestradiol and 17β-trenbolone

© 2011 Li et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background - Endocrine disrupting chemicals (e.g., estrogens, androgens and their mimics) are known to affect reproduction in fish. 17α-ethynylestradiol is a synthetic estrogen used in birth control pills. 17β-trenbolone is a relatively stable metabolite of trenbolone acetate, a synthetic androgen used as a growth promoter in livestock. Both 17α-ethynylestradiol and 17β-trenbolone have been found in the aquatic environment and affect fish reproduction. In this study, we developed a physiologically-based computational model for female fathead minnows (FHM, Pimephales promelas), a small fish species used in ecotoxicology, to simulate how estrogens (i.e., 17α-ethynylestradiol) or androgens (i.e., 17β-trenbolone) affect reproductive endpoints such as plasma concentrations of steroid hormones (e.g., 17β-estradiol and testosterone) and vitellogenin (a precursor to egg yolk proteins). Results - Using Markov Chain Monte Carlo simulations, the model was calibrated with data from unexposed, 17α-ethynylestradiol-exposed, and 17β-trenbolone-exposed FHMs. Four Markov chains were simulated, and the chains for each calibrated model parameter (26 in total) converged within 20,000 iterations. With the converged parameter values, we evaluated the model's predictive ability by simulating a variety of independent experimental data. The model predictions agreed with the experimental data well. Conclusions - The physiologically-based computational model represents the hypothalamic-pituitary-gonadal axis in adult female FHM robustly. The model is useful to estimate how estrogens (e.g., 17α-ethynylestradiol) or androgens (e.g., 17β-trenbolone) affect plasma concentrations of 17β-estradiol, testosterone and vitellogenin, which are important determinants of fecundity in fish.The Medical Research Foundation of Oregon, U.S. Environmental Protection Agency, and the National Center for Computational Toxicology of the EPA Office of Research and Development

Evidence of estrogenic mixture effects on the reproductive performance of fish

The official published version can be obtained from the link below - Copyright @ 2007 American Chemical SocietyRecent research into the effects of mixtures of estrogenic chemicals has revealed the capacity for similarly acting chemicals to act in combination, according to the principles of concentration addition. This means that, collectively, they may pose a significant environmental risk, even when each component is present at a low and individually ineffective concentration. The aim of this study was to investigate the ecological significance of mixture effects at low-effect concentrations by assessing the combined effect of estrogenic chemicals on the reproductive performance of fish. Pairs of fathead minnows were exposed to five estrogenic chemicals. Endpoints analyzed included fecundity, the expression of male secondary sexual characteristics, somatic indices, and vitellogenin induction. In the first phase of the study, a concentration-response analysis was performed to investigate the relative sensitivity of these endpoints. In the second phase, mixture effects at low-effect concentrations were explored by exposing fish to each of the mixture components, individually and in combination. Data from these experiments provide evidence of mixture effects on fitness and fecundity, demonstrating the capacity for chemicals to act together to affect reproductive performance, even when each component is present belowthe threshold of detectable effects. This has important implications for hazard assessment and contributes to our understanding of mixture effects at increasing levels of biological complexity.This work was funded by the European Commission, under contract EVK1-2001-00091

Efficacy of sacubitril/valsartan vs. enalapril at lower than target doses in heart failure with reduced ejection fraction: the PARADIGM-HF trial.

AimsIn this analysis, we utilized data from PARADIGM-HF to test the hypothesis that participants who exhibited any dose reduction during the trial would have similar benefits from lower doses of sacubitril/valsartan relative to lower doses of enalapril.Methods and resultsIn a post-hoc analysis from PARADIGM-HF, we characterized patients by whether they received the maximal dose (200 mg sacubitril/valsartan or 10 mg enalapril twice daily) throughout the trial or had any dose reduction to lower doses (100/50/0 mg sacubitril/valsartan or 5/2.5/0 mg enalapril twice daily). The treatment effect for the primary outcome was estimated, stratified by dose level using time-updated Cox regression models. In the two treatment arms, participants with a dose reduction (43% of those randomized to enalapril and 42% of those randomized to sacubitril/valsartan) had similar baseline characteristics and similar baseline predictors of the need for dose reduction. In a time-updated analysis, any dose reduction was associated with a higher subsequent risk of the primary event [hazard ratio (HR) 2.5, 95% confidence interval (CI) 2.2-2.7]. However, the treatment benefit of sacubitril/valsartan over enalapril following a dose reduction was similar (HR 0.80, 95% CI 0.70-0.93, P < 0.001) to that observed in patients who had not experienced any dose reduction (HR 0.79, 95% CI 0.71-0.88, P < 0.001).ConclusionsIn PARADIGM-HF, study medication dose reduction identified patients at higher risk of a major cardiovascular event. The magnitude of benefit for patients on lower doses of sacubitril/valsartan relative to those on lower doses of enalapril was similar to that of patients who remained on target doses of both drugs

Altered Neurocircuitry in the Dopamine Transporter Knockout Mouse Brain

The plasma membrane transporters for the monoamine neurotransmitters dopamine, serotonin, and norepinephrine modulate the dynamics of these monoamine neurotransmitters. Thus, activity of these transporters has significant consequences for monoamine activity throughout the brain and for a number of neurological and psychiatric disorders. Gene knockout (KO) mice that reduce or eliminate expression of each of these monoamine transporters have provided a wealth of new information about the function of these proteins at molecular, physiological and behavioral levels. In the present work we use the unique properties of magnetic resonance imaging (MRI) to probe the effects of altered dopaminergic dynamics on meso-scale neuronal circuitry and overall brain morphology, since changes at these levels of organization might help to account for some of the extensive pharmacological and behavioral differences observed in dopamine transporter (DAT) KO mice. Despite the smaller size of these animals, voxel-wise statistical comparison of high resolution structural MR images indicated little morphological change as a consequence of DAT KO. Likewise, proton magnetic resonance spectra recorded in the striatum indicated no significant changes in detectable metabolite concentrations between DAT KO and wild-type (WT) mice. In contrast, alterations in the circuitry from the prefrontal cortex to the mesocortical limbic system, an important brain component intimately tied to function of mesolimbic/mesocortical dopamine reward pathways, were revealed by manganese-enhanced MRI (MEMRI). Analysis of co-registered MEMRI images taken over the 26 hours after introduction of Mn^(2+) into the prefrontal cortex indicated that DAT KO mice have a truncated Mn^(2+) distribution within this circuitry with little accumulation beyond the thalamus or contralateral to the injection site. By contrast, WT littermates exhibit Mn^(2+) transport into more posterior midbrain nuclei and contralateral mesolimbic structures at 26 hr post-injection. Thus, DAT KO mice appear, at this level of anatomic resolution, to have preserved cortico-striatal-thalamic connectivity but diminished robustness of reward-modulating circuitry distal to the thalamus. This is in contradistinction to the state of this circuitry in serotonin transporter KO mice where we observed more robust connectivity in more posterior brain regions using methods identical to those employed here