inflammation as a co-stressor - northeastern university · double strand break glycosylase ap...

Inflammation as a Co-Stressor

Jennifer Kay PhDEngelward Laboratory

MIT Superfund Research ProgramNortheast Superfund Meeting

4419

Inflammation and Cancer

Pancreatitis

Pancreatic Cancer

Liver Cancer

Colon Cancer

Gastric cancer

Lung cancer

Kidney Cancer

Inflammation Cancer

Crohnrsquos disease

Ulcerative Colitis

Hepatitis

Cirrhosis

Nephritis

H pylori infection

COPD

Inflammation and Superfund Chemicals

PFAS


bull Inflammation is a strong promoter of cancer

bull Many chemical exposures cause inflammation

bull Inflammation is also modulated by

ndash Diet

ndash Behaviors

ndash Disease

bull As long as inflammation is happening there is

a greater risk for compounded consequences

of carcinogenic exposures

Multistep Model of Cancer

5

DNA Damage

3 n

Cell division and additional mutationsNormal cells

1 2

Initiating mutation

Cancer

Mutations

Inflammation

Inflammation Causes DNA Damage

Adapted from Dedon and Tannenbaum Arch Biochem Biophys 2004 6

NO

O2

ONOO-

ONOOCO2-

CO2

H2O2

N2O3O2

OH

NO2

CO3Macrophage

H2O2 + Cl-

NO2-

HOCl

NO2

Myeloperoxidase

H2O2 + Br- HOBr

Eosinophil

Eosinophil

peroxidase

Neutrophil

8oxoG

DNA Damage Causes Point Mutations

1280771279958oxoG C

8oxoG 8oxoG A

128078127995

G C

Mutation

Correct base pairing

DNA Damage Impedes DNA

Replication

8

Homologous Recombination(DNA Repair Pathway)

Double strand break

Replication Fork Breakdown

DNA replication

DNA Repair of Inflammation-Induced DamageBase Excision Repair

Base lesion


Direct ReversalBase lesion

εA3rsquoOH

εA

9

A

Homologous RecombinationDouble strand break

Glycosylase

AP lyase APE1

Polymerase

Ligase

Inflammation

Mutations

Proliferation


10

DNA Damage

3 n


1 2

Initiating mutation

Cancer


11

Inflammation Cancer

Proliferation

Cytokines chemokines growth

factors

Survival

Migration


factors

Inflammation Causes Proliferation

Orsolya Kiraly et al PLoS Genetics 2015

Every time a cell divides it has the opportunity to acquire new mutations

Ki67 A protein expressed during cell division

Inflammation

Mutations

Proliferation


13

DNA Damage

3 n


1 2

Initiating mutation

Cancer

RaDR Mice A Tool to Measure Mutations In Situ

Fluorescent spot=

Mutated cell(s)

RaDR Mouse Liver

Replication fork restoration

Sukup-Jackson et al PLoS Genetics 2014

DNA Damage During Proliferation Synergistically Increases Mutations

MNU = DNA damaging agentInf = InflammationProlif = Cellular proliferation following inflammation

Bright spot =

Mutant cell(s)

Orsolya Kiraly PLoS Genetics 2015

bull Many hazardous chemicals are metabolized to form DNA-reactive speciesndash N-nitrosamines (eg NDMA)

ndash Polycyclic aromatic hydrocarbons (PAHs eg Benzo[a]pyrene)

ndash Polychlorinated bisphenyls (PCBs)

ndash Many more PCB Adducts

Chemical Exposures Damage DNA






NDMA Contaminates Water Near the Olin Chemical Superfund Site in Wilmington MA

National Polychemicals Inc 1967

Alarming rates of child brain cancer Hodgkins disease non-Hodgkins

lymphoma and leukemia

Ground Water

Soil

NDMA-Induced DNA Lesions Promote Mutations

DNA Repair of NDMA-Induced DamageBase Excision Repair

Base lesionDouble strand break

Homologous Recombination


O6meG

3rsquoOH

3meA

G

Aag


20

AagTg animals overexpress Aag

NDMA Induces DNA DSBs

Wild Type

AagTg

Saline NDMA

With Joshua Corrigan

Pan-nuclear γH2AX = Hyperactive signaling

suggests overwhelming DNA damage

γH2AX Foci = Localized at DNA DSBs

Cell is ldquoγH2AX+rdquo if foci ge 5

γH2AX staining at DNA double strand breaks24 hours after NDMA

exposure


Wild Type

AagTg

Saline NDMA



exposure

NDMA Causes Proliferation


AagTg

Saline NDMA


Wild Type

Ki67 shows increased cell division 24 hours after

NDMA exposure

NDMA Causes Inflammatory Tissue Damage

Saline NDMA

AagTg

WT

Liver 20xWith Sebastian Carrasco

Cancer

25

Reactive Oxygen and

Nitrogen Species

DNA Damage Response

Inflammation DNA Damage

DNA repair

Inflammation DNA Damage and Cancer

BER (Aag--)

