environmental exposures and the immune system: gender specific differences and consequences allen...

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Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Allen Silverstone, SUNY Upstate Medical University Dept. of Medical University Dept. of Microbiology and Immunology and Microbiology and Immunology and University of Rochester School of University of Rochester School of Medicine, Dept. of Environmental Medicine, Dept. of Environmental Medicine Medicine

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Page 1: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

Environmental Exposures and the

Immune System: Gender Specific Differences and

consequences

Allen Silverstone, SUNY Upstate Medical Allen Silverstone, SUNY Upstate Medical University Dept. of Microbiology and University Dept. of Microbiology and

Immunology and University of Rochester School Immunology and University of Rochester School of Medicine, Dept. of Environmental Medicineof Medicine, Dept. of Environmental Medicine

Page 2: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

ON THE EVE OF THE REISSUANCE OF THE GREAT

1970’S CLASSIC THE JOY OF SEX

IT GIVES ME GREAT PLEASURE TO TALK TO YOU, ABOUT

THE JOY OF IMMUNOLOGY

Which can last longer than sex.

Page 3: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

THE FUNCTION OF THE THE FUNCTION OF THE IMMUNE SYSTEM IS FIRST IMMUNE SYSTEM IS FIRST

AND FOREMOST TO AND FOREMOST TO PROTECT US FROM THE PROTECT US FROM THE

MICROBIAL WORLD (THE MICROBIAL WORLD (THE PATHOGENIC PART PATHOGENIC PART

ANYWAY)ANYWAY)

Page 4: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

IT DOES THIS BY UTILIZING A IT DOES THIS BY UTILIZING A LARGE NUMBER OF DIFFERENT LARGE NUMBER OF DIFFERENT CELL TYPES WHICH IN VARIOUS CELL TYPES WHICH IN VARIOUS

INTERACTIONS DELIVER A INTERACTIONS DELIVER A RESPONSE THAT IS MORE OR RESPONSE THAT IS MORE OR

LESS SPECIFIC, AND, WITH LESS SPECIFIC, AND, WITH LUCK CONTROLS AND LUCK CONTROLS AND

ELIMINATES THE MICROBIAL ELIMINATES THE MICROBIAL AGENT BEFORE THE ORGANISM AGENT BEFORE THE ORGANISM

IS KILLED.IS KILLED.

Page 5: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of
Page 6: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

THESE DIFFERENT CELL THESE DIFFERENT CELL TYPES DEVELOP WITHIN TYPES DEVELOP WITHIN

THE ORGANISM IN SPECIFIC THE ORGANISM IN SPECIFIC TISSUES AND IN SPECIFIC TISSUES AND IN SPECIFIC

STAGES.STAGES.

Page 7: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of
Page 8: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

IMMUNOTOXICOLOGY

A SUBDISCIPLINE OF IMMUNOPHARMACOLOGY

SORT OF A NEGLECTED CHILD OF IMMUNOLOGY

Page 9: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of
Page 10: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

PHARMACOLOGICAL AGENTS CAUSE IMMUNOSUPPRESSION

1- Steroids: Affect cell traffic (lymphocytopenia; monocytopenia; neutrophilia); Cell function ( Inhibit T and B cell maturation; inhibit IL-1 and TNF production, IL-2,4,6, and 10 production reduced).

2-Alkylating agents for Chemotherapy (kill stem cells; useful in establishing tolerance) e.g. Cyclophosphamide; nitrogen mustards.

3- Nucleotide Synthesis Inhibitors: Azathioprine, allopurinal, methotrexate.

4-Cyclosporin, FK506, Rapamycin

Page 11: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

IMPROPER NUTRITION CAN LEAD TO REDUCED IMMUNE RESPONSES

1-Malnutrition reduces lymphatic tissue, lymphoid atrophy, reduced CD4/CD8 ratio; reduced Th-2 activity, reduced IgA production to vaccines (problems in developing countries); reduced opsonization (reduced complement production )

2-Zinc deficiency: (reduced CD4/8; T-cell anergy)

3-Vitamin A deficiency (reduced mitogen responses)

4-Iron deficiency (reduced neutrophil activity; ferritin-transferrin binding vs. bacterial iron binding proteins).

