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molecular vs. physiological mode of action for sub-lethal effects

molecular vs. physiological mode of action for sub-lethal effects. Tjalling Jager, Bas Kooijman Olga Alda Álvarez, Jan Kammenga. toxicant. target site. ‘Classic’ mode of action …. Based on molecular target, e.g.: narcosis (cell membranes) uncoupling (mitochondria) AChE inhibition.

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molecular vs. physiological mode of action for sub-lethal effects

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  1. molecular vs. physiological mode of actionfor sub-lethal effects Tjalling Jager, Bas Kooijman Olga Alda Álvarez, Jan Kammenga

  2. toxicant target site ‘Classic’ mode of action … • Based on molecular target, e.g.: • narcosis (cell membranes) • uncoupling (mitochondria) • AChE inhibition • Popular for predicting acute LC50 Questions • Predictive for life-cycle and population? • To what extent species-specific?

  3. log concentration log descriptor sub-lethal QSARs? ECx

  4. A. nanus C. elegans body size EC10 body size reproduction reproduction time time What is sub-lethal ‘toxicity’? • ECx is a poor measure of ‘the toxicity’ • Species respond differently to PeCB

  5. toxicant target site molecular MoA physiological MoA What causes effects? toxicokinetics toxicodynamics rest of the organism ENERGY BUDGET effect on life cycle/population

  6. Energy budgets

  7. assimilation reproduction maintenance growth Energy budgets Each phys. MoA has specific effects on life cycle

  8. Population consequences

  9. Population consequences

  10. assimilation reproduction growth Population consequences Each phys. MoA has specific effects for populations maintenance

  11. Experiments nematodes Species • Caenorhabditis elegans and Acrobeloides nanus Chemicals • cadmium, pentachlorobenzene and carbendazim Exposure • in agar Endpoints • survival, body size, reproduction over full life cycle • analysed with extended DEBtox Studies published as: Alda Álvarez et al., 2005 (Func. Ecol.), 2006 (ES&T), 2006 (ET&C)

  12. Biology-based (DEBtox) toxicokinetics target parameter assimilation reproduction DEB model maintenance growth Life-cycle effects Kooijman & Bedaux, 1996 (Wat. Res.)

  13. A. nanus PeCB in A. nanus Effects on assimilation

  14. C. elegans PeCB in C. elegans Costs for growth and reproduction

  15. Physiological MoA nematodes

  16. Physiological MoA nematodes

  17. Physiological MoA nematodes

  18. Physiological MoA nematodes

  19. Conclusions ‘Molecular’ MoA is important, but … • not enough to predict effects life cycle/population • does not consider toxicodynamics ‘Physiological’ MoA gives extra information • includes toxicodynamics • direct link to population effects Clearly, species differ in phys. MoA …

  20. toxicant target site toxicant target site maintenance maintenance reproduction reproduction … … Species differences? Species A Species B

  21. toxicant target site phys. process maintenance effect on life cycle/population reproduction … Outlook Why useful? • number of chemicals and species is very large … • but number of target sites and processes is limited! ? Once we know the normal biological processes, all external stressors are merely perturbations of these processes (Yang et al., 2004) www.bio.vu.nl/thb

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