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.

Lysosomal responses to nutritional and contaminant stress in mussel hepatopancreatic digestive cells: a modelling study.

The lysosomal system occupies a central and crucial role in cellular food degradation (intracellular digestion), toxic responses and internal turnover (autophagy) of the hepatopancreatic digestive cell of the blue mussel Mytilus edulis. Understanding the dynamic response of this system requires factors affecting performance, conceived as a function of the throughput, degradative efficiency and lysosomal membrane stability, to be defined and quantified. A previous carbon/nitrogen flux model has been augmented by separately identifying lysosomal 'target' material (autophagocytosed or endocytosed proteins, carbohydrates and lipids) and 'internal' material (digestive enzymes and lipid membrane components). Additionally, the whole cell's energetic costs for maintaining lysosomal pH and production of these internal components have been incorporated, as has the potentially harmful effect of generation of lipofuscin on the transitory and semi-permanent lysosomal constituents. Inclusion of the three classes of nutrient organic compounds at the whole cell level allows for greater range in the simulated response, including deamination of amino acids to provide molecules as a source of energy, as well as controlling nitrogen and carbon concentrations in the cytosol. Coupled with a more functional framework of pollutant driven reactive oxygen species (ROS) production and antioxidant defence, the separate and combined effects of three stressors (nutritional quality, nutrient quantity and a polycyclic aromatic hydrocarbon [PAH-phenanthrene]) on the digestive cell are simulated and compare favourably with real data.

Towards computational models of cells for environmental toxicology.

This paper outlines an approach to the development of computational models of cells for marine environmental toxicology. Exposure of cells to pollutants can lead to lysosomal damage and dysfunction, augmented autophagy, cellular dysfunction and atrophy and ultimately tissue pathology and organ damage. The application of carbon and nitrogen based models of intra cellular vesicular traffic for simulating the autophagic and lysosomal response of the hepatopancreatic digestive cells of marine molluscs is described. Two numerical models of the vesicular transport of carbon and nitrogen in the cell are presented. These demonstrate the importance of endocytotic uptake as a driver of lysosomal dynamics and the need to recognize and model it as a discrete process. Conceptual and mathematical models of the toxic impact of polycyclic aromatic hydrocarbons on the digestive gland are presented. The role of experimental research and the need to integrate it with modelling is highlighted.

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.