Page 12: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

ENVIRONMENTAL AGENTS CAN AFFECT IMMUNITY

1-Dioxins/PCBs: Reduced CMI, humoral responses; increased sensitivity to viral, bacterial, parasitic infections.

2- Heavy Metals: Cadmium, mercury , lead(Dietert and Associates have shown that immunosuppression by lead is gender affected

3-Diesel Fuel Particulates: (opsonizing functions; neutrophil activity, CMI effects

4- Many pesticides and herbicides:

Page 13: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

TCDD (the most toxic dioxin): Arises as a byproduct inmanufacture and in combustion. Its toxicity is such thatit is the reference standard for toxicity of other PHAH’S

These Compounds are relatively resistant to environmentaland metabolic accumulation, and are thus highly persistent.They are very lipophilic and are persistent in human tissues.

Page 14: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

• Fatal Cachexia

•Chloracne

•Hepatotoxicity

•Repro Toxicity

•Cancer

Dioxins & Dioxin Like PCBsWhat do they do?

•Decreased T-cell responses to tumors•Decreased primary and memory responses • Increased susceptibility to bacterial, parasitic and viral infections

Toxicities: Immunotoxicity:

THYMIC ATROPHYTHYMIC ATROPHY

Page 15: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

UNLIKE DEXAMETHASONE, DIOXIN CAUSESTHYMIC ATROPHY SLOWLY, BUT ALSO IN

BCL-2 TRANSGENIC MICE

Page 16: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

HO

CH3

OH

C = CHO OH

C2

H5

C2

H5

-Estradiol Diethylstilbestrol (DES)

Important for normal physical development, maintain reproductive cycles and regulation for liver metabolism and immune function, and ensure balance of normal body systems

Physiological levels

Hormone replacement therapy and treatment for prostate cancer

Pharmaceutical therapy

*

Page 17: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

HO

CH3

OH

C = CHO OH

C2

H5

C2

H5

-Estradiol Diethylstilbestrol (DES)

* Related to autoimmune diseases* Related to breast and reproductive organ cancer* Influence on the development and functions of

reproductive system* Influence on neural-endocrine system and behavior* Effects on immune system

High levels

Page 18: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

The effects of estrogen on immune system (1)

Induction of thymic atrophy and decrease of all CD4/8 subsets of thymocytes

Inhibition of spleen T-cell proliferation response to stimulants in vitro

Increase of INF- , IL-4 and shift immune response to Th2 from Th1

Decrease of numbers of peripheral T cells

Impairment of T-cells

Page 19: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

Inhibition of differentiation, proliferation and survival of BM B cell precursor

Increase of number of plasma cells, immuno-globulins and autoantibodies.

Reduction of NK cell number and activity Reduction of delayed type hypersensitivity

Increase of susceptibility and death to infection

The effects of estrogen on immune system (2)

Inhibition of BM B-cell precursor

Hyperactivity of B-cells

Page 20: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

0 2 4 6 8 10 12

0

20

40

60

80

100

120P

erce

nt

of c

ontr

ol (

%)

Days after E2 injection

number of total cells*****

ESTROGEN ALSO CAUSES ATROPHYESTROGEN ALSO CAUSES ATROPHY

Page 21: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

BESIDES SUPPRESSIVE BESIDES SUPPRESSIVE EFFECTS ON THE IMMUNE EFFECTS ON THE IMMUNE SYSTEM, MANY ESTROGEN SYSTEM, MANY ESTROGEN AFFECTING XENOBIOTICS AFFECTING XENOBIOTICS

AND EVEN PHYSIOLOGICAL AND EVEN PHYSIOLOGICAL LEVELS OF ESTROGEN ARE LEVELS OF ESTROGEN ARE

ASSOCIATED WITH ASSOCIATED WITH HYPERIMMUNITY HYPERIMMUNITY

(ASTHMA,ALLERGY, ETC.)(ASTHMA,ALLERGY, ETC.)

