SLIDE 1
Outline
- Sources of arsenic exposure
- Arsenic and human health
- Innate immune function of the lung in response
to Pseudomonas infection
- Arsenic suppresses the innate immune function
- f lung epithelial cells and professional immune
Adverse Effects of Arsenic on the Immune Response of the Lungs to - - PowerPoint PPT Presentation
Adverse Effects of Arsenic on the Immune Response of the Lungs to - - PowerPoint PPT Presentation
Adverse Effects of Arsenic on the Immune Response of the Lungs to Pseudomonas Infection Bruce A. Stanton, Ph.D. Director, Dartmouth Superfund Research Program October 31, 2016 Outline Sources of arsenic exposure Arsenic and human health
SLIDE 2
SLIDE 3
ATSDR list of substances that pose the most threat to public health
hHps://www.atsdr.cdc.gov/spl/ Google images
SLIDE 4
Sources of arsenic exposure
Google images and EHP
SLIDE 5
Arsenic exposure in the US
- Total arsenic consumpFon in the
US from water, rice and rice based products is 10-25 ppb/day per person.
- This is equal to drinking 1 to 2.5
liters of water/day containing 10 ppb of arsenic (EPA limit).
SLIDE 6
Arsenic in well water. ~3 million drink well water > 10 ppb
SLIDE 7
Arsenic and human disease
Google images
SLIDE 8
Arsenic enhances viral and bacterial infections in zebrafish
Nayak, Kim, et al. Toxicol. Sci. 2007
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Prenatal exposure to iAs is associated with dysregulated fetal immune gene and protein expression
Laine and Fry, Ann Global Health, 2016
SLIDE 10
Arsenic enhances lung infections in infants
In utero arsenic exposure increases the risk of infections and respiratory symptoms in infants
Gilbert-Diamond, et al, EHP, 2016
SLIDE 11
How does low-dose arsenic increase Pseudomonas aeruginosa lung infections? What is the mechanism?
SLIDE 12
Pseudomonas aeruginosa (Pa)
- Pa is a
ubiquitous,
- pportunisFc
pathogen that is found in burn wounds, UTIs, and lungs in paFents with COPD and CF
- Pa
develops drug resistant biofilms
SLIDE 13
Innate immunity in the lung
Pathogens (bacteria, viruses)
Mucus
IL-8, CXCL1, CXCL2 IL-1β Antimicrobial peptides Antigen presentation Epithelial cells Neutrophils Macrophages Images-fineartamerica.com
SLIDE 14
Control 5ppb DMA 10ppb DMA 5ppb MMA 10ppb MMA 5ppb AS 10ppb AS 5ppb Mix 10ppb Mix
Arsenic reduces chloride secretion by lung epithelial cells
20 40 60
Isc(uA/cm2) * * * * * * * *
CFTR Chloride SecreCon
Goodale, Barnaby and Stanton, 2016
SLIDE 15
Arsenic increases the ubiquitination and proteasomal degradation of CFTR
Bomberger and Stanton, J. Biol. Chem. 2012
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iArsenic reduces Pa stimulated IL-8 and CXCL1 secretion by lung epithelial cells
Notch, Goodale, Stanton, PLoS One, 2015
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iArsenic reduces Pa stimulated IL-1β secretion by human macrophages
IL-1β cytokine secretion (% PA01 Control) 150 100 50 PA01 No PA01
* *
5 10 iAs (ppb)
Images-fineartamerica.com Notch and Stanton, unpublished, 2016
SLIDE 18
MMA reduces Pa stimulated IL-1β secretion by macrophages
150 PA01 No PA01 100 50 IL-1β cytokine secretion (% PA01 Control)
* * *
5 10
MMA (ppb) Images-fineartamerica.com Notch and Stanton, unpublished, 2016
SLIDE 19
DMA has no effect on Pa stimulated IL-1β secretion by macrophages
IL-1β cytokine secretion (% PA01 Control) 150 100 50
DMA (ppb)
PA01 No PA01 5 10
Images-fineartamerica.com Notch and Stanton, unpublished, 2016
SLIDE 20
Arsenic reduces MCC and cytokine secretion and thereby enhances bacterial infection
Antimicrobial peptides Pathogens (bacteria, viruses)
Mucus
Macrophages Neutrophils Epithelial cells Antigen presentation
Images-fineartamerica.com
IL-8, CXCL1, MCC IL-1β
SLIDE 21
RNAseq to identify novel genes and pathways affected by arsenic
1) Human lung cells in cell culture (6 donors) 2) Exposed cells to 0, 5, 10 or 50 ppb As (25% iAs, 25% MMA, 50% DMA) for 6 days 3) RNA seq analysis of gene expression 4) Media collected for cytokine analysis
SLIDE 22
Arsenic decreases antimicrobial peptide gene expression
Lysozyme Cysteine-rich secretory protein 3
- 33%
decrease
−1
10 20 30 40 50
- 10
20 30 40 50
46% decrease
2
Log2 LYZ Counts
3.5 3.0
Log2 CRISP3 Counts Donor Donor
- A
A B
- 1
B C
- C
- D
- E
- F
- D
- E
2.5 2.0
- F
AsMix (ppb) AsMix (ppb)
Goodale and Stanton, unpublished, 2016
SLIDE 23
Arsenic decreases antigen presentation pathway gene expression
Goodale and Stanton, unpublished, 2016
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Dartmouth Superfund Program EducaConal/Outreach AcCviCes to Reduce Exposure to Arsenic in the US
SLIDE 25
EPA environmental educaConal program
Building school and community collaboraFons to eliminate arsenic from drinking water in Maine and New Hampshire: A model for the US
SLIDE 26
EPA environmental educaCon grant
- All About
Arsenic website (hHp:// www.allaboutarsenic.org/)
- CreaFon of classroom arsenic
curriculum with a focus on watershed and home well tesFng
- Partnership with community partners
to expand work on private wells
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Encouraging/facilitaCng well water tesCng for arsenic
http://www.dartmouth.edu/~toxmetal/
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Yes, EPA rules may be too lenient. Some filters reduce lead, pesCcides, chlorine, arsenic, anCbioCcs and hormones found in regulated public water supplies. New York Times
SLIDE 29
Control Zero Water PUR Brita Home Depot Wal-Mart
Zero Water filters remove arsenic from drinking water
1000 1500 * ** ** ** ** Arsenic ppb 500
Stanton et al, 2016
I have no financial stake or anything financial or other wise to gain from promoFng the use of ZERO WATER filters
SLIDE 30
Research supported by P42ES007373 from the NaConal InsCtute of Environmental Health Sciences.