Biocomplexity: the post-genome challenge in ecotoxicology

There are four crucial challenges for the environmental toxicologists in the next decade: (1) understanding the mechanisms of molecular and subcellular interactions with pollutant chemicals, including genomic and proteomic aspects; (2) the development of predictive simulation models of toxic effects on complex cellular and physiological processes; (3) linking molecular, cellular and patho-physiological 'endpoints' with higher level ecological consequences; and (4) precautionary anticipation of possible harmful impacts of novel developments in industrial processes, including biotechnology and nanotechnology. One of the major difficulties in ecotoxicology is to link harmful effects of chemical pollutants in individual animals and plants with the ecological consequences. Consequently, this obstacle has resulted in a 'knowledge-gap' for those seeking to develop policies for sustainable use of resources and environmental protection. The overall problem is: how to develop effective procedures for environmental/ecological impact and risk assessment? However, the use of diagnostic 'clinical-type' tests or 'biomarkers' has started to provide information on the health-status of populations based on relatively small samples of individuals. Also, biomarkers can now be used to begin to link processes of molecular and cellular damage through to the higher levels (i.e. prognostic capability), where they can result in reduced performance and reproductive success. Research effort to meet this challenge must be inter-disciplinary in character, since the key questions mainly involve complex interfacial problems. These include effects of physico-chemical speciation on uptake and toxicity, the toxicity of complex mixtures; and linking the impact of pollutants through the various hierarchical levels of biological organisation to ecosystem and human health. Finally, the development and use of process-based computational simulation models (i.e. 'virtual' cells, organs and animals), illustrated using an endosomal/lysosomal uptake and cell injury model, will facilitate the development of a predictive capacity for estimating risk associated with the possibility of future environmental events.     

A review of the aquatic ecotoxicology of polychlorinated dibenzo-p-dioxins and dibenzofurans

This paper reviews published studies on polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans that are relevant to an assessment of their aquatic ecotoxicology. The available data suggest that laterally substituted congeners containing altogether 4,5, or 6 chlorine atoms are highly toxic, particularly to the early life stages of fish, with reported effect concentrations in the ng L¹ range. These congeners are also the most readily bioaccumulated. An aquatic toxicity threshold concentration of 0.011–0.038 ng L^?1, applicable to natural ecosystems, was determined for 2,3,7,8-tetrachlorodibenzo-p-dioxin (or for mixtures of congeners expressed as 2,3,7,8-TCDD equivalents). This threshold corresponds to the no observed effect concentration/lowest-observed effect concentration determined for mortality, growth, and behavioral effects seen in rainbow trout early life stages, exposed to 2,3,7,8-TCDD in a flow-through system over a 28-day period, followed by 28 days of depuration. An investigation was also made into the potential for using mammalian-derived toxic equivalency factors (TEFs) in aquatic ecosystems. This revealed that such an approach may underestimate the aquatic toxicity of some congeners, and that the use of organism-specific TEFs may be more appropriate. © by John Wiley & Sons, Inc.     

Ecotoxicogenomics: linkages between exposure and effects in assessing risks of aquatic contaminants to fish

Understanding the biological effects of exposures to chemicals in the environment relies on classical methods and emerging technologies in the areas of genomics, proteomics, and metabonomics. Linkages between the historical and newer toxicological tools are currently being developed in order to predict and assess risk. Being able to classify chemicals and other stressors based on effects they have at the molecular, tissue, and organismal levels helps define a systems biology approach to development of streamlined, cost-effective, and comprehensive testing approaches for evaluating environmental hazards. The challenges of the individual technologies and the combinations of tools for ecotoxicogenomics are discussed in application to aquatic toxicology with a particular emphasis on fish testing.     

From genetics and genomics to drug discovery: yeast rises to the challenge

Yeast expands its role from eukaryotic genetics and genomics to drug discovery.     

Translational research into sexual disorders: pharmacology and genomics

The existence of sexual dysfunctions in men, including premature and retarded ejaculation poses challenges to develop translational models in rats that may help in improving treatment and delineate the neural mechanisms of action. Most of our current understanding of the neurobiology, neuroanatomy and psychopharmacology of sexual behavior and ejaculatory function has been derived from preclinical studies in the rat. When large populations of male rats are tested on sexual activity during four successive tests, over time individual rats display a very stable sexual behavior that is either slow, normal or fast as characterized by the number of ejaculations performed. These sexual endophenotypes are postulated as rat counterparts of premature (fast rats) or retarded ejaculation (slow rats). Psychopharmacology in these endophenotypes may help to delineate the underlying mechanisms and pathology. This is illustrated by the effects of serotonergic antidepressants and serotonergic compounds on sexual and ejaculatory behavior of rats. Further unravelling of sexual endophenotypes may benefit from the use of chromosomal substitution strains in mice that enable the localization of relevant chromosomal areas and genes involved in ejaculation processes. These preclinical studies and models contribute to a better understanding of the neurobiology of ejaculation and boost the development of novel drug targets to treat ejaculatory disorders such as premature and retarded ejaculation.     