OR AUTOIMMUNE DISEASEOR AUTOIMMUNE DISEASE

Page 22: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

AUTO-IMMUNE MODELS SHOW THE DEPENDENCE OF BOTH

GENETICS AND SEX

Page 23: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

Immune System

Environmental Triggers/

Potentiators

Sex Hormones Genetics

Page 24: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

Immune System

Hyper

Immunity

Auto- Immune Disease

Immune Suppression

Sex Hormones

Page 25: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

Immune System

Hyper

Immunity

Auto- Immune Disease

Immune Suppression

Environmental Triggers/

Potentiators

Page 26: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

Immune System

Hyper

Immunity

Auto- Immune Disease

Immune Suppression

Genetics

Page 27: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

GETTING BY WITH A LITTLE HELP GETTING BY WITH A LITTLE HELP FROM MY FRIENDSFROM MY FRIENDS

TOM GASIEWICZTOM GASIEWICZ OF THE OF THE UNIVERSITY OF ROCHESTER WHO UNIVERSITY OF ROCHESTER WHO INTRODUCED ME TO DIOXIN AND INTRODUCED ME TO DIOXIN AND ITS RECEPTOR AND WITH WHOM I ITS RECEPTOR AND WITH WHOM I HAVE CREATED A PARADIGM FOR HAVE CREATED A PARADIGM FOR

STUDYING HOW RECEPTOR STUDYING HOW RECEPTOR MEDIATED ACTIONS AFFECT THE MEDIATED ACTIONS AFFECT THE

IMMUNE SYSTEMIMMUNE SYSTEM

& John MacLachlan who insisted we study E2& John MacLachlan who insisted we study E2

Page 28: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

AhR-KO Chimeras Eliminate Epithelial Targets

Page 29: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

DP

CD44+CD25-

CD44+CD25+HSA+

CD44-CD25hi

HSA+

CD44-CD25int

HSA+

CD4+CD8+HSA+/-

TCRCD3+CD4+

TCRCD3+CD8+

RIP

Stem cellfrom bonemarrow orfetal liver

CD8- CD4- DN

SP

CD44-CD25lo

HSA+

=DN 1

=DN 2

=DN 3

=DN 4A

=DN 4B

Cl Cl

O

TCDD

O

Cl Cl

RAG Block

HSA+ LY 5.1+or LY 5.2+

Page 30: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

CD44+CD25+HSA+

CD44-CD25hi

HSA+

CD44-CD25-HSA+

BrdU incorporation in the CD44-CD25hi HSA+ Cell Population after TCDD Treatment

CD44+CD25-

CD44-CD25int

HSA+

Hours after TCDD Treatment

Per

cen

t of

Cel

ls I

nco

rpor

atin

g B

rdU

p<0.01

Oil 30 g/kg TCDD

***

***

*** **

*

0 6 12 18 24 40 60 80 100 120 1400

5

10

15

20

25

30

Page 31: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of
Page 32: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

100

300

500

700

900

1100

0 h 3 h 6 h 24 h 1 w 2 w 7 w

exposure time

adseverin

HPRT

Svensson C. and Lundberg K., In manuscript

*

**

*

*

*

*

AADSEVERIN INDUCTION OCCURS WITHIN

THREE HOURS OF TCDD EXPOSURE IN VIVO

Page 33: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

0

20

40

60

80

V T V T V T

% TUMOR CELL CYTOTOXICITY

-/- Ÿ +/+ +/+Ÿ +/+ B6 W.T.

SPLEEN CELLS FROM MICE INNOCULATED WITH P815TUMOR TESTED AT 100/1 FOR TUMOR CYTOTOXICITY

Page 34: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

Hemopoietic Expression of ER is required for maximum response to E2

WT >WT KO >WT WT >KO KO >KO

Th

ym

ic c

ellu

lari

ty (

x 1

0

7 )

0

5

10

15

20

25

30

controlestradiol

ER- ER- is is required for a full sized thymus!! required for a full sized thymus!!

Page 35: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

Wild Type ER KO ER KO ER KO

Th

ymu

s W

eigh

t (m

gs)

0

10

20

30

40

50

60

70

Oil E2

ERKO ARE PARTIALLY SENSITIVE TO E2

. ERKO ARE FULLY SENSITIVE TO E2

Ovx (cst) results in full size thymuses!Ovx (cst) results in full size thymuses!

