MERCURY and THE IMMUNE SYSTEM: OLD WINE IN NEW BOTTLES? - PowerPoint PPT Presentation

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MERCURY and THE IMMUNE SYSTEM: OLD WINE IN NEW BOTTLES?

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Title: MERCURY and THE IMMUNE SYSTEM: OLD WINE IN NEW BOTTLES?


1
MERCURY and THE IMMUNE SYSTEM OLD WINE IN NEW
BOTTLES?
  • ELLEN SILBERGELD
  • JOHNS HOPKINS SCHOOL OF PUBLIC HEALTH
  • DEPARTMENT OF ENVIRON HEALTH SCIENCES
  • SPRING 2005 MEETING
  • AE-SOT
  • PITTSBURGH

2
ACKNOWLEDGEMENTS
  • STUDENTS and COLLEAGUES
  • Prof Donna Mergler, UQAM
  • Dr Jennifer Sass, NRDC
  • Dr Peter Crompton, Harvard
  • Ines Silva, Univ of Michigan
  • Dr Jennifer Nyland, Dr Noel Rose, Dr DeLisa
    Fairweather, Johns Hopkins
  • Dr Charles Via, Dr John Sacci, Dr G T Strickland,
    Univ Maryland
  • Dr Emma Calderon Aranda, CINVESTAV Mexico
  • Dr Jose Maria de Souza, Dr Ana Maria Ventura, Dr
    Elisabeth Santos, Ms Iracina de Jesus FNS-IEC --
    Brazil

3
FUNDING
  • NATIONAL INSTITUTES OF HEALTH
  • PAN AMERICAN HEALTH ORGANIZATION
  • ARTHRITIS FOUNDATION
  • AMERICAN HEART ASSOCIATION
  • CURE AUTISM NOW FOUNDATION

4
MERCURY IN THE ENVIRONMENT
  • INCREASINGLY RECOGNIZED AS A GLOBAL POLLUTANT
    (UNEP, WHO)
  • MAJOR ENVIRONMENTAL RISK TO CHILDRENS HEALTH
    (EPA, WHO, CEC)
  • CRITICAL EFFECT - DEVELOPMENTAL NEUROTOXICITY
    (WHO, NAS)
  • FISH CONSUMPTION MAJOR ROUTE OF HUMAN EXPOSURE TO
    MeHg
  • AIRBORNE Hg EXPOSURES?
  • MERCURY EXPOSURES CONTINUE IN WORKPLACES

5
THE CONTINUING PROBLEM OF METHYL MERCURY IN FISH
HOW MUCH METHYLMERCURY IS THERE IN TUNA?
  • 0.5-1.0 ppm CONSIDERED SAFE (EPA/FDA)
  • 2-10 ppm FISH CONSUMPTION CAUSES PROBLEMS
  • 10 ppm 10 ug/gm
  • In 6 oz 1.8 mg
  • FOR A 70 KG PERSON, DOSE 26 ug/kg

6
MERCURY RISKS and CAUGHT FISH CONSUMPTION
7
MERCURY HAZARDS are LOCAL, REGIONAL and GLOBAL
8
TOXIC EFFECTS OF MERCURY COMPOUNDS
  • NEUROTOXICITY
  • DEVELOPMENTAL EFFECTS (NRC, WHO)
  • ADULTS MAY BE AS SENSITIVE
  • NEPHROTOXICITY
  • DERMATOTOXICITY
  • IMMUNOTOXICITY?

9
HOW ARE IMMUNOTOXIC MECHANISMS INVOLVED in
MERCURY TOXICITY
  • NEPHROPATHY IMMUNE COMPLEX (GBMP Abs)
  • NEUROTOXICITY INHIBITION OF NEURAL MIGRATION
    DEV, NEURODEGEN DISEASE
  • IMMUNE SUPPRESSION
  • AUTOIMMUNE DYSFUNCTION

10
IMMUNOLOGIC MECHANISMS ARE INVOLVED IN
DEVELOPMENTAL NEUROTOXICITY OF MERCURY (Sass et
al 2001 Calderon et al in press)
  • Mercury induces glial activation
  • Microglia are macrophage lineage cells
  • Microglia direct neuronal migration through
    cytokine/chemokine/CAM pathways
  • Developmental mercury exposure affects these
    signaling pathways
  • signal transduction events in cerebellar cell
    cultures from neonatal mice
  • altered gene expression, cytokine production, and
    cellular protein levels