BER (AagTg)

DR(Mgmt--)

NDMA ampSuperfund Chemicals

NDMA PCBs PAHs more

Acknowledgments

P42 ES027707

Prof Bevin Engelward

Joshua Corrigan

Christy Chao

Dr Norah Owiti

Dr Simran Kaushal

Yuge Ji

Aimee Moise

Dr Orsolya Kiraly

Dr Michelle Sukup-Jackson

Sebastian Carrasco

T32-ES007020

Cancer

27

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more


Pancreatitis

Pancreatic Cancer

Liver Cancer

Colon Cancer

Gastric cancer

Lung cancer

Kidney Cancer

Inflammation Cancer

Crohnrsquos disease

Ulcerative Colitis

Hepatitis

Cirrhosis

Nephritis

H pylori infection

COPD


PFAS





ndash Diet

ndash Behaviors

ndash Disease





5

DNA Damage

3 n


1 2

Initiating mutation

Cancer

Mutations

Inflammation



NO

O2

ONOO-

ONOOCO2-

CO2

H2O2

N2O3O2

OH

NO2

CO3Macrophage

H2O2 + Cl-

NO2-

HOCl

NO2

Myeloperoxidase

H2O2 + Br- HOBr

Eosinophil

Eosinophil

peroxidase

Neutrophil

8oxoG


1280771279958oxoG C

8oxoG 8oxoG A

128078127995

G C

Mutation



Replication

8


Double strand break


DNA replication


Base lesion



εA3rsquoOH

εA

9

A


Glycosylase

AP lyase APE1

Polymerase

Ligase

Inflammation

Mutations

Proliferation


10

DNA Damage

3 n


1 2

Initiating mutation

Cancer


11

Inflammation Cancer

Proliferation


factors

Survival

Migration


factors





Inflammation

Mutations

Proliferation


13

DNA Damage

3 n


1 2

Initiating mutation

Cancer


Fluorescent spot=

Mutated cell(s)

RaDR Mouse Liver





Bright spot =

Mutant cell(s)
















Ground Water

Soil






O6meG

3rsquoOH

3meA

G

Aag


20



Wild Type

AagTg

Saline NDMA







exposure


Wild Type

AagTg

Saline NDMA



exposure



AagTg

Saline NDMA


Wild Type


NDMA exposure


Saline NDMA

AagTg

WT


Cancer

25

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more

Acknowledgments

P42 ES027707


Joshua Corrigan

Christy Chao

Dr Norah Owiti

Dr Simran Kaushal

Yuge Ji

Aimee Moise

Dr Orsolya Kiraly


Sebastian Carrasco

T32-ES007020

Cancer

27

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more


PFAS





ndash Diet

ndash Behaviors

ndash Disease





5

DNA Damage

3 n


1 2

Initiating mutation

Cancer

Mutations

Inflammation



NO

O2

ONOO-

ONOOCO2-

CO2

H2O2

N2O3O2

OH

NO2

CO3Macrophage

H2O2 + Cl-

NO2-

HOCl

NO2

Myeloperoxidase

H2O2 + Br- HOBr

Eosinophil

Eosinophil

peroxidase

Neutrophil

8oxoG


1280771279958oxoG C

8oxoG 8oxoG A

128078127995

G C

Mutation



Replication

8


Double strand break


DNA replication


Base lesion



εA3rsquoOH

εA

9

A


Glycosylase

AP lyase APE1

Polymerase

Ligase

Inflammation

Mutations

Proliferation


10

DNA Damage

3 n


1 2

Initiating mutation

Cancer


11

Inflammation Cancer

Proliferation


factors

Survival

Migration


factors





Inflammation

Mutations

Proliferation


13

DNA Damage

3 n


1 2

Initiating mutation

Cancer


Fluorescent spot=

Mutated cell(s)

RaDR Mouse Liver





Bright spot =

Mutant cell(s)
















