molecular vs. physiological mode of action for sub-lethal effects
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molecular vs. physiological mode of action for sub-lethal effects Tjalling Jager, Bas Kooijman Olga Alda Álvarez, Jan Kammenga
description
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. - PowerPoint PPT Presentation
Transcript of 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
‘Classic’ mode of action …
Based on molecular target, e.g.:• narcosis (cell membranes)• uncoupling (mitochondria)• AChE inhibition
target sitetoxicant
Questions Predictive for life-cycle and population? To what extent species-specific?
Questions Predictive for life-cycle and population? To what extent species-specific?
Popular for predicting acute LC50
sub-lethal QSARs?
ECx
log descriptor
log
co
nce
ntr
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n
Cl
Cl
Cl Cl
Cl
What is sub-lethal ‘toxicity’?
ECx is a poor measure of ‘the toxicity’ Species respond differently to PeCB
ECx is a poor measure of ‘the toxicity’ Species respond differently to PeCB
EC
10
time time
body sizebody size
reproduction reproduction
A. nanus
C. elegans
Cl
Cl
Cl Cl
Cl
What causes effects?
effect onlife cycle/population
ENERGYBUDGET
toxicodynamicstoxicokinetics
rest of the organismtarget sitetoxicant
molecular MoA
physiological MoA
Energy budgets
Energy budgets
growth
reproduction
assimilation
Each phys. MoA has
specific effects on life cycle
Each phys. MoA has
specific effects on life cycle
maintenance
Population consequences
Population consequences
Population consequences
growth
reproduction
maintenance
assimilation
Each phys. MoA has
specific effects for populations
Each phys. MoA has
specific effects for populations
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)
reproduction
DEB model
Biology-based (DEBtox)
targetparameter
toxicokinetics
growthmaintenance
assimilation
Life-cycle effectsKooijman & Bedaux, 1996 (Wat. Res.)
PeCB in A. nanus
0 5 10 15 20 25 3015
20
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time (days)
bo
dy
len
gth
020406080
0 5 10 15 20 25 30 35 400
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time (days)
cum
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tive
off
sp
rin
g
020406080
Effects on assimilation
A. nanus
PeCB in C. elegans
0 2 4 6 8 10 120
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time (days)
bo
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gth
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0 2 4 6 8 10 12 14 160
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time (days)
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Costs for growth and reproduction
C. elegans
Physiological MoA nematodes
C. elegans A. nanus
PeCB(narcotic)
Cadmium(heavy metal)
Carbendazim(inhibits mitosis)
Physiological MoA nematodes
C. elegans A. nanus
PeCB(narcotic)
costs for growth and reproduction
assimilation
Cadmium(heavy metal)
Carbendazim(inhibits mitosis)
Physiological MoA nematodes
C. elegans A. nanus
PeCB(narcotic)
costs for growth and reproduction
assimilation
Cadmium(heavy metal)
assimilation costs for growth
(+ ageing)
Carbendazim(inhibits mitosis)
Physiological MoA nematodes
C. elegans A. nanus
PeCB(narcotic)
costs for growth and reproduction
assimilation
Cadmium(heavy metal)
assimilation costs for growth
(+ ageing)
Carbendazim(inhibits mitosis)
assimilation assimilation
(- ageing)
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 …
Species differences?
Species A Species B
target sitetoxicanttarget sitetoxicant
maintenance
reproduction
…
maintenance
reproduction
…
target sitetoxicant phys. process
effect onlife cycle/population
maintenance
reproduction
…
Outlook
?
Why useful? number of chemicals and species is very large … but number of target sites and processes is limited!
www.bio.vu.nl/thbwww.bio.vu.nl/thb
Once we know the normal biological processes, all external stressors are merely perturbations of these processes (Yang et al., 2004)
Once we know the normal biological processes, all external stressors are merely perturbations of these processes (Yang et al., 2004)
