MERCURY EXPOSURES and AUTOIMMUNE DISEASE

1、MERCURY and THE IMMUNE SYSTEM: OLD WINE IN NEW BOTTLES? ELLEN SILBERGELDJOHNS HOPKINS SCHOOL OF PUBLIC HEALTHDEPARTMENT OF ENVIRON HEALTH SCIENCESSPRING 2005 MEETINGAE-SOTPITTSBURGHACKNOWLEDGEMENTSSTUDENTS and COLLEAGUES Prof Donna Mergler, UQAM Dr Jennifer Sass, NRDC Dr Peter Crompton, Harvard Ines

2、 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 - B

3、razilFUNDING NATIONAL INSTITUTES OF HEALTH PAN AMERICAN HEALTH ORGANIZATION ARTHRITIS FOUNDATION AMERICAN HEART ASSOCIATION CURE AUTISM NOW FOUNDATIONMERCURY IN THE ENVIRONMENTMERCURY IN THE ENVIRONMENT INCREASINGLY RECOGNIZED AS A GLOBAL POLLUTANT (UNEP, WHO) MAJOR ENVIRONMENTAL RISK TO CHILDRENS H

4、EALTH (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 THE CONTINUING PROBLEM OF METHYL MERCURY IN FISH: HOW MUCH METHYLMERCURY IS THERE IN TUNA?0.5-1.0 ppm

5、CONSIDERED “SAFE (EPA/FDA)2-10 ppm FISH CONSUMPTION CAUSES PROBLEMS10 ppm = 10 ug/gm; In 6 oz 1.8 mg FOR A 70 KG PERSON, DOSE = 26 ug/kgMERCURY RISKS and CAUGHT FISH CONSUMPTIONMERCURY HAZARDS are LOCAL, REGIONAL and GLOBALTOXIC EFFECTS OF MERCURY COMPOUNDS NEUROTOXICITY DEVELOPMENTAL EFFECTS (NRC,

6、WHO) ADULTS MAY BE AS SENSITIVE NEPHROTOXICITY DERMATOTOXICITY IMMUNOTOXICITY?HOW ARE IMMUNOTOXIC MECHANISMS INVOLVED in MERCURY TOXICITY NEPHROPATHY IMMUNE COMPLEX (GBMP Abs) NEUROTOXICITY INHIBITION OF NEURAL MIGRATION DEV, NEURODEGEN DISEASE IMMUNE SUPPRESSION AUTOIMMUNE DYSFUNCTIONIMMUNOLOGIC ME

7、CHANISMS 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 pathwaysDevelopmental mercury exposure affects these s

8、ignaling pathways signal transduction events in cerebellar cell cultures from neonatal mice altered gene expression, cytokine production, and cellular protein levelsAUTOIMMUNE DISEASE COMPLEX DISORDERS (ORGAN SPECIFIC and SYSTEMIC) BASIC MECHANISM: FAILURE TO RECOGNIZE “SELF RISK FACTORS INCLUDE GEN

9、ETICS and ACQUIRED EXPOSURES STRONG SEX BIAS IN DISEASE INCIDENCE AND SEVERITY GEOGRAPHIC PATTERNS OF DISEASE POORLY MANAGED, INCURABLE DISEASESAUTOIMMUNE DISEASE A WOMENS HEALTH ISSUEMERCURY AND AUTOIMMUNE DISEASE CAN MERCURY CAUSE AI DISEASE? HUMAN DATA? NEPHROTOXICITY MAY INVOLVE AUTOIMMUNE MECHA

10、NISMS 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 HIGHMERCURY and HUMAN AUTOIMMUNE DISEASE:

11、 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: 1928-1933CAN MERCURY ACCELERATE AI D

12、ISEASE? 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 DISEAS

13、E; WE JUST MAKE IT WORSEHg and GVHD/LUPUS The model: C57Bl/6 x DBA/2 F1 DBA/2 females + B6D2-F1 pretreated with iHg, 20 or 200 mcg/kg . for 15 da. Transfer maternal splenocytes (100 cells) Chronic SLE-like disease develops over 18-20 months Signs include: proteinuria, tubular nephropathy, vascular d