Ground Water

Soil






O6meG

3rsquoOH

3meA

G

Aag


20



Wild Type

AagTg

Saline NDMA







exposure


Wild Type

AagTg

Saline NDMA



exposure



AagTg

Saline NDMA


Wild Type


NDMA exposure


Saline NDMA

AagTg

WT


Cancer

25

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more

Acknowledgments

P42 ES027707


Joshua Corrigan

Christy Chao

Dr Norah Owiti

Dr Simran Kaushal

Yuge Ji

Aimee Moise

Dr Orsolya Kiraly


Sebastian Carrasco

T32-ES007020

Cancer

27

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more





ndash Diet

ndash Behaviors

ndash Disease





5

DNA Damage

3 n


1 2

Initiating mutation

Cancer

Mutations

Inflammation



NO

O2

ONOO-

ONOOCO2-

CO2

H2O2

N2O3O2

OH

NO2

CO3Macrophage

H2O2 + Cl-

NO2-

HOCl

NO2

Myeloperoxidase

H2O2 + Br- HOBr

Eosinophil

Eosinophil

peroxidase

Neutrophil

8oxoG


1280771279958oxoG C

8oxoG 8oxoG A

128078127995

G C

Mutation



Replication

8


Double strand break


DNA replication


Base lesion



εA3rsquoOH

εA

9

A


Glycosylase

AP lyase APE1

Polymerase

Ligase

Inflammation

Mutations

Proliferation


10

DNA Damage

3 n


1 2

Initiating mutation

Cancer


11

Inflammation Cancer

Proliferation


factors

Survival

Migration


factors





Inflammation

Mutations

Proliferation


13

DNA Damage

3 n


1 2

Initiating mutation

Cancer


Fluorescent spot=

Mutated cell(s)

RaDR Mouse Liver





Bright spot =

Mutant cell(s)
















Ground Water

Soil






O6meG

3rsquoOH

3meA

G

Aag


20



Wild Type

AagTg

Saline NDMA







exposure


Wild Type

AagTg

Saline NDMA



exposure



AagTg

Saline NDMA


Wild Type


NDMA exposure


Saline NDMA

AagTg

WT


Cancer

25

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more

Acknowledgments

P42 ES027707


Joshua Corrigan

Christy Chao

Dr Norah Owiti

Dr Simran Kaushal

Yuge Ji

Aimee Moise

Dr Orsolya Kiraly


Sebastian Carrasco

T32-ES007020

Cancer

27

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more


5

DNA Damage

3 n


1 2

Initiating mutation

Cancer

Mutations

Inflammation



NO

O2

ONOO-

ONOOCO2-

CO2

H2O2

N2O3O2

OH

NO2

CO3Macrophage

H2O2 + Cl-

NO2-

HOCl

NO2

Myeloperoxidase

H2O2 + Br- HOBr

Eosinophil

Eosinophil

peroxidase

Neutrophil

8oxoG


1280771279958oxoG C

8oxoG 8oxoG A

128078127995

G C

Mutation



Replication

8


Double strand break


DNA replication


Base lesion



εA3rsquoOH

εA

9

A


Glycosylase

AP lyase APE1

Polymerase

Ligase

Inflammation

Mutations

Proliferation


10

DNA Damage

3 n


1 2

Initiating mutation

Cancer


11

Inflammation Cancer

Proliferation


factors

Survival

Migration


factors





Inflammation

Mutations

Proliferation


13

DNA Damage

3 n


1 2

Initiating mutation

Cancer


Fluorescent spot=

Mutated cell(s)

RaDR Mouse Liver





Bright spot =

Mutant cell(s)
















