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ES 120 TOXICS IN THE ENVIRONMENT LECTURE 9 - 10: Biochemical and Physiological Effects of Pollutants SCOPE OF LECTURES • Coping and neutralization mechanisms • Intoxication mechanisms • Interactive effects BOTTOM LINE Pollutants are toxic because they interfere with normal biochemical and physiological processes. Molecular toxicity may translate into – – – – reduced growth and reproduction rates lower population densities altered community structures changed ecosystem functioning RESPONSES TO POLLUTANTS • Activation of mechanisms that aim to neutralize or to cope with pollutants • Toxicant effects proper NEUTRALIZATION AND COPING MECHANISMS • Reparation – Response to stress: induction of stress proteins. – General goal: maintaining homeostasis in presence of stressors • Sequestering • Biotransformation DNA repair after binding of mutagen, e.g. a polycyclic hydrocarbon COPING AND NEUTRALIZATION MECHANISMS • Reparation • Sequestering – Intracellular ionic concentrations of essential metals need to stay within tight margins – Metals such as Cu, Zn, Cd, Pb bind to S ligands of metallothionins – Metallothionin are cystein rich proteins – Expression of metallothionins increases after exposure to ‘heavy’ metals • Biotransformation cystein O HS OH NH2 SEQUESTERING AND DETOXICATION OF METALS COPING AND NEUTRALIZATION MECHANISMS • Reparation • Sequestering • Biotransformation – General result: lipophilicity is reduced and thus elimination is enhanced BIOTRANSFORMATION CONTINUED – Wide variety of enzymes of the P450 family, notably mixed function oxidases with low substrate specificity – Found in many tissues, especially in gut, liver (vertebrates), fat body and hepatopancreas (invertebrates) – Found in all types of organisms: natural detox system – Expression increases after exposure BIOTRANSFORMATION MAY INVOLVE 2 PHASES • Phase 1 transformation – Increasing water solubility by adding O or OH, breaking double bonds, removing groups • Phase 2 transformation – Increasing water solubility by adding polar groups such as sugars, sulfate or glutathione PHASE 1 TRANSFORMATIONS 1. Mixed Function Oxidases: Adding O, OH groups PHASE 1 TRANSFORMATIONS 2. Esterases: Breaking molecules at R1-O-R2 bonds 3. Hydrolases, reductases SPECIES DEPENDENCE OF PHASE 1 TRANSFORMATION ACTIVITY • Size • Phylum (invertebrates have lower MFO activity) • Food source • Environment ACTIVATION OF TOXICITY Some pollutants may be relatively harmless but become toxic after phase 1 transformation • Oxidation of organophosphorus insecticides yields potent inhibitors of central nervous system • Oxidation of some PAHs, vinyl chloride and aflatoxin yields carcinogens PHASE 2 TRANSFORMATIONS Adding polar groups • Glucuronic acid • Sulfate • Amino acid (glutathione) Next Lecture • Biochemical and Physiological Effects, continued • Homework: – Toxicokinetics assignment – Read 8.1 – 8.4.1, 9 RESPONSES TO POLLUTANTS • Activation of mechanisms that aim to neutralize or cope with pollutants • Toxicant effects proper GENERAL VERSUS SPECIFIC TOXICITY • Mode of action – General: multiple target sites in different tissues, e.g. Pb, Cd, “anesthetic” compounds – Specific: a single site in a specific tissue, e.g. neurotoxic compounds • Species dependence – Presence/ absence of target site – Coping and neutralization mechanisms • Life stage dependence – Teratogenic effects In pharmacology “anesthetic” refers to compounds that change physicochemical properties of lipid bilayers TERATOGENIC EFFECTS: SENSITIVITY DEPENDS ON LIFE OR DEVELOPMENTAL STAGE INTOXICATION MECHANISMS I 1. Genotoxic compounds. Compounds that bind to DNA (adducts) may cause mutations when repair mechanisms fail • PAHs, vinyl chloride, aflatoxin after activation by MFO 2. Neurotoxic compounds NEUROTOXIC ACTION Neurotoxic compounds affect signal transduction • Deterioration of myelin sheet – TCOP, gas additive and plasticizer • Inhibition of acetylcholinesterases: acetylcholine remains bound and active at receptor causing muscles to stay contracted (tetanus) – Organophosphorus insecticides • Retarded closure of sodium channels, leading to uncoordinated muscle tremors • Blocking GABA controlled chloride/potassium channels, causing convulsions (vertebrates) INTOXICATION MECHANISMS II 3. Vitamin K antagonists inhibit production of blood clotting proteins • Warfarin, flocoumafen 4. Mitochondrial poisons 5. Chloroplast poisons MITOCHONDRIAL TOXICITY • Dissipation of proton motive force: uncoupling by weak acids • Inhibition of enzyme complexes: cyanide, rotenone, cadmium PHYTOTOXICITY • Dissipation of proton motive force: uncoupling by weak acids • Inhibition of enzyme complexes: triazines INTOXICATION MECHANISMS III 6. ATPase inhibitors. ATPases are proton pumps involved in osmoregulation • 7. DDE inhibits Ca-ATPase in avian oviduct causing thin egg shells Non-competitive inhibition of enzymes • 8. Pb, Hg, Cd ions bind to sulfhydryl groups of enzymes Plant growth hormone analogues • 9. Uncontrolled growth of vascular tissue Endocrine disruptors • • • Estrogenic compounds leading to feminization, e.g. vitellogenin production in male fish Androgenic compounds leading to masculinization, e.g. imposex in gastropods Organochlorine insecticides, phtalates, nonylphenols, tributyltin INTERACTIVE EFFECTS • In natural environments organisms are usually exposed to a mixture of pollutants • How do pollutants interact in organisms? INTERACTIVE EFFECTS • Additive effects: – net toxicity is the sum of the toxicities of individual pollutants – most common effect – pollutants with similar intoxication mechanisms • Antagonistic effects – net toxicity is less than the sum of the toxicities of individual pollutants • Synergistic effects – net toxicity is greater than the sum of the toxicities of individual pollutants: potentiation POTENTIATION 1. Inhibition of detoxication – One compound inhibits enzyme system that detoxifies another compound – Piperonyl butoxide, some fungicides and organophosphorus insecticides inhibit phase 1 transformation of pyrethroid and carbamate insecticides 2. Stimulation of activation – One compounds induces the expression of enzyme system that activates toxicity of another – Activation of malathion by fungicides – Activation of PAHs by PCBs, dioxins SUMMARY • Coping and neutralization mechanisms • Intoxication mechanisms • Interactive effects Next Lecture • Effects on individual organisms • Homework: – Read “From Molecules to Ecosystems through Dynamic Energy Budget Models” – Read 8.4.2 - 8.7 – Read “Case Studies” (download)