Toxicology Study of Inhalable Soil Dusts from the Paso del Norte

RegionDr. N. Shane Cutler, Ph.D.

University of UtahSalt Lake City, UT

SCERP grant A-05-06

Soil Dusts

• JE-Juarez City Street Dust, Mexico • WM-West Mesa, New Mexico • DD-Tooele Desert Dust, Utah• WTR-Well Test Road, Arizona• UTEP-U. of Texas, El Paso parking lot• MC-Mancos, Colorado• FB-Ft. Bliss, Texas• BA-Burned Artillery Range, New Mexico

Soil Dusts are collected from arid regions and separated out into an inhalable 2.5 μm diameter fraction. Cells are treated at 40 μg/cm2

Veranth, et al Environ Health Perspectives. 2006 Mar;114(3):341-9

Veranth, et al Environ Health Perspectives. 2006 Mar;114(3):341-9

Univariate correlations of soil-derived dust composition variables with the concentration of IL-6 in the cell media at 24 hr.(A) EC1 (R2 = 0.50). (B) OP (R2 = 0.46). (C) Calcium/aluminum (R2 = 0.21). (D) Endotoxin (R2 = 0.43). (E) Iron (R2 = 0.03). (F) Arsenic + selenium + mercury + lead (R2 = 0.01).

The MAP Kinase Pathways

Raf, Mos, Tpl2

Mek1/2

Erk1/2

MKK3/6

P38 MAPK α/β/γ

MLK3, TAK, DLK

MKK4/7

JNK1/2/3

U0126

p38i JNKi

Growth Factors, Mitogens, GPCR

Stress, Inflammatory Cytokines, Growth Factors, Mitogens, GPCR

Inflammation, Apoptosis, Growth, Differentiation

Growth, DifferentiationDevelopment

Stimulus

MAPKKK

MAPKK

MAPK

BiologicalResponse

MEKK1,4MLK3,ASK1

Inhibitors of Map Kinase Pathways Block IL-6 Production in vitro

0

20

40

60

80

100

120

BA

DD

FB JE MC

UTE

P

WM

WTR

Soil Dust

IL-6

(pg/m

L)

0U0126p38iJ NKiCONTROL

Inflammatory Dust Induces p38 MAPK phosphorylation

in vitro

TotalERK ►

U0126: - + - + - + - +

phosphop38 ►

GAPDH►

phosphoJNK►

TotalJNK ►

SOIL DUSTUTEP JE WM Nonep38i: - + - + - + - +

JNKi: - + - + - + - +

PhosphoERK ►

Tracheal Instillation of Soil Dust

----

Bronchial Alveolar Lavage

----

Bronchial Alveolar Lavage

----

Bronchial Alveolar Lavage

Neutrophil

Eosinophil

Basophil Lymphocyte

Monocyte

Lactate DehydrogenaseIL-6

Total Protein

Inhaled poorly

Inhaled well

Lactate Dehydrogenase

0.0

1.0

2.0

3.0

4.0

5.0

6.0L

DH

Ac

tiv

ity

Serum IL-6

0.00

0.050.10

0.15

0.20

0.250.30

0.35

0.40

Saline coarse JE

A45

0-A

540

Neutrophil

Eosinophil

Basophil Lymphocyte

Monocyte

%Neutrophils By Treatment

%N

eu

tro

ph

ils

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

Coarse Fine Saline

Treatment

Analysis Display

Oneway Anova

Summary of FitRSquareRSquare AdjRoot Mean Square ErrorMean of ResponseObservations (or Sum Wgts)

0.3225040.2182740.0883660.399189

16

Analysis of VarianceSourceModelErrorC Total

DF 2

13 15

Sum of Squares0.048321780.101511190.14983297

Mean Square0.0241610.0078090.009989

F Ratio 3.0942Prob>F 0.0796

Means for Oneway AnovaLevelCoarseFineSaline

Number 5 6 5

Mean0.4764440.3833710.340915

Std Error0.039520.036080.03952

Std Error uses a pooled estimate of error variance

%Neutrophils By Treatment

%N

eu

tro

ph

ils

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

Coarse Fine Saline

Treatment

Analysis Display

Oneway Anova

Summary of FitRSquareRSquare AdjRoot Mean Square ErrorMean of ResponseObservations (or Sum Wgts)

0.3225040.2182740.0883660.399189

16

Analysis of VarianceSourceModelErrorC Total

DF 2

13 15

Sum of Squares0.048321780.101511190.14983297

Mean Square0.0241610.0078090.009989

F Ratio 3.0942Prob>F 0.0796

Means for Oneway AnovaLevelCoarseFineSaline

Number 5 6 5

Mean0.4764440.3833710.340915

Std Error0.039520.036080.03952

Std Error uses a pooled estimate of error variance

phospho38

Saline Fine JE Coarse JE

phosphoJNK

Total JNK

The MAP Kinase Pathways

Raf, Mos, Tpl2

Mek1/2

Erk1/2

MKK3/6

P38 MAPK α/β/γ

MLK3, TAK, DLK

MKK4/7

JNK1/2/3

U0126

p38i JNKi

Growth Factors, Mitogens, GPCR

Stress, Inflammatory Cytokines, Growth Factors, Mitogens, GPCR

Inflammation, Apoptosis, Growth, Differentiation

Growth, DifferentiationDevelopment

Stimulus

MAPKKK

MAPKK

MAPK

BiologicalResponse

MEKK1,4MLK3,ASK1

Neutrophil Enrichment in Rat Bronchialveolar Lavage Fluid

0%

10%

20%

30%

40%

50%

60%

Saline Fine JE Coarse JE

% N

eu

tro

ph

ils

Neutrophil

Eosinophil

Basophil Lymphocyte

Monocyte