Biomedical subjects

Michael N Moore

Publications and source records attributed to Michael N Moore.

9 recordsLinked to original sources

PubMed2006

Lysosomal and autophagic reactions as predictive indicators of environmental impact in aquatic animals.

The lysosomal-autophagic system appears to be a common target for many environmental pollutants as lysosomes accumulate many toxic metals and organic xenobiotics, which perturb normal function and damage the lysosomal membrane. In fact, lysosomal membrane integrity or stability appears to be an effective generic indicator of cellular well-being in eukaryotes: in bivalve molluscs and fish, stability is correlated with many toxicological responses and pathological reactions. Prognostic use of adverse lysosomal and autophagic reactions to environmental pollutants has been explored in relation to predicting cellular dysfunction and health in marine mussels, which are extensively used as sensitive bioindicators in monitoring ecosystem health. Derivation of explanatory frameworks for prediction of pollutant impact on health is a major goal; and we have developed a conceptual mechanistic model linking lysosomal damage and autophagic dysfunction with injury to cells and tissues. This model has also complemented the creation of a cell-based computational model for molluscan hepatopancreatic cells that simulates lysosomal, autophagic and other cellular reactions to pollutants. Experimental and simulated results have also indicated that nutritional deprivation-induced autophagy has a protective function against toxic effects mediated by reactive oxygen species (ROS). Finally, coupled measurement of lysosomal-autophagic reactions and modelling is proposed as a practical toolbox for predicting toxic environmental risk.

Animals↗

PubMed2006

Autophagy: role in surviving environmental stress.

This conceptual paper addresses the role of lysosomal autophagy in cellular defence against oxidative stress. A hypothesis is proposed that autophagic removal of oxidatively damaged organelles and proteins provides a second tier of defence against oxidative stress. Age pigment or lipofuscin is a product of oxidative attack on proteins and lipids and can accumulate in lysosomes, where it can generate reactive oxygen species (ROS) and inhibit lysosomal function, resulting in autophagic failure. It is further hypothesised that repeated triggering of augmented autophagy can protectively minimise lipofuscin generation; and that animals living in fluctuating environments, where autophagy is repeatedly stimulated by natural stressors, will be generically more tolerant of pollutant stress. Data for resistance to pollutant stress is presented, together with evidence for a correlation between lysosomal stability and macrobenthic diversity. Finally, we speculate that organisms making up functional ecological assemblages in fluctuating environments, where up-regulation of autophagy should provide a selective advantage, may be pre-selected to be tolerant of pollutant-induced oxidative stress.

Animals↗

PubMed2005

Environmental prognostics: an integrated model supporting lysosomal stress responses as predictive biomarkers of animal health status.

The potential prognostic use of lysosomal reactions to environmental pollutants is explored in relation to predicting animal health in marine mussels, based on diagnostic biomarker data. Cellular lysosomes are already known to accumulate many metals and organic xenobiotics and the lysosomal accumulation of the carcinogenic polycyclic aromatic hydrocarbon 3-methylcholanthrene (3-MC) is demonstrated here in the hepatopancreatic digestive cells and ovarian oocytes of the blue mussel. Lysosomal membrane integrity or stability appears to be a generic indicator of cellular well-being in eukaryotes; and in bivalve molluscs it is correlated with total oxygen and nitrogen radical scavenging capacity (TOSC), protein synthesis, scope for growth and larval viability; and inversely correlated with DNA damage (micronuclei), as well as lysosomal swelling (volume density), lipidosis and lipofuscinosis, which are all characteristic of failed or incomplete autophagy. Integration of multiple biomarker data is achieved using multivariate statistics and then mapped onto "health status space" by using lysosomal membrane stability as a measure of cellular well-being. This is viewed as a crucial step towards the derivation of explanatory frameworks for prediction of pollutant impact on animal health; and has facilitated the development of a conceptual mechanistic model linking lysosomal damage and autophagic dysfunction with injury to cells, tissues and the whole animal. This model has also complemented the creation and use of a cell-based bioenergetic computational model of molluscan hepatopancreatic cells that simulates lysosomal and cellular reactions to pollutants. More speculatively, the use of coupled empirical measurements of biomarker reactions and modelling is proposed as a practical approach to the development of an operational toolbox for predicting the health of the environment.

Animal Structures↗

PubMed2004

An integrated biomarker-based strategy for ecotoxicological evaluation of risk in environmental management.

