10 – BIOMARKERS Introduction

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Presentation transcript:

10 – BIOMARKERS Introduction BIOMARKERS AND TOXICITY MECHANISMS 10 – BIOMARKERS Introduction Luděk Bláha, PřF MU, RECETOX www.recetox.cz

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)

Biomarkers in ECOLOGY / GEOLOGY

Biomarkers in HUMAN HEALTH Potential applications of biomarkers:

Biomarkers in HUMAN HEALTH … a lot of work

Biomarkers in HUMAN HEALTH … a lot of work

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)

Biomarkers & Exposure h: homeostatic conditions c: reversible stage Health effect intensity 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 ! Stressor / time Biomarker intensity Stressor / time

Ideal biomarker

Biomarkers at different levels of biological organisation

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

Various biomarker types Specific (selective) in vivo biomarkers Biomarkers 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 Biomarkers of general stress E.g. induction of Heat Shock Proteins (hsp) + general information about stress - sensitive to many "stressors" (temperature, salinity ...)

Sampling biological materials for biomarker analyses Non-destructive (non-invasive) blood / haemolymph collection & analyses skin, feather, hair … (life of the organism not affected) Destructive (invasive) whole animal  3R principles: maximum use of the material multiple biomarker evaluation

EXAMPLE - Paracetamol

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

Toxicity biomarkers – examples

Other examples Toxicity biomarkers