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“ 二二二”二二二二二二二 二二二 Ph.D. 二二二二二二二二二二 2011.11.4 E-mail: [email protected] 二二6875 9982 QQ 1520357237

“ 二噁英”污染与人类健康

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“ 二噁英”污染与人类健康. 袁占鹏 Ph.D. 武汉大学公共卫生学院 2011.11.4 E-mail: [email protected] 电话: 6875 9982 ; QQ : 1520357237. 目的. 以“二噁英”为例了解一类(种)污染物从来源到公共卫生的系统考量. 内容. “ 二噁英”是什么? 来源 对环境的污染与在环境中的变迁 暴露途径 代谢与分布 毒性及其机制 公共卫生考量 — 健康危害与对策. “ 二噁英”. 是二噁英和二噁英样物质的统称 Polychlorinated dibenzodioxins, PCDDs - PowerPoint PPT Presentation

Text of “ 二噁英”污染与人类健康

  • Ph.D.

    2011.11.4E-mail: [email protected] 9982QQ1520357237

  • Polychlorinated dibenzodioxins, PCDDsPolychlorinated dibenzofurans, PCDFsPolychlorinated biphenyls, PCBs

    2,3,7,8-tetrachlorodibenzo-p-dioxin2,3,7,8-TCDDTCDDdioxin

  • TCDDDibenzo-p-dioxin

  • PCDDsChlorine atoms are attached to this structure at any of 8 different places on the moleculeAt positions 14 and 69There are 75 PCDD congeners

  • PCDFsPolychlorinated dibenzofurans

    2,3,7,8-tetrachlorodibenzofuran

  • PCBsTheoretically 209 different PCB congeners are possible, although only about 130 are found in commercial PCB mixtures

  • HAHs halogenated aryl hydrocarbons PCDD/Fs, PCBsNote:Chlorine () and Bromide ()

    Along with Polycyclic aryl hydrocarbons PAHs,

    Form aryl hydrocarbons (AHs) family

  • The term dioxin or dioxins is used almost exclusively to refer to compounds from the above groups which demonstrate the same specific toxic mode of action associated with 2,3,7,8-TCDD.

    Incidents of contamination with PCBs are often reported as Dioxin Affair since it is this toxic characteristic which is of most public and regulatory concern.

  • Dioxins and dioxin-like compounds (DLC) are by-products of various industrial processes, except for occasional purposeful production, and are commonly regarded as highly toxic compounds that are also called persistent organic pollutants (POPs).

  • PCDD/Fs

    1848Leblanc Process

    1872

  • PCBs1930

    1946Monsanto

  • PAHsBaPHAHsdioxin

    HAHsDioxins/Furans, PCBsPAHs

  • Leblanc ProcessHAHs

    Dioxins (TCDD), Furans, PCBs, etc.

  • PCBs, Herbicides (Agent Orange)

    PVC

    HAHsDioxins, furans, and PCBs

  • Major SourcesAccording to the most recent US EPA dataCombustion sourcesmunicipal waste incineratorsMetal smeltingRefining and process sourcesChemical manufacturing sources Natural sources Environmental reservoirs

  • Concentration profile of PCDD in a 2001 sediment core from Esthwaite Water, Cumbria, UK

  • (photolytic)

  • (1)

  • (2)

    (sediments)

  • The major sources of human exposure (96%) areAnimal fats found in meatsFull fat dairy products Fatty fish (herring, mackerel, salmon, sardines, trout, tuna)

  • Breathing incineration gases released from medical, municipal, and hazardous waste incinerators

    Breathing gases released by industrial processes from paper mills, cement kilns, and metal smelters

  • People who perform the following types of work can be exposed to dioxinsProduction and handling of certain chlorinated phenols (such as 2,4,5-trichlorophenol or pentachlorophenol [PCP]) Production or handling of chlorinated pesticides, such as 2-4-dichlorophenoxyacetic acid (2,4-D) and other herbicides Chlorinated pesticide application Pressure treatment of wood with PCP and handling of PCP-treated wood Production of chlorinated paper at pulp and paper mills Operation of municipal solid waste or hazardous waste incinerators Hazardous waste clean-up operations

  • (accidental exposure)Seveso, Italy (dioxin, 1976) (PCBs, 1960s)

    Children are passed substantial body burdens by their mothers, so breast-feeding increases the child's body burden

  • The estimated half-life for highly chlorinated dioxins (4-8 chlorine atoms) in humans ranges from 7.8 to 132 years

  • Dioxins refer to such a broad class of compounds that vary widely in toxicitythe concept of toxic equivalent (TEQ) has been developed to facilitate risk assessment and regulatory control.Toxic equivalent factors (TEFs) exist for selected congeners of dioxins, furans and PCBsThe reference congener is the most toxic dioxin 2,3,7,8-TCDD which per definition has a TEF of one

  • (wasting syndrome) (developmental toxicity) (reproductive toxicity teratology) (carcinogenesis) (immunotoxicity, immunological tox.) (neurotoxicity, neurological tox.)