Environmental impacts by both natural events and man-made interventions are a fact of life; and developing the capacity to minimise these impacts and their harmful consequences for biological resources, ecosystems and human health is a daunting task for environmental legislators and regulators. A major challenge in impact and risk assessment, as part of integrated environmental management (IEM), is to link harmful effects of pollution (including toxic chemicals) in individual sentinel animals to their ecological consequences. This obstacle has resulted in a knowledge-gap for those seeking to develop effective policies for sustainable use of resources and environmental protection. Part of the solution to this problem may lie with the use of diagnostic clinical-type laboratory-based ecotoxicological tests or biomarkers, utilising sentinel animals as integrators of pollution, coupled with direct immunochemical tests for contaminants. These rapid and cost-effective ecotoxicological tools can provide information on the health status of individuals and populations based on relatively small samples of individuals. In the context of ecosystem status or health of the environment, biomarkers are also being used to link processes of molecular and cellular damage through to higher levels (i.e., prognostic capability), where they can result in pathology with reduced physiological performance and reproductive success. Complex issues are involved in evaluating environmental risk, such as the effects of the physico-chemical environment on the speciation and uptake of pollutant chemicals and inherent inter-individual and inter-species differences in vulnerability to toxicity; and the toxicity of complex mixtures. Effectively linking the impact of pollutants through the various hierarchical levels of biological organisation to ecosystem and human health requires a pragmatic integrated approach based on existing information that either links or correlates processes of pollutant uptake, detoxication and pathology with each other and higher level effects. It is further proposed here that this process will be facilitated by pursuing a holistic or whole systems approach with the development of computational simulation models of cells, organs and animals in tandem with empirical data (i.e., the middle-out approach). In conclusion, an effective integrated environmental management strategy to secure resource sustainability requires an integrated capability for risk assessment and prediction. Furthermore, if such a strategy is to influence and help in the formulation of environmental policy decisions, then it is crucial to demonstrate scientific robustness of predictions concerning the long-term consequences of pollution to politicians, industrialists and environmental managers; and also increase stakeholder awareness of environmental problems.

Animals↗

PubMed2004

Editorial: computational modelling of cell & tissue processes & function.

Computational modelling of whole biological systems from cells to organs is gaining momentum in cell biology and disease studies. This pathway is essential for the derivation of explanatory frameworks that will facilitate the development of a predictive capacity for estimating outcomes or risk associated with particular disease processes and therapeutic or stressful treatments. This article introduces a series of invited papers covering a hierarchy of issues and modelling problems, ranging from crucial conceptual considerations of the validity of cellular modelling through to multi-scale modelling up to organ level. The challenges and approaches in cellular modelling are described, including the potential of 'in silico ' modelling applications for receptor-ligand interactions in cell signalling, simulated organ dysfunction (i.e., heart), human and environmental toxicity and the progress of the IUPS Physiome Project. A major challenge now facing biologists is how to translate the wealth of reductionist detail about cells and tissues into a real understanding of how these systems function and are perturbed in disease processes. In biomedicine, simulation models of biological systems now contain sufficient detail, not only to reconstruct normal functions, but also, to reconstruct major disease states. More widely, simulation modelling will aid the targeting of current 'knowledge gaps' and how to fill them; and also provide a research tool for selecting critical factors from multiple simulated experiments for real experimental design. The envisaged longer-term end- product is the creation of simulation models for predicting drug interactions and harmful side-effects; and their use in therapeutic and environmental health risk management. Finally, we take a speculative look at possible future scenarios in cellular modelling, where it is envisioned that integrative biology will move from being largely qualitative and instead become a highly quantitative, computer-intensive discipline.

Cell Physiological Phenomena↗

PubMed2002

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.

Animals↗

PubMedDate not supplied

Diet restriction induced autophagy: a lysosomal protective system against oxidative- and pollutant-stress and cell injury.

Nutrient deprivation or dietary restriction (DR) confers protection against ageing and stress in many animals and induced lysosomal autophagy is part of this mechanism. The effects of dietary restriction on the toxicity of copper and the polycyclic aromatic hydrocarbon phenanthrene have been investigated in the common marine mussel Mytilus edulis. The findings show that DR-induced autophagy facilitates the recovery of the digestive gland (i.e., molluscan liver analogue) from cell injury caused by both copper and phenanthrene. It is inferred that DR-induced autophagy and lysosomal proteolysis results in improved cellular "housekeeping" through the more efficient removal of oxidatively and pollutant damaged proteins (e.g., protein carbonyls, protein adducts, etc.) and that this contributes to stress resistance.

Animals↗

PubMedDate not supplied

Environmental prognostics: is the current use of biomarkers appropriate for environmental risk evaluation?

Environmental Prognostics is proposed as an integrated explanatory framework for adverse changes in whole systems, from cells to animals to ecosystems. The aim is to develop such frameworks for the evaluation of "health of the environment" and prediction of consequences resulting from future environmental events based on integrating the reactions of biomarkers for cellular and physiological processes, through conceptual, statistical and computational modelling. These are urgently needed to synthesise complex information on environmental chemistry and injurious effects of pollutants into predicted harmful impact on health of sentinel animals.

Biomarkers↗

PubMedDate not supplied

A computational model of the digestive gland epithelial cell of marine mussels and its simulated responses to oil-derived aromatic hydrocarbons.

This paper describes a computational model of digestive gland epithelial cells (digestive cells) of marine mussels. These cells are the major environmental interface for uptake of contaminants, particularly those associated with natural particulates that are filtered from seawater by mussels. Digestive cells show well characterised reactions to exposure to lipophilic xenobiotics, such as oil-derived aromatic hydrocarbons (AHs), which accumulate in these cells with minimal biotransformation. The simulation model is based on processes associated with the flux of carbon through the cell. Physiological parameters such as fluctuating food concentration, cell volume, respiration, secretion/excretion, storage of glycogen and lipid, protein/organelle turnover (autophagy/resynthesis) and export of carbon to other tissues of the mussel are all included in the model. The major response to AHs is induction of increased autophagy in these cells. Simulations indicate that the reactions to AHs and food deprivation correspond well with responses measured in vivo.

Animals↗