11
AUTOIMMUNE DISEASE
  • COMPLEX DISORDERS (ORGAN SPECIFIC and SYSTEMIC)
  • BASIC MECHANISM FAILURE TO RECOGNIZE SELF
  • RISK FACTORS INCLUDE GENETICS and ACQUIRED
    EXPOSURES
  • STRONG SEX BIAS IN DISEASE INCIDENCE AND SEVERITY
  • GEOGRAPHIC PATTERNS OF DISEASE
  • POORLY MANAGED, INCURABLE DISEASES

12
AUTOIMMUNE DISEASE A WOMENS HEALTH ISSUE
13
MERCURY AND AUTOIMMUNE DISEASE
  • CAN MERCURY CAUSE AI DISEASE?
  • HUMAN DATA?
  • NEPHROTOXICITY MAY INVOLVE AUTOIMMUNE MECHANISMS
  • FRANK AI DISEASE NOT DEMONSTRATED IN OCC STUDIES
    BUT EPI DATA ARE LIMITED
  • NEUROTOXICITY MORE SENSITIVE OUTCOME
  • EXPERIMENTAL DATA YES
  • INBRED RODENT STRAINS ARE SUSCEPTIBLE
  • RESPONSE CAN INCLUDE AUTOANTIBODIES, VASCULITIS,
    NEPHROPATHY
  • DOSES ARE RELATIVELY HIGH

14
MERCURY and HUMAN AUTOIMMUNE DISEASE THE LATEST
STUDY!
  • CAROLINA LUPUS STUDY
  • CASECONTROL (265355)
  • CASES 90 FEMALE, 60 AFRICAN AMERICAN
  • INCREASED ODDS FOUND FOR
  • OCCUPATIONAL EXPOSURES TO MERCURY
  • EMPLOYMENT AS DENTAL TECHNICIAN
  • MIXING PESTICIDES (NOT IDENTIFIED)
  • Cooper et al J Rheumatol 2004 31 1928-1933

15
CAN MERCURY ACCELERATE AI DISEASE? the BASF
approach
  • EXPERIMENTAL DATA
  • Hg accelerates pathology in lupus-prone strains
    of mice (NZB, BXB)
  • Hg accelerates disease in Graft Versus Host model
    of LUPUS, Cardiac Myosin model of autoimmune
    myocarditis and cardiomyopathy (Via et al 2003
    Nyland et al 2003, 2004)

WE DONT CAUSE DISEASE WE JUST MAKE IT WORSE
16
Hg and GVHD/LUPUS
  • The model C57Bl/6 x DBA/2 F1
  • DBA/2 females B6D2-F1 pretreated with iHg, 20
    or 200 mcg/kg a.d. for 15 da.
  • Transfer maternal splenocytes (100 cells)
  • Chronic SLE-like disease develops over 18-20
    months
  • Signs include proteinuria, tubular nephropathy,
    vascular damage, autoABs anti-ss-DNA ANA

17
GVHD/SLE iHg accelerates death
18
Hg ACCELERATES AUTOIMMUNE NEPHROPATHY
19
Hg increases serum antinuclear antibodies - GVHD
/- Hg
20
Hg increases serum anti-SS DNA antibodies
21
Hg and Autoimmune Myocarditis
  • AM leading cause of sudden cardiac failure in
    young post-infection autoimmune disease
  • BALB/c female mice pretreated with iHg 10, 20,
    100 or 200 µg/kg a.d. for 15 da
  • EAM induced by injecting antigen cardiac myosin
    peptide (CMP) CFA pertussis toxin or by
    infection with Coxsackie B3 virus
  • CMP by 30 da, cardiomyopathy develops
    characterized by cardiac enlargement,
    arrhythmias, IgG1/2 antiCMP ABs
  • CB3V after infection and viral clearance, CM
    develops by 35 da

22
Murine model of myocarditis used
  • CB3 virus-induced model (BALB/c)
  • not susceptible to iHg-induced autoimmune disease

Acute phase
Chronic phase
23
CARDIOMYOPATHY /- MERCURY Hg exposure prior to
antigenPREVALENCE 50
77 92 0
A/J male mice
EAM alone
EAM iHg10
EAM iHg100
iHg100 alone
24
iHg treatment prior to CB3V infection increases
myocarditis


25
HISTOPATHOLOGY OF EXPERIMENTAL AUTOIMMUNE
MYOCARDITIS
Control CB3V
Hg CB3V
26
CAN WE FIND BIOMARKERS OF Hg-INDUCED AUTOIMMUNITY
IN HUMANS?
  • INCONSISTENT FINDINGS IN WORKERS, BUT ONLY
    STUDIES OF MEN EXPOSED TO iHG
  • NO FRANK AUTOIMMUNE DISEASE ASSOCIATIONS
  • RELATIVELY NONSPECIFIC MARKERS USED
    IMMUNOGLOBULINS, CELL SUBSETS

