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Lecture 14

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Department
Biology
Course
BIOL 354
Professor
Bruce Greenberg
Semester
Summer

Description
BIOL354 – Environmental Toxicology I Spring 2012 Lecture 14 – Biochemical and Physiological Effects of Chemicals – Part II Organic Pollutants - Organics: Complex molecules compare to inorganics, more specific interactions & more mechanisms. Polycyclic Aromatic Hydrocarbons (PAHs) (Fused Benzene Rings) - Low water solubility, lipophillic (Membrane accumulation). - Innate form is relatively unreactive/stable, are pro-carcinogens & causes narcosis only @ high []s. - Can be metabolized & are photoactive (absorbs UV radiation ↑ toxicity), do not magnify. o E.g. Cigarette, nicotine do not cause cancer but addiction; the most stable PAH - Benzo(a)pyrene is formed during combustion & it is carcinogenic.  Not direct cause & effect but Benzo(a)pyrene is one of the major carcinogens in cigarettes (correlations only, not proof – tests are too expensive to conduct) - oxyPAHs/PAH quinones (Oxidized aromatic compounds): Highly reactive, very toxic @ low []s, cytotoxic, genotoxic & mutagenic (carcinogenic). - 3 Mechanisms to Activate PAHs: o Photochemical Activation  PAHs within the organism absorbs UV radiation as exposed to light (Photosensitization)  Pre exposure of PAHs (In or out of the cell) to UV → Photomodification/Photooxidation of PAHs → Production of oxyPAHs  Mechanisms of Photo-induced Toxicity 1 -  PAH ground state: singlet PAHs (↑↓e spin is -0.5 + 0.5 = 0)  1PAH*: Activated as it absorbs a photon (hν) → Excited & Singlet state, then PAH* → 3PAH* (↑↑, change in e spin direction) 3 -  Oxygen ground state: triplicate O (2↑e spin is 0.5 + 0.5 = 1), not reactive with singlet state biomolecules.  Photomodification/Photooxidation: PAH* reacts with O to form oxyPAHs 3 3 1 2  Photosensitization: PAH* transfers energy to O → O2 2 o 1O 2excited & singlet) reacts w/ singlet state biomolecules → Tissue damage  Photomodification (oxyPAHs Production): PAHs can be inside or outside of the organism.  E.g. Anthroquinone → 1, 2-dihydroxy-anthroquinone (Inhibits photosynthesis & respiration) 1  Photosensitization ( O 2roduction): PAHs must be in the organism (transparent organisms are most sensitive). o Biochemical Activation  Enzymatic transformation of PAHs (to minimize PAH accumulation within membranes)  General Route: Phase I Hydroxylation → Phase II Conjugation (Glutathione-attachment or glycosylation) → Excretion  Mechanisms of Enzyme-induced Toxicity (↑ PAH solubility for excretion)  99% PAHs Hydroxylated by Cytochrome P450 system or detoxified by Epoxide Hydroxylase → Glycosylation & Glutathionation → Excretion  1% PAHs escapes glutathionation & glycosylation → carcinogenic (e.g. Diol epoxides) o Endocrine Disruption (Subset of Biochemical Activation)  Post-metabolism, some oxyPAHs can mimic existing hormones  PAH induced Cytochrome P450 system hydroxylates PAH but can also disrupt the hormone system of the organism by degrading steroid hormones. - PAHs & Liver Carcinogenesis in Fish Vignette o High MW (4-6 Benzene Rings) PAHs are highly mutagenic; they do not bio-magnify up the food chain, but are activated through photochemical or biochemical pathways (@ liver). o Excretion is not 100%, some oxyPAH attacks hepatocyte DNA. BIOL354 – Environmental Toxicology I Spring 2012  E.g. Hepatocellular Carcinoma rate ↑ in fishes found Industrialized Regions.  Histopathology (Microscopic examination of tissues) is the End-Point.  E.g. Hepatocellular Carcinoma rate ↑ in Fishes (mummichog) from creosote contaminated sites (PAH wood preservatives) on the Eastern Seaboard. - Positive Effects of PAHs: Induce Cytochrome P450 expression Polychlorinatd Biphenyls (PCBs) - Not very photoactive & are harder to metabolize than PAHs o Not manufactured anymore, they must be removed if produced as a by-product - Highly lipophilic (Persistent in sediments - Membrane accumulation) - 209 possible congeners/forms (Planer or Eclipsed depends on Cl position & # – Steric Hindrance) o Eclipsed congeners are more toxic due to higher #s of Cls - Short Term Acute Toxicity is NOT LIKELY - Biochemical Activation o General Route: Uptake → Blood → Liver Metabolism → Excretion o PCBs hydroxylated by Cytochrome P450 System  Hydroxylation require PCB to have 2 adjacent Cs bonded with H instead of Cl  The greater the # of Cls a PCB has, the harder they are to metabolize  If PCB is not metabolized, they persist in the organism → PCB bioaccumulation & Cl displacement of DNA bases → Narcosis & Mutations - Endocrine Disruption o Activated PCBs can mimic existing hormones & the induced Cytochrome P450 System can disrupt the natural hormone system of the organism.  E.g. Pophyria: ↑ Aminolevulenic A
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