Ground Water

Soil






O6meG

3rsquoOH

3meA

G

Aag


20



Wild Type

AagTg

Saline NDMA







exposure


Wild Type

AagTg

Saline NDMA



exposure



AagTg

Saline NDMA


Wild Type


NDMA exposure


Saline NDMA

AagTg

WT


Cancer

25

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more

Acknowledgments

P42 ES027707


Joshua Corrigan

Christy Chao

Dr Norah Owiti

Dr Simran Kaushal

Yuge Ji

Aimee Moise

Dr Orsolya Kiraly


Sebastian Carrasco

T32-ES007020

Cancer

27

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more



NO

O2

ONOO-

ONOOCO2-

CO2

H2O2

N2O3O2

OH

NO2

CO3Macrophage

H2O2 + Cl-

NO2-

HOCl

NO2

Myeloperoxidase

H2O2 + Br- HOBr

Eosinophil

Eosinophil

peroxidase

Neutrophil

8oxoG


1280771279958oxoG C

8oxoG 8oxoG A

128078127995

G C

Mutation



Replication

8


Double strand break


DNA replication


Base lesion



εA3rsquoOH

εA

9

A


Glycosylase

AP lyase APE1

Polymerase

Ligase

Inflammation

Mutations

Proliferation


10

DNA Damage

3 n


1 2

Initiating mutation

Cancer


11

Inflammation Cancer

Proliferation


factors

Survival

Migration


factors





Inflammation

Mutations

Proliferation


13

DNA Damage

3 n


1 2

Initiating mutation

Cancer


Fluorescent spot=

Mutated cell(s)

RaDR Mouse Liver





Bright spot =

Mutant cell(s)
















Ground Water

Soil






O6meG

3rsquoOH

3meA

G

Aag


20



Wild Type

AagTg

Saline NDMA







exposure


Wild Type

AagTg

Saline NDMA



exposure



AagTg

Saline NDMA


Wild Type


NDMA exposure


Saline NDMA

AagTg

WT


Cancer

25

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more

Acknowledgments

P42 ES027707


Joshua Corrigan

Christy Chao

Dr Norah Owiti

Dr Simran Kaushal

Yuge Ji

Aimee Moise

Dr Orsolya Kiraly


Sebastian Carrasco

T32-ES007020

Cancer

27

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more


1280771279958oxoG C

8oxoG 8oxoG A

128078127995

G C

Mutation



Replication

8


Double strand break


DNA replication


Base lesion



εA3rsquoOH

εA

9

A


Glycosylase

AP lyase APE1

Polymerase

Ligase

Inflammation

Mutations

Proliferation


10

DNA Damage

3 n


1 2

Initiating mutation

Cancer


11

Inflammation Cancer

Proliferation


factors

Survival

Migration


factors





Inflammation

Mutations

Proliferation


13

DNA Damage

3 n


1 2

Initiating mutation

Cancer


Fluorescent spot=

Mutated cell(s)

RaDR Mouse Liver





Bright spot =

Mutant cell(s)
















Ground Water

Soil






O6meG

3rsquoOH

3meA

G

Aag


20



Wild Type

AagTg

Saline NDMA







exposure


Wild Type

AagTg

Saline NDMA



exposure



AagTg

Saline NDMA


Wild Type


NDMA exposure


Saline NDMA

AagTg

WT


Cancer

25

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more

Acknowledgments

P42 ES027707


Joshua Corrigan

Christy Chao

Dr Norah Owiti

Dr Simran Kaushal

Yuge Ji

Aimee Moise

Dr Orsolya Kiraly


Sebastian Carrasco

T32-ES007020

Cancer

27

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more


Replication

8


Double strand break


DNA replication


Base lesion



εA3rsquoOH

εA

9

A


Glycosylase

AP lyase APE1

Polymerase

Ligase

Inflammation

Mutations

Proliferation


10

DNA Damage

3 n


1 2

Initiating mutation

Cancer


11

Inflammation Cancer

Proliferation


factors

Survival

Migration


factors





Inflammation

Mutations

Proliferation


13

DNA Damage

3 n


1 2

Initiating mutation

Cancer


Fluorescent spot=

Mutated cell(s)

RaDR Mouse Liver





Bright spot =

Mutant cell(s)
















Ground Water

Soil






O6meG

3rsquoOH

3meA

G

Aag


20



Wild Type

AagTg

Saline NDMA







exposure


Wild Type

AagTg

Saline NDMA



exposure



AagTg

Saline NDMA


Wild Type


NDMA exposure


Saline NDMA

AagTg

WT


Cancer

25

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more

Acknowledgments

P42 ES027707


Joshua Corrigan

Christy Chao

Dr Norah Owiti

Dr Simran Kaushal

Yuge Ji

Aimee Moise

Dr Orsolya Kiraly


Sebastian Carrasco

T32-ES007020

Cancer

27

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more


Base lesion



εA3rsquoOH

εA

9

A


Glycosylase

AP lyase APE1

Polymerase

Ligase

Inflammation

Mutations

Proliferation


10

DNA Damage

3 n


1 2

Initiating mutation

Cancer


11

Inflammation Cancer

Proliferation


factors

Survival

Migration


factors





Inflammation

Mutations

Proliferation


13

DNA Damage

3 n


1 2

Initiating mutation

Cancer


Fluorescent spot=

Mutated cell(s)

