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 Luděk Bláha, PřF MU, RECETOX
www.recetox.cz
BIOMARKERS AND TOXICITY MECHANISMS
10 – BIOMARKERS
Introduction
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Definition and applications
•- markers in biological systems with a sufficently long half-life which allow location where in
the biological system change occur and to quantify the change.
•
•Various definitions and applications of „biomarkers“
–– Ecology / Geology
-Human health and diseases
-Toxicology (special focus in this class)

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Biomarkers in ECOLOGY / GEOLOGY
http://www.birmingham.ac.uk/Images/College-LES-only/GEES/staff-research/high-utility-biomarker-appl
ications.jpg

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Biomarkers in HUMAN HEALTH
http://www.nature.com/nrd/journal/v12/n5/images/nrd3979-f1.jpg
Examples of biomarker
applications
in human health:

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Biomarkers in TOXICOLOGY
-Identification of markers of long-term risks
-Human: health, toxicology and carcinogenesis
-Ecotoxicology: early markers of toxic effects
-
-BIOMARKER
-Change which occurs as response to "stressors“ (xenobiotics, disease, temperature...) extending
the adaptive response beyond the normal range
-In vivo biomarkers:
-changes measured in stressed organisms ("classical biomarkers")
-In vitro biomarkers
-in vitro testing characterizing potencies  of xenobiotic to induce specific biological activity
(or toxicity mechanism)
-= biological potencies (markers of potential hazards)
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Biomarkers - classification
•Categorization by US National Academy of Sciences
• - Biomarkers of exposure
• - Biomarkers of response or effect
• - Biomarkers of susceptibility
•
•Continuum exists among biomarkers
• example: adducts of toxicant to DNA
    ? biomarker of exposure /  ? response
•
•

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Various biomarker types
•Specific (selective) in vivo biomarkers
ØBiomarkers selectively reflecting specific types (mechanisms) of toxicity
•E.g. inhibition of AcCholE :
exposure = organophosphates; effect = neurotoxicity
•
• + provides specific information
• -  multiple biomarkers must be measured in parallel
•
•
•Non-specific (non-selective) in vivo biomarkers
ØBiomarkers of general stress
•E.g. induction of Heat Shock Proteins (hsp)
•
• + general information about stress
• - sensitive to many "stressors" (temperature, salinity ...)
•
•

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Biomarkers
at different
levels
of biological
organisation
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These
mainly
covered
in this
class

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Sampling biological materials for biomarker analyses
•Non-destructive (non-invasive)
–blood / haemolymph collection & analyses
–skin, feather, hair, urine …
–(life of the organism not affected)
•
•Destructive (invasive)
–whole animal
à 3R principles: maximum use of the material
–multiple biomarker evaluation
•
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Biomarkers
& Exposure
•
•
•
•h: homeostatic conditions
•c: reversible stage
•r: irreversible effects of pollutants
-
-
•Various biomarker profiles
- temporal changes–B2; B4
•
• - repeated occurrence (B5)
•
 - continuous increase (B1)
• - increase with maximum (B3)
•
•: B1 + B3 are candidate biomarkers !
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Biomarker intensity
Health effect intensity
Stressor / time
Stressor / time

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Ideal biomarker
http://www.jcancer.org/v01/p0150/jcav01p0150g01.jpg

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Towards the practical use of biomarkers … a lot of work
http://www.molecularmedicineireland.ie/uploads/BiomarkerImage_210910.jpg
PROPER VALIDATION (!) IS
THE MOST DEMANDING STEP

EXAMPLE
- Paracetamol
http://upload.wikimedia.org/wikipedia/commons/thumb/1/12/Paracetamol_metabolism.svg/2000px-Paraceta
mol_metabolism.svg.png

EXAMPLE
- Paracetamol
•
•
•
•
•
•
(1)paracetamol
(2)parent compound measurement - biomarker of exposure
(3)activation to reactive metabolite (N-ac-p-benzoquinone, NAPQI) by CYP
à reaction with GSH / measurement – levels of CYPs; levels of GSH – susceptibility
(4)GSH-NAPQI conjugate – exposure, susceptibility
(5)NAPQI-protein adducts à toxicity: exposure, effective dose
(6)adaptations: GSH depletion, inhibition of protein synthesis – biomarkers of response
(7)protein alkylation à degeneration of hepatocytes: necrosis
à increase concentrations of bilirubin in plasma + inflammation - response / effect
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Toxicity biomarkers – examples
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