14、amage, autoABs anti-ss-DNA; ANAGVHD/SLE: iHg accelerates deathPROTEINURIA IN GVHD+/-Hg00.511.522.51234Time since graft (months)Mean Proteinuria ScoreControlMercury TxHg ACCELERATES AUTOIMMUNE Hg ACCELERATES AUTOIMMUNE NEPHROPATHYNEPHROPATHYHg increases serum antinuclear Hg increases serum antinuclea

15、r antibodies - GVHD +/- Hgantibodies - GVHD +/- HgABCDHg increases serum anti-SS DNA antibodiesHg and Autoimmune MyocarditisHg 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 g

16、/kg . 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 deve

17、lops by 35 daMurine model of myocarditis used CB3 virus-induced model (BALB/c) not susceptible to iHg-induced autoimmune disease0510152025303540371014182128354256Days piMyocarditis(% inflammation)BALB/cChronic phaseAcute phaseEAM aloneEAM + iHg10EAM + iHg100iHg100 aloneA/J male miceCARDIOMYOPATHY +/

18、- MERCURY: CARDIOMYOPATHY +/- MERCURY: Hg exposure prior to antigenHg exposure prior to antigenPREVALENCE 50% 77% 92% 0PREVALENCE 50% 77% 92% 0iHg treatment prior to CB3V infection increases myocarditisB. Myocarditis Day 35pi Pretreatment01020304050PBSMercuryMyocarditis (% inflammation)DC: 30%DC: 10

19、0%A. Myocarditis Day 12pi Pretreatment051015202530PBSMercuryMyocarditis (% inflammation)DC: 60%DC: 50%*HISTOPATHOLOGY OF EXPERIMENTAL AUTOIMMUNE MYOCARDITIS:Control + CB3VHg + CB3VCAN WE FIND BIOMARKERS OF Hg-CAN WE FIND BIOMARKERS OF Hg-INDUCED AUTOIMMUNITY IN HUMANS?INDUCED AUTOIMMUNITY IN HUMANS?

20、 INCONSISTENT FINDINGS IN WORKERS, BUT ONLY STUDIES OF MEN EXPOSED TO iHG NO FRANK AUTOIMMUNE DISEASE ASSOCIATIONS RELATIVELY NONSPECIFIC MARKERS USED IMMUNOGLOBULINS, CELL SUBSETSOUR STUDY: Hg exposures and autoimmunity in gold workers POPULATION ARTISANAL GOLD MINERS and RIVERINE POPULATIONS LOCAT

21、ION 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 COLLECTIONSSmall (Artisanal) scale mining: major exposures to elemental, inorganic, and methyl mercury World wide activit

22、y 2 to 6 million persons Women and children Hazardous conditions Toxic chemicals Illegal, unregulated Regional, national, transboundary impactsAIRBORNE MERCURY LEVELS in GARIMPOS in LATIN AMERICA WHO guidance 100 Levels near gold shops in towns 20ARTISANAL GOLD MINING: AMAZONIA TAPAJS WATERSHED, PAR

23、 BRAZILDEFORESTATION: Rio Rato, TapajosHYDRAULIC MINING - garimpo RIO RATO, TAPAJOSAMALGAMATION WITH MERCURY BURNING THE AMALGAM AT THE GARIMPOCHILD LABOR IN ARTISANAL MININGHg EXPOSURES IN GOLD MINERS BRAZILBLOOD Hg LEVELSRio-Rato ANA Percentages47%24%1%17%8%2%1%01 101 201 401 801 1601 320Rio-Rato

24、ANoA Percentages26%1%59%7%3%1%3%01 101 201 401 801 1601 320 C)E) F)Tabatinga-AdultsANA Percentages93%1%4%2%01 101 201 40c Tabatinga-AdultsANoA Percentages98%2%0%0%01 101 201 40AUTOANTIBODIES (ANA, ANoA) IN PERSONS AUTOANTIBODIES (ANA, ANoA) IN PERSONS EXPOSED TO INORGANIC HgEXPOSED TO INORGANIC HgIS

25、 ANTIFIBRILLARIN A BIOMARKER OF Hg AUTOIMMUNITY in HUMANS?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 descr

26、ibed (0.4 g/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?A CONCEPTUAL MODEL FOR Hg AND AUTOIMMUNITY (Step 1)A CONCEPTUAL MODEL FOR Hg AND AUTOIMMUNITY (Step 2)A CONCEPTUAL MODEL FOR Hg AND AUTOIMMUNITY (Step 1 + 2 = 3)IF MERCURY IS ASSOCIATED WITH AU