Page 36: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of
Page 37: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

GETTING BY WITH A LITTLE GETTING BY WITH A LITTLE HELP FROM MY FRIENDSHELP FROM MY FRIENDS

KEN KORACH, DENNIS LUBAHN, KEN KORACH, DENNIS LUBAHN, AND SYLVIA HEWITT FOR HELP AND SYLVIA HEWITT FOR HELP AND SUPPLYING MICE LACKING AND SUPPLYING MICE LACKING

ESTROGEN RECEPTOR ALPHA ESTROGEN RECEPTOR ALPHA (AERKO’S) AND BETA (BERKO’S)(AERKO’S) AND BETA (BERKO’S)

And for only being able to give us males in And for only being able to give us males in sufficient number … that lead us to realize how sufficient number … that lead us to realize how important the ER is for Male Immune system.important the ER is for Male Immune system.

Page 38: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

GETTING BY WITH A LITTLE GETTING BY WITH A LITTLE HELP FROM MY FRIENDSHELP FROM MY FRIENDS

Emilie RissmanEmilie Rissman who gave us Tfm AERKO’s who gave us Tfm AERKO’s to rule out Androgen receptor involvement to rule out Androgen receptor involvement in certain estrogen effectsin certain estrogen effects

Ken Olden and NIEHSKen Olden and NIEHS for their support for for their support for the last 13 years for our work in this area.the last 13 years for our work in this area.

Page 39: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

******

*** ***a

***

***

0 20 40 60 0 1 2 3 4 0 4 8 12

Thymus weight number of cells BrdU positive cells

mg/thymus 108/thymus % of thymocytes

Oil

1 E2

3 E2

Estradiol (E2) inhibits BrdU incorporation in DNAand induces thymic atrophy

Page 40: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

Effects of E2 on proliferation activity of subpopulations

*CD3-CD8+

*****

******

***

***

**

CD3-DP

CD3-DN*

** ***

*********

*****

***

***

CD44+CD25+

CD44-CD25+

CD44-CD25-

A B

0 2 4 6 8 10 0 2 4 6 8 10

100

80

60

40

20

0

Days after E2 injection

Per

cen

t of

con

trol

(%

)

Page 41: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

Control Estradiol Estradiol DES 24 Hours 24 Hours 60 Hours 24 Hours

0% Serum5% Charcoal

Stripped Serum 5% Full Serum

18-81 Proliferation and DNA Profile

0% Serum

DNA content

0% Serum

1.E+04

1.E+05

1.E+06

1.E+07

0 12 24 36 48 60 72

Hours

Nu

mb

er o

f V

iab

le C

ells

Dioxane (Control)Estradiol (20 uM)DES (20 uM)

107

106

105

104

5% Charcoal-Stripped Serum

1.E+04

1.E+05

1.E+06

1.E+07

0 12 24 36 48 60 72Hours

Nu

mb

er

of

Via

ble

Ce

lls

Dioxane

Estradiol (20 uM)

DES (20 uM)

107

106

105

104

5% Full Serum

1.E+04

1.E+05

1.E+06

1.E+07

0 12 24 36 48 60 72Hours

Nu

mb

er o

f V

iab

le C

ells

Dioxane

Estradiol (20 uM)

DES (20 uM)

107

106

105

104

G2/M build up

Page 42: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

Wild Type ER KO

Per

cen

t of

Oil

Tre

ated

Con

trol

0

20

40

60

80

100

120

Oil E2 Prog Prog + E2 DHT

PROGESTERONE POTENTIATES THE ER KO RESPONSE TO E2

Page 43: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

GETTING BY WITH A LITTLE HELP GETTING BY WITH A LITTLE HELP FROM MY FRIENDS (CORNELL)FROM MY FRIENDS (CORNELL)

INFORMATION AND DISCUSSIONS INFORMATION AND DISCUSSIONS WITH WITH ROD DIETERTROD DIETERT (GENDER (GENDER

AFFECTS ON LEAD ALTERATIONS OF AFFECTS ON LEAD ALTERATIONS OF THE IMMUNE SYSTEMTHE IMMUNE SYSTEM))

THE SAME DISCUSSIONS WITH THE SAME DISCUSSIONS WITH FRED QUIMBYFRED QUIMBY ON GENDER ON GENDER

EFFECTS ON DEVELOPMENT OF EFFECTS ON DEVELOPMENT OF DOGGIE LUPUS in high PCB areasDOGGIE LUPUS in high PCB areas..

