Transcript ES 120 TOXICS IN THE ENVIRONMENT

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
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–
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
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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
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7.
DDE inhibits Ca-ATPase in avian oviduct causing thin egg
shells
Non-competitive inhibition of enzymes
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8.
Pb, Hg, Cd ions bind to sulfhydryl groups of enzymes
Plant growth hormone analogues
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9.
Uncontrolled growth of vascular tissue
Endocrine disruptors
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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)