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

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. ACKNOWLEDGEMENTS. STUDENTS and COLLEAGUES Prof Donna Mergler, UQAM Dr Jennifer Sass, NRDC

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

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  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 CHILDREN’S 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 WOMEN’S 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 • CASE:CONTROL (265:355) • 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 DON’T 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 <0.01 mg/m3 • Levels near amalgam burning in garimpos >100 • Levels in camps - 0.03-10 • Levels near gold shops in towns >20

  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. A) B) AUTOANTIBODIES (ANA, ANoA) IN PERSONS EXPOSED TO INORGANIC Hg 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 • YES…IN MICE • HOW WOULD WE STUDY THIS? • AUTOIMMUNE DISEASES ARE RARE • CASE:CONTROL? 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

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