  • AHAHsAH (AhR, Aryl Hydrocarbon Receptor) (Hankinson, 1995)

  • AhRXREpromotergene (CYP1A1)

  • AhRPAS (Per-AhR/Arnt-Sim)Per circadianArnt AhRSim Drosophila single-minded, an orthologue of Arnt, essential for midline differentiation

    AhR

  • AhR pathway participantsXREpromotergene (ie.CYP1A1)Target DNA

  • AhR

  • AhRhttp://www.helsinki.fi/science/dentenv/dioxin.html

  • AhR

  • AhR

  • AhRRapid receptor degradation (2)Ubiquitination proteosomal degradationOnly happen in SUSTAINED AhR activityThe action of an AhR Repressor (AhRR) (3)Agonist depletion through an enzymatic negative feedback loop (5)

    The evolution of multiple mechanisms to suppress sustained AhR activity implies that its prolonged signaling is physiologically deleterious.

  • G1 arrestSustained+Transient

    Constitutively active AhR (CA-AhR)Marked incidence in gastric tumorsIt is tempting to speculate that CA-AhR may actually suppresses normal growth in the stomach and liver thereby conferring a growth advantage upon any transformed cells in the tissue

  • ConclusionsTransient and sustained AhR activation affect the transcriptome differentlyculminating in distinct biological responses to receptor activationhighlights the importance of tightly regulating AhR signaling

    Suffice it to say that sustained AhR activity invokes a homeostatic disequilibriumunderscored by a dramatically altered transcriptome.

  • /(reactive oxygen species, ROS)

    ROSDNA, RNA, Protein, peroxidization of lipids, organelles

  • DNA

  • DNA

  • DNADNA Double Strand Breaks (DSBs)

    DNAUVDNA

  • DNA SB RepairNature, 411:366-374, 2001

  • DNA DSBsNo!They operate in diverse biological settingsV(D)JGenerating immune-receptor diversityProduction of gametes for sexual reproductionMeiosis I () and II. Sister chromatin exchange proceeds M I, involving Spol I that bound DSBsTelomere homeostasis and ageing

    Transportable Elements

  • DDR protein Role at normal telomeres

    MRN Telomere length regulator, role in end processingATM, CHK2 and ATR Maintain telomere length, phosphorylate Shelterin-complex components, possible roles in telomerase activationand recruitmentKu and DNA-PKcs Telomere components and telomere-length regulators, possible telomere-capping functionsRAD9RAD1HUS1 (9-1-1) Telomere component and telomere-length regulator; aids telomerase recruitment/activationNucleases EXO1, FEN1, Processing of telomeric termini to promote XPF/ERCC1 and Apollo telomerase action; regulate telomere integrityPARP1 Potential telomere-length regulatorBRCA1 Telomere maintenanceRPA Telomere component, in telomerase recruitmentWRN Maintains telomere structure and functions in telomere replicationRAD51D and other HR proteins Regulate telomeric integrity

  • DNADNAHAHs cause ROS elevation)

    Neurodegenerative disordersRemember Sim? And AhR belongs to PAS?

    Immune deficiencies and infertilitymutations in NHEJ factors yield B- and T-cell immune deficiencySpermatogenesis

    Genome Instability in Other Heritable hDiseases

  • TCDD, a Group 1 carcinogen by the Intl Agency for Research on Cancer (IARC)US EPAPotential human carcinogen 94non-cancer effects (reproduction and sexual development, immune system) may pose an even greater threat to human healthNo threshold dose 00

  • Developmental abnormalitiesCentral and peripheral nervous system pathologyThyroid disorders Damage to the immune systemsDiabetesExposure to dioxins changes the ratio of male to female births among a population More females are born than malesetc.

  • Proper incineration of contaminated material is the best available method of preventing and controlling exposure to dioxins >850C

    Trimming fat from meat and consuming low fat dairy productsA balanced diet (adequate fruits, vegetables etc.)

  • Identify and measure dioxins in the environment and food The quantitative chemical analysis of dioxins requires sophisticated methodsTime consumingCapital consuming: > US$1700/sample

    Advocate for biological-based methodsUse for screeningConfirm by chemical analysis