RaDR Mouse Liver





Bright spot =

Mutant cell(s)
















Ground Water

Soil






O6meG

3rsquoOH

3meA

G

Aag


20



Wild Type

AagTg

Saline NDMA







exposure


Wild Type

AagTg

Saline NDMA



exposure



AagTg

Saline NDMA


Wild Type


NDMA exposure


Saline NDMA

AagTg

WT


Cancer

25

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more

Acknowledgments

P42 ES027707


Joshua Corrigan

Christy Chao

Dr Norah Owiti

Dr Simran Kaushal

Yuge Ji

Aimee Moise

Dr Orsolya Kiraly


Sebastian Carrasco

T32-ES007020

Cancer

27

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more

Inflammation

Mutations

Proliferation


10

DNA Damage

3 n


1 2

Initiating mutation

Cancer


11

Inflammation Cancer

Proliferation


factors

Survival

Migration


factors





Inflammation

Mutations

Proliferation


13

DNA Damage

3 n


1 2

Initiating mutation

Cancer


Fluorescent spot=

Mutated cell(s)

RaDR Mouse Liver





Bright spot =

Mutant cell(s)
















Ground Water

Soil






O6meG

3rsquoOH

3meA

G

Aag


20



Wild Type

AagTg

Saline NDMA







exposure


Wild Type

AagTg

Saline NDMA



exposure



AagTg

Saline NDMA


Wild Type


NDMA exposure


Saline NDMA

AagTg

WT


Cancer

25

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more

Acknowledgments

P42 ES027707


Joshua Corrigan

Christy Chao

Dr Norah Owiti

Dr Simran Kaushal

Yuge Ji

Aimee Moise

Dr Orsolya Kiraly


Sebastian Carrasco

T32-ES007020

Cancer

27

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more


11

Inflammation Cancer

Proliferation


factors

Survival

Migration


factors





Inflammation

Mutations

Proliferation


13

DNA Damage

3 n


1 2

Initiating mutation

Cancer


Fluorescent spot=

Mutated cell(s)

RaDR Mouse Liver





Bright spot =

Mutant cell(s)
















Ground Water

Soil






O6meG

3rsquoOH

3meA

G

Aag


20



Wild Type

AagTg

Saline NDMA







exposure


Wild Type

AagTg

Saline NDMA



exposure



AagTg

Saline NDMA


Wild Type


NDMA exposure


Saline NDMA

AagTg

WT


Cancer

25

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more

Acknowledgments

P42 ES027707


Joshua Corrigan

Christy Chao

Dr Norah Owiti

Dr Simran Kaushal

Yuge Ji

Aimee Moise

Dr Orsolya Kiraly


Sebastian Carrasco

T32-ES007020

Cancer

27

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more





Inflammation

Mutations

Proliferation


13

DNA Damage

3 n


1 2

Initiating mutation

Cancer


Fluorescent spot=

Mutated cell(s)

RaDR Mouse Liver





Bright spot =

Mutant cell(s)
















Ground Water

Soil






O6meG

3rsquoOH

3meA

G

Aag


20



Wild Type

AagTg

Saline NDMA







exposure


Wild Type

AagTg

Saline NDMA



exposure



AagTg

Saline NDMA


Wild Type


NDMA exposure


Saline NDMA

AagTg

WT


Cancer

25

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more

Acknowledgments

P42 ES027707


Joshua Corrigan

Christy Chao

Dr Norah Owiti

Dr Simran Kaushal

Yuge Ji

Aimee Moise

Dr Orsolya Kiraly


Sebastian Carrasco

T32-ES007020

Cancer

27

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more


Fluorescent spot=

Mutated cell(s)

RaDR Mouse Liver





Bright spot =

Mutant cell(s)
















Ground Water

Soil






O6meG

3rsquoOH

3meA

G

Aag


20



Wild Type

AagTg

Saline NDMA







exposure


Wild Type

AagTg

Saline NDMA



exposure



AagTg

Saline NDMA


Wild Type


NDMA exposure


Saline NDMA

AagTg

WT


Cancer

25

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more

Acknowledgments

P42 ES027707


Joshua Corrigan

Christy Chao

Dr Norah Owiti

Dr Simran Kaushal

Yuge Ji

Aimee Moise

Dr Orsolya Kiraly


Sebastian Carrasco

T32-ES007020

Cancer

27

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more



Bright spot =

Mutant cell(s)
















