Title: MERCURY and THE IMMUNE SYSTEM: OLD WINE IN NEW BOTTLES?
1MERCURY 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
2ACKNOWLEDGEMENTS
- 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
3FUNDING
- NATIONAL INSTITUTES OF HEALTH
- PAN AMERICAN HEALTH ORGANIZATION
- ARTHRITIS FOUNDATION
- AMERICAN HEART ASSOCIATION
- CURE AUTISM NOW FOUNDATION
4MERCURY 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
5THE 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
6MERCURY RISKS and CAUGHT FISH CONSUMPTION
7MERCURY HAZARDS are LOCAL, REGIONAL and GLOBAL
8TOXIC EFFECTS OF MERCURY COMPOUNDS
- NEUROTOXICITY
- DEVELOPMENTAL EFFECTS (NRC, WHO)
- ADULTS MAY BE AS SENSITIVE
- NEPHROTOXICITY
- DERMATOTOXICITY
- IMMUNOTOXICITY?
9HOW ARE IMMUNOTOXIC MECHANISMS INVOLVED in
MERCURY TOXICITY
- NEPHROPATHY IMMUNE COMPLEX (GBMP Abs)
- NEUROTOXICITY INHIBITION OF NEURAL MIGRATION
DEV, NEURODEGEN DISEASE - IMMUNE SUPPRESSION
- AUTOIMMUNE DYSFUNCTION
10IMMUNOLOGIC 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
11AUTOIMMUNE 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
12AUTOIMMUNE DISEASE A WOMENS HEALTH ISSUE
13MERCURY 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
14MERCURY 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
15CAN 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
16Hg 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
17GVHD/SLE iHg accelerates death
18Hg ACCELERATES AUTOIMMUNE NEPHROPATHY
19Hg increases serum antinuclear antibodies - GVHD
/- Hg
20Hg increases serum anti-SS DNA antibodies
21Hg 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
22Murine model of myocarditis used
- CB3 virus-induced model (BALB/c)
- not susceptible to iHg-induced autoimmune disease
Acute phase
Chronic phase
23CARDIOMYOPATHY /- MERCURY Hg exposure prior to
antigenPREVALENCE 50
77 92 0
A/J male mice
EAM alone
EAM iHg10
EAM iHg100
iHg100 alone
24iHg treatment prior to CB3V infection increases
myocarditis
25HISTOPATHOLOGY OF EXPERIMENTAL AUTOIMMUNE
MYOCARDITIS
Control CB3V
Hg CB3V
26CAN 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
27OUR 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
28Small (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
29AIRBORNE 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
30ARTISANAL GOLD MINING AMAZONIA TAPAJÓS
WATERSHED, PARÁ BRAZIL
31DEFORESTATION Rio Rato, Tapajos
32HYDRAULIC MINING - garimpo RIO RATO, TAPAJOS
33AMALGAMATION WITH MERCURY
34BURNING THE AMALGAM AT THE GARIMPO
35CHILD LABOR IN ARTISANAL MINING
36Hg EXPOSURES IN GOLD MINERS BRAZILBLOOD Hg
LEVELS
37AUTOANTIBODIES (ANA, ANoA) IN PERSONS EXPOSED TO
INORGANIC Hg
A) B)
C)
E) F)
38IS ANTIFIBRILLARIN A BIOMARKER OF Hg AUTOIMMUNITY
in HUMANS?
39CONCLUSIONS
- 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?
40A CONCEPTUAL MODEL FOR Hg AND AUTOIMMUNITY (Step
1)
41A CONCEPTUAL MODEL FOR Hg AND AUTOIMMUNITY (Step
2)
42A CONCEPTUAL MODEL FOR Hg AND AUTOIMMUNITY (Step
1 2 3)
43IF 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
44PRENATAL MERCURY EXPOSURE AFFECTS
IMMUNODEVELOPMENT Silva et al 2005
Note inorganic Hg was used some similar effects
observed with MeHg
45MERCURY 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
46NEVER FORGET MINAMATA DISEASE JAPAN
Eugene Smith