Long-term effects of early-life exposures on immunity and - - PowerPoint PPT Presentation

▶
long term effects of early life exposures on immunity and
SMART_READER_LITE
LIVE PREVIEW

Long-term effects of early-life exposures on immunity and - - PowerPoint PPT Presentation

Oct 14, 2023 221 likes •562 views

Long-term effects of early-life exposures on immunity and (infec8ous) disease risk Fenna Sill, Ph.D. Department of Environmental Health Sciences, UC Berkeley School of Public Health Department of Environmental Health & Engineering, Johns

slide-1
SLIDE 1

Long-term effects of early-life exposures on immunity and (infec8ous) disease risk

Fenna Sillé, Ph.D.

Department of Environmental Health Sciences, UC Berkeley School of Public Health Department of Environmental Health & Engineering, Johns Hopkins Bloomberg School of Public Health

The Interplay Between Environmental Exposures and InfecFous Agents, session III: Environmental Chemicals and Immune Response NIEHS Superfund Research Program Webinar, 7 November 2016

slide-2
SLIDE 2

Immunomodula8on

Adapted from: CasareQ & Doull’s EssenFals of Toxicology, 2010. 2nd ediFon (Klaassen CD, Watkins JB, eds) New York: McGraw-Hill. ISBN – 978-0-07-162240-0

May lead to: Autoimmune diseases; hypersensitivity & allergy; inflammatory diseases & tissue damage May lead to: Enhanced susceptibility to cancer, (infectious) diseases

Immuno- enhancement Homeostasis Immuno- suppression

Environmental exposures: e.g. pharmaceuticals, pollutants, toxic chemicals, metals, mineral fibers, nanoparticles, dietary and microbiome metabolites No Effect

slide-3
SLIDE 3

Arsenic, immunity & (infec8ous) disease risk

slide-4
SLIDE 4

Arsenic prevalence

  • Modeled global probability of geogenic arsenic in groundwater under reducing and

high-pH/oxidizing aquifer condiFons

  • US EPA & WHO drinking water standard = 10 µg/L .

Eawag modeled from Amini M., et al. Environ Sci Technol. 2008.

Google Images, Wikimedia Commons

slide-5
SLIDE 5

Arsenic exposure

Contaminated drinking water Industrial & agricultural Contaminated crops

Arsenic

Coal burning

Nigel Bruce/WHO

Google Images, Wikimedia Commons, WHO

slide-6
SLIDE 6

Arsenic-related adverse health effects

Skin lesions Cancer (skin, lung, bladder & kidney) Cardiovascular diseases Reproduc8ve effects Diabetes Respiratory diseases

WHO, Wikimedia Commons

slide-7
SLIDE 7

Early-life exposure to arsenic in Chile

Arsenic removal plant installed New water source

Ferreccio, C., et al. Epidemiology 2000; Smith, A., et al. EHP 2006 ; Yuan, Y., et al. Epidemiology 2010; Steinmaus, C., et al. CEBP 2013

Chile

slide-8
SLIDE 8

Early-life exposure to arsenic in Chile

Standard Mortality Rate

Arsenic removal plant installed New water source

> 40 years later

Smith, A., et al. EHP 2006 ; Yuan, Y., et al. Am.J.Epi. 2007; Yuan, Y., et al. Epidemiology 2010; Steinmaus, C., et al. CEBP 2013

Chile

slide-9
SLIDE 9

Early-life exposure to arsenic in Chile

Smith, A., et al. EHP 2006 ; Yuan, Y., et al. Am.J.Epi. 2007; Yuan, Y., et al. Epidemiology 2010; Steinmaus, C., et al. CEBP 2013

Rare evidence supporFng the “Developmental Origins of Health and Disease” hypothesis.

Standard Mortality Rate

> 40 years later Chile

slide-10
SLIDE 10

Early-life exposure to arsenic in Chile

Smith, A., et al. EHP 2006; Smith, A. et al. Am. J. Epi. 2011

Tuberculosis mortality

Chile

slide-11
SLIDE 11

Eawag modeled from Amini M., et al. Environ Sci Technol. 2008.

Arsenic prevalence

slide-12
SLIDE 12

Tuberculosis incidence

slide-13
SLIDE 13

0 wks 30 42 10 20

GestaFonal period Child development Adulthood

0 years 18 45 Basic immune system complete

Increased disease incidence & mortality Arsenic Arsenic

Memory cells Macrophages T cells Treg cells B cells NK cells DendriFc cells TH1 vs TH2 cells

AdapFve Innate

Early-life exposure to arsenic

slide-14
SLIDE 14

General hypothesis: Exposure-induced immune developmental changes contribute to the persistent global burden of infecFous and chronic diseases. Study models: Arsenic & TB

Google Images, Wikimedia Commons

slide-15
SLIDE 15

Arsenic & macrophages

Specific hypothesis:

Early-life exposure to arsenic alters macrophage development & function causing increased disease later in life.

Cytokines/chemokines Signaling lipids

Macrophages TLR

Nitric Oxide

M1: Pro-inflammatory, Bactericidal acFvity, Tumor suppression M2: Scavenging, Tissue repair, Angiogenesis, Tumor promoFon

Arsenic

?

Wikimedia Commons

slide-16
SLIDE 16

How does arsenic alter macrophages?

Macrophages Arsenic-treated macrophages Mouse bone marrow

Metabolite analysis

Homeostasis

Google Images, Wikimedia Commons

slide-17
SLIDE 17

Arsenic alters signaling lipids expression

Macrophages Arsenic-treated macrophages

Metabolite analysis

Mouse bone marrow

Homeostasis

Sillé et al, unpublished

slide-18
SLIDE 18

Pro-inflammatory and pro-tumorigenic signaling lipids

Arsenic alters signaling lipids expression

Homeostasis

Sillé et al, unpublished

slide-19
SLIDE 19

How does arsenic alter macrophages?