27
OUR STUDY Hg exposures and autoimmunity in gold
workers
  • POPULATION ARTISANAL GOLD MINERS and RIVERINE
    POPULATIONS
  • LOCATION AMAZONIAN BRAZIL
  • CENSUS BASED SAMPLE and CONVENIENCE SAMPLE (98
    132)
  • Hg EXPOSURE BIOMARKERS (HAIR and URINE)
  • HEALTH/OCCUP-RES-DIET INFO by QUESTIONNAIRE,
    CLINICAL EXAM
  • SERUM COLLECTIONS

28
Small (Artisanal) scale mining major exposures
to elemental, inorganic, and methyl mercury
  • World wide activity 2 to 6 million persons
  • Women and children
  • Hazardous conditions
  • Toxic chemicals
  • Illegal, unregulated
  • Regional, national, transboundary impacts

29
AIRBORNE MERCURY LEVELS in GARIMPOS in LATIN
AMERICA WHO guidance lt0.01 mg/m3
  • Levels near amalgam burning in garimpos gt100
  • Levels in camps - 0.03-10
  • Levels near gold shops in towns gt20

30
ARTISANAL GOLD MINING AMAZONIA TAPAJÓS
WATERSHED, PARÁ BRAZIL
31
DEFORESTATION Rio Rato, Tapajos
32
HYDRAULIC MINING - garimpo RIO RATO, TAPAJOS
33
AMALGAMATION WITH MERCURY
34
BURNING THE AMALGAM AT THE GARIMPO
35
CHILD LABOR IN ARTISANAL MINING
36
Hg EXPOSURES IN GOLD MINERS BRAZILBLOOD Hg
LEVELS
37
AUTOANTIBODIES (ANA, ANoA) IN PERSONS EXPOSED TO
INORGANIC Hg
A) B)
C)
E) F)
38
IS ANTIFIBRILLARIN A BIOMARKER OF Hg AUTOIMMUNITY
in HUMANS?
39
CONCLUSIONS
  • Hg is immunotoxic, affecting host response to
    infections, susceptibility to autoimmune disease,
    and acting on immune mechanisms in target organ
    disease
  • The immunotoxic effects of Hg in animals are the
    lowest dose/effects yet described (0.4 µg/kg)
  • There may be genetic susceptibility factors for
    Hg immunotoxicity
  • Hg may play a contributing role in the incidence
    and severity of autoimmune disease
  • DO WE NEED TO RE-ASSESS THE RISKS OF MERCURY, ESP
    FOR ADULTS?

40
A CONCEPTUAL MODEL FOR Hg AND AUTOIMMUNITY (Step
1)
41
A CONCEPTUAL MODEL FOR Hg AND AUTOIMMUNITY (Step
2)
42
A CONCEPTUAL MODEL FOR Hg AND AUTOIMMUNITY (Step
1 2 3)
43
IF MERCURY IS ASSOCIATED WITH AUTOIMMUNE DISEASE
  • WHAT ARE THE CRITICAL EXPOSURE BIOMARKERS
  • CHRONIC, CURRENT?
  • INORGANIC AS WELL AS ORGANIC?
  • LATENCIES BETWEEN EXPOSURE/OUTCOME?
  • DOES HG AFFECT THE DEVELOPING IMMUNE SYSTEM
  • YESIN MICE
  • HOW WOULD WE STUDY THIS?
  • AUTOIMMUNE DISEASES ARE RARE
  • CASECONTROL? ENRICHED POPULATIONS?
  • ARE THERE SUSCEPTIBLE SUBPOPULATIONS?
  • PERSONS FROM AI DISEASE FAMILIES
  • PERSONS WITH SPECIFIC GENETIC POLYMORPHISMS
  • WOMEN

44
PRENATAL MERCURY EXPOSURE AFFECTS
IMMUNODEVELOPMENT Silva et al 2005
Note inorganic Hg was used some similar effects
observed with MeHg
45
MERCURY and ASD
  • Do mercury compounds CAUSE or CONTRIBUTE to ASD?
  • Epidemiological studies are needed
  • Are the mechanisms of mercury toxicity relevant
    as MODELS (not necessarily as CAUSES) of the
    mechanistic processes in ASD?
  • Examples APO E -/- mouse and Alzheimers
  • 6-OHDA and Parkinsonism

46
NEVER FORGET MINAMATA DISEASE JAPAN
Eugene Smith
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