Ground Water

Soil






O6meG

3rsquoOH

3meA

G

Aag


20



Wild Type

AagTg

Saline NDMA







exposure


Wild Type

AagTg

Saline NDMA



exposure



AagTg

Saline NDMA


Wild Type


NDMA exposure


Saline NDMA

AagTg

WT


Cancer

25

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more

Acknowledgments

P42 ES027707


Joshua Corrigan

Christy Chao

Dr Norah Owiti

Dr Simran Kaushal

Yuge Ji

Aimee Moise

Dr Orsolya Kiraly


Sebastian Carrasco

T32-ES007020

Cancer

27

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more















Ground Water

Soil






O6meG

3rsquoOH

3meA

G

Aag


20



Wild Type

AagTg

Saline NDMA







exposure


Wild Type

AagTg

Saline NDMA



exposure



AagTg

Saline NDMA


Wild Type


NDMA exposure


Saline NDMA

AagTg

WT


Cancer

25

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more

Acknowledgments

P42 ES027707


Joshua Corrigan

Christy Chao

Dr Norah Owiti

Dr Simran Kaushal

Yuge Ji

Aimee Moise

Dr Orsolya Kiraly


Sebastian Carrasco

T32-ES007020

Cancer

27

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more






O6meG

3rsquoOH

3meA

G

Aag


20



Wild Type

AagTg

Saline NDMA







exposure


Wild Type

AagTg

Saline NDMA



exposure



AagTg

Saline NDMA


Wild Type


NDMA exposure


Saline NDMA

AagTg

WT


Cancer

25

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more

Acknowledgments

P42 ES027707


Joshua Corrigan

Christy Chao

Dr Norah Owiti

Dr Simran Kaushal

Yuge Ji

Aimee Moise

Dr Orsolya Kiraly


Sebastian Carrasco

T32-ES007020

Cancer

27

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more


Wild Type

AagTg

Saline NDMA







exposure


Wild Type

AagTg

Saline NDMA



exposure



AagTg

Saline NDMA


Wild Type


NDMA exposure


Saline NDMA

AagTg

WT


Cancer

25

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more

Acknowledgments

P42 ES027707


Joshua Corrigan

Christy Chao

Dr Norah Owiti

Dr Simran Kaushal

Yuge Ji

Aimee Moise

Dr Orsolya Kiraly


Sebastian Carrasco

T32-ES007020

Cancer

27

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more


Wild Type

AagTg

Saline NDMA



exposure



AagTg

Saline NDMA


Wild Type


NDMA exposure


Saline NDMA

AagTg

WT


Cancer

25

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more

Acknowledgments

P42 ES027707


Joshua Corrigan

Christy Chao

Dr Norah Owiti

Dr Simran Kaushal

Yuge Ji

Aimee Moise

Dr Orsolya Kiraly


Sebastian Carrasco

T32-ES007020

Cancer

27

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more



AagTg

Saline NDMA


Wild Type


NDMA exposure


Saline NDMA

AagTg

WT


Cancer

25

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more

Acknowledgments

P42 ES027707


Joshua Corrigan

Christy Chao

Dr Norah Owiti

Dr Simran Kaushal

Yuge Ji

Aimee Moise

Dr Orsolya Kiraly


Sebastian Carrasco

T32-ES007020

Cancer

27

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more


Saline NDMA

AagTg

WT


Cancer

25

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more

Acknowledgments

P42 ES027707


Joshua Corrigan

Christy Chao

Dr Norah Owiti

Dr Simran Kaushal

Yuge Ji

Aimee Moise

Dr Orsolya Kiraly


Sebastian Carrasco

T32-ES007020

Cancer

27

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more

Cancer

25

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more

Acknowledgments

P42 ES027707


Joshua Corrigan

Christy Chao

Dr Norah Owiti

Dr Simran Kaushal

Yuge Ji

Aimee Moise

Dr Orsolya Kiraly


Sebastian Carrasco

T32-ES007020

Cancer

27

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more

Acknowledgments

P42 ES027707


Joshua Corrigan

Christy Chao

Dr Norah Owiti

Dr Simran Kaushal

Yuge Ji

Aimee Moise

Dr Orsolya Kiraly


Sebastian Carrasco

T32-ES007020

Cancer

27

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more

Cancer

27

Reactive Oxygen and

Nitrogen Species

DNA Damage Response


DNA repair


BER (Aag--)

BER (AagTg)

DR(Mgmt--)


NDMA PCBs PAHs more

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