Polymer genomics: an insight into pharmacology and toxicology of nanomedicines

Synthetic polymers and nanomaterials display selective phenotypic effects in cells and in the body signal transduction mechanisms involved in inflammation, differentiation, proliferation, and apoptosis. When physically mixed or covalently conjugated with cytotoxic agents, bacterial DNA or antigens, polymers can drastically alter specific genetically controlled responses to these agents. These effects, in part, result from cooperative interactions of polymers and nanomaterials with plasma cell membranes and trafficking of polymers and nanomaterials to intracellular organelles. Cells and whole organism responses to these materials can be phenotype or genotype dependent. In selected cases, polymer agents can bypass limitations to biological responses imposed by the genotype, for example, phenotypic correction of immune response by polyelectrolytes. Overall, these effects are relatively benign as they do not result in cytotoxicity or major toxicities in the body. Collectively, however, these studies support the need for assessing pharmacogenomic effects of polymer materials to maximize clinical outcomes and understand the pharmacological and toxicological effects of polymer formulations of biological agents, i.e. polymer genomics.     

The SeeDs approach: integrating fragments into drug discovery

Finding novel compounds as starting points for optimization is a major challenge in drug discovery research. Fragment-based methods have emerged in the past ten years as an effective way to sample chemical diversity with a limited number of low molecular weight compounds. The structures of the fragments(s) binding to the protein can then be used to design new compounds with increased affinity, specificity and novelty. This article describes the Vernalis approach to fragment based drug discovery, called SeeDs (Structural exploitation of experimental Drug startpoints). The approach includes the design of a fragment library, identification of fragments that bind competitively to a target by ligand-based NMR techniques and protein crystal structures to characterize binding. Fragments that bind are then evolved to hits, either by growing the fragment or by combining structural features from a number of compounds. The process is illustrated with examples from recent medicinal chemistry programmes to discover compounds against the oncology targets Hsp90 and PDK1. In addition, we summarise our experience with using molecular docking calculations to predict fragment binding and anecdotes on the selectivity and binding modes for fragments seen against a range of targets.     

A review on the toxicity and non-target effects of macrocyclic lactones in terrestrial and aquatic environments

The avermectins, milbemycins and spinosyns are collectively referred to as macrocyclic lactones (MLs) which comprise several classes of chemicals derived from cultures of soil micro-organisms. These compounds are extensively and increasingly used in veterinary medicine and agriculture. Due to their potential effects on non-target organisms, large amounts of information on their impact in the environment has been compiled in recent years, mainly caused by legal requirements related to their marketing authorization or registration. The main objective of this paper is to critically review the present knowledge about the acute and chronic ecotoxicological effects of MLs on organisms, mainly invertebrates, in the terrestrial and aquatic environment. Detailed information is presented on the mode-of-action as well as the ecotoxicity of the most important compounds representing the three groups of MLs. This information, based on more than 360 references, is mainly provided in nine tables, presenting the effects of abamectin, ivermectin, eprinomectin, doramectin, emamectin, moxidectin, and spinosad on individual species of terrestrial and aquatic invertebrates as well as plants and algae. Since dung dwelling organisms are particularly important non-targets, as they are exposed via dung from treated animals over their whole life-cycle, the information on the effects of MLs on dung communities is compiled in an additional table. The results of this review clearly demonstrate that regarding environmental impacts many macrocyclic lactones are substances of high concern particularly with larval instars of invertebrates. Recent studies have also shown that susceptibility varies with life cycle stage and impacts can be mitigated by using MLs when these stages are not present. However information on the environmental impact of the MLs is scattered across a wide range of specialised scientific journals with research focusing mainly on ivermectin and to a lesser extent on abamectin doramectin and moxidectin. By comparison, information on compounds such as eprinomectin, emamectin and selamectin is still relatively scarce.     

Incorporating exposure into aquatic toxicological studies: an imperative

The field of aquatic toxicology has been expanding rapidly in recent years. The ecotoxicological study of environmental toxicants encompasses three basic frameworks: environmental behavior/transport, bioavailability/bioaccumulation (exposure), and toxicity at different biological levels. Environmental risk assessments are then based on this knowledge to provide sound advice for environmental management and policies. In this article I will highlight the need to further understand the exposure to toxicants and its direct relationship with toxicological responses at different levels. Exposure considerations generally include the route, species, concentration and duration of exposure, among which the importance of the exposure route has been little considered. A typical aquatic toxicological study simply exposes the organisms to toxicants in the water for a certain period of time under different concentrations. This approach may not be environmentally relevant. Future studies should attempt to understand the toxicology under different exposure regimes. Incorporating exposure will allow aquatic toxicology to be placed in a context of environmental relevance and enhance our understanding of the impacts of toxicants on our living environments.