Page 44: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

GETTING BY WITH A LITTLE GETTING BY WITH A LITTLE HELP FROM MY FRIENDSHELP FROM MY FRIENDS

JERRIE GAVALCHIN: NOW AT JERRIE GAVALCHIN: NOW AT CORNELL UNIVERSITY FOR HER CORNELL UNIVERSITY FOR HER FEMALE SPECIFIC LUPUS-LIKE FEMALE SPECIFIC LUPUS-LIKE

AUTOIMMUNE MODEL … WHICH AUTOIMMUNE MODEL … WHICH ALLOWED US TO SHOW ALLOWED US TO SHOW

EXOGENOUS ESTROGENS AND EXOGENOUS ESTROGENS AND PCB’S COULD MAKE MALES HAVE PCB’S COULD MAKE MALES HAVE

DISEASEDISEASE

Page 45: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of
Page 46: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

NoNormal (A) and Successively worse nephrotic damage

Page 47: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of
Page 48: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

HISTOLOGICAL EVALUATIONOF KIDNEY DAMAGE

11

Page 49: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of
Page 50: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

TCDD Increases Memory TCDD Increases Memory Phenotype in Autoimmune MicePhenotype in Autoimmune Mice

Page 51: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

RECENT RESULTS WITH SNF-1 MODELRECENT RESULTS WITH SNF-1 MODEL

1- ESTROGEN TREATMENT OF NON 1- ESTROGEN TREATMENT OF NON AUTOIMMUNE INTACT FEMALE DB-1 AUTOIMMUNE INTACT FEMALE DB-1 MICE PRODUCES AUTOIMMUNE MICE PRODUCES AUTOIMMUNE DISEASEDISEASE

2- CHIMERIC FEMALE MICE (DB 1 2- CHIMERIC FEMALE MICE (DB 1 GIVEN HSCs FROM SNF-1) GIVEN HSCs FROM SNF-1)

DEVELOP AUTOIMMUNE DISEASEDEVELOP AUTOIMMUNE DISEASE

3- ER ALPHA KO’S IN ABOVE ARE 3- ER ALPHA KO’S IN ABOVE ARE RESISTANT TO E-2 TREATMENTRESISTANT TO E-2 TREATMENT

Page 52: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

THE BOTTOM LINE SEEMS TO THE BOTTOM LINE SEEMS TO ME THE FOLLOWINGME THE FOLLOWING

1- WE MUST DO MORE GENDER 1- WE MUST DO MORE GENDER SPECIFIC STUDIES ON SPECIFIC STUDIES ON

IMMUNOTOXIC EFFECTSIMMUNOTOXIC EFFECTS

2- WE MUST IDENTIFY THE 2- WE MUST IDENTIFY THE SPECIFIC CELLULAR SPECIFIC CELLULAR

TARGETS FOR TOXIC AGENTS TARGETS FOR TOXIC AGENTS THAT CAUSE IMMUNE THAT CAUSE IMMUNE

EFFECTSEFFECTS

Page 53: Environmental Exposures and the Immune System: Gender Specific Differences and consequences Allen Silverstone, SUNY Upstate Medical University Dept. of

3- WE MUST DETERMINE HOW 3- WE MUST DETERMINE HOW ESTROGEN ITSELF PLAYS A NORMAL ESTROGEN ITSELF PLAYS A NORMAL

AND NECESSARY AS WELL AS AND NECESSARY AS WELL AS ABNORMAL AND DAMAGING ROLE IN ABNORMAL AND DAMAGING ROLE IN

THE IMMUNE SYSTEMTHE IMMUNE SYSTEM

4- THIS MEANS IDENTIFYING THE 4- THIS MEANS IDENTIFYING THE CELLULAR TARGETS FOR EFFECTS, CELLULAR TARGETS FOR EFFECTS, AND THEN WHAT GENE AND THEN WHAT GENE ALTERATIONS OCCUR TO CAUSE ALTERATIONS OCCUR TO CAUSE THOSE EFFECTSTHOSE EFFECTS