Signaling protein analysis

Macrophages Arsenic-treated macrophages

Homeostasis

Mouse bone marrow

Google Images, Wikimedia Commons

slide-20
SLIDE 20

! ! **! ! ! ***! **! **! ! ! ! ! ! **! ! ! ! **! ***! ! ***! **! !

200 400 600 800 1000 1200 Eotaxin G-CSF GM-CSF IFN-g IL-10 IL-12 (p40) IL-12 (p70) IL-13 IL-17A IL-1a IL-1b IL-2 IL-3 IL-4 IL-5 IL-6 IL-9 KC MCP-1 MIP-1a MIP-1b RANTES TNF-a Relative units Unexposed MMA3 exposed (1uM)

Arsenic alters cytokine/chemokine expression

Macrophages Arsenic-treated macrophages

Signaling protein analysis

Mouse bone marrow

Homeostasis

Sillé et al, unpublished

slide-21
SLIDE 21

! ! **! ! ! ***! **! **! ! ! ! ! ! **! ! ! ! **! ***! ! ***! **! !

200 400 600 800 1000 1200 Eotaxin G-CSF GM-CSF IFN-g IL-10 IL-12 (p40) IL-12 (p70) IL-13 IL-17A IL-1a IL-1b IL-2 IL-3 IL-4 IL-5 IL-6 IL-9 KC MCP-1 MIP-1a MIP-1b RANTES TNF-a Relative units Unexposed MMA3 exposed (1uM)

Arsenic alters cytokine/chemokine expression

Homeostasis

Sillé et al, unpublished

slide-22
SLIDE 22

Does arsenic alter macrophage ac8va8on?

Macrophages Arsenic-treated macrophages TLR2 acFvaFon: PamCys3

slide-23
SLIDE 23

Arsenic alters cytokine/chemokine expression in ac8vated macrophages

Macrophages Arsenic-treated macrophages TLR2 acFvaFon: PamCys3

Sillé et al, unpublished

slide-24
SLIDE 24

Arsenic alters nitric oxide produc8on in ac8vated macrophages

Macrophages Arsenic-treated macrophages TLR2 acFvaFon: PamCys3

Sillé et al, unpublished

slide-25
SLIDE 25

Arsenic & macrophages

Monocytes / resFng macrophages

Arsenic

TLRs TLRs M2 M1 M1: Pro-inflammatory Bactericidal acFvity Tumor suppression M2: Scavenging Tissue repair Angiogenesis Tumor promoFon ` TLRs

iNOS

Adapted from: Bosurgi, L., et al. Front. Immunol. 2011

VGEFs GlucocorFcoids PGE VitD3

Google Images, Wikimedia Commons

slide-26
SLIDE 26

Arsenic-targeted pathways that favor tumor progression

Stefano Fogli, et al. (2008) The molecular bases of cannabinoid action in cancer. Cancer Therapy Vol 6, 103-116, 2008.

slide-27
SLIDE 27

Arsenic-targeted pathways relevant to TB

Kanehisa M, et al. (2000) Kegg: Kyoto encyclopedia of genes and genomes. Nucleic acids research. (28):27-30. PMCID: 102409.

NOD-like receptor signaling pathway TOLL-like receptor signaling pathway PPAR signaling pathway

slide-28
SLIDE 28

Does arsenic alter tuberculosis outcome?

Macrophages Arsenic-treated macrophages

Mycobacterium tuberculosis

Mouse bone marrow

Google Images, Wikimedia Commons

slide-29
SLIDE 29

Arsenic during differen8a8on alters M. tuberculosis infec8ons

Macrophages Arsenic-treated macrophages

Mycobacterium tuberculosis

Mouse bone marrow 6hrs MMA3 + 24hrs M. tuberculosis

Sillé et al, unpublished

slide-30
SLIDE 30

Arsenic alters innate immunity & disease risk

Macrophages

Arsenic

M1: Pro-inflammatory Bactericidal acFvity Tumor suppression M2: Scavenging Tissue repair Angiogenesis Tumor promo4on TB suscep8bility

Google Images, Wikimedia Commons

slide-31
SLIDE 31

Next steps:

Arsenic-treated macrophages In vitro In vivo Early-life arsenic- exposed mouse studies Ex vivo Early-life arsenic exposed human popula8on study Differen8a8on Aim 1 Aim 2 Aim 3

Google Images, Wikimedia Commons

slide-32
SLIDE 32

IdenFfy biomarkers and maybe even therapeuFc targets! Understand the long-term effects of early-life exposure Test immune funcFon during disease Screen for signaling molecules & metabolites

Next steps:

slide-33
SLIDE 33

COLLEAGUES:

  • PI: Martyn Smith, PhD (UC Berkeley)

Ø Sylvia Sanchez (UC Berkeley) Ø Felicia Castriota (UC Berkeley) Ø Smith lab members

  • PI: Daniel Nomura, PhD (UC Berkeley)

Ø Daniel Medina-Cleghorn (UC Berkeley) Ø Breanna Ford (UC Berkeley) COLLABORATORS:

  • Craig Steinmaus, MD, MPH (UC Berkeley)
  • CaQerina Ferreccio, MD, MPH (PonFficia Universidad Católica de Chile)
  • Allan Smith, PhD (UC Berkeley)
  • Lee Riley, MD, PhD (UC Berkeley)
  • Sarah Stanley, PhD (UC Berkeley)

FUNDING:

  • NIEHS SuperFund Grant # P42ES004705
  • NIEHS K99 Grant# K99ES024808

For further informa4on please contact Fenna Sillé, PhD : FSILLE1@JHU.EDU

Thank you!