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Systems biology and toxic metals: Linking biological pathways and long term human health effects

Systems biology and toxic metals: Linking biological pathways and long term human health effects. Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA. Fry Lab Mission.

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Systems biology and toxic metals: Linking biological pathways and long term human health effects

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  1. Systems biology and toxic metals: Linking biological pathways and long term human health effects Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA

  2. Fry Lab Mission Explore biological effects of exposure to environmental agents: Prevent detrimental health effects from exposure Understand impact on human health: Molecular basis for disease Accurately detect exposure Biomarkers of population exposure, biomarkers of disease state Predict inter-individual differences in susceptibility to disease

  3. A global poison: iAs contamination is affecting individuals around the world iAs continues to poison the drinking water of tens of millions of people around the world

  4. A global poison: iAs contamination is affecting individuals around the world Southeast Asia alone 40 million exposed to levels above 50 ppb iAs continues to poison the drinking water of tens of millions of people around the world

  5. iAs continues to poison the drinking water of tens of millions of people around the world Raise awareness of areas of concern

  6. More than 2.3 million people in North Carolina use water from private, unregulated wells • Abstract #477: AP Sanders: Association between metals in private wells and birth defects 2009 75,000 people >63,000 wells over 10 yrs 1436 wells >10 ppb Hundreds > 50 ppb Max=800 ppb Sanders et al. Environ Int 2012

  7. Toxic metals are detectable in pregnant women in North Carolina Mercury: 5 exceed pregnancy level of concern (3.5 ug/L) Lead: 1 exceeds CDC pregnant women advisory (5 ug/dL)

  8. Health effects of arsenic: cancer and non cancer endpoints • Cancer (Group 1 IARC) • Liver, lung, bladder, kidney, prostate • Non-cancer • peripheral vascular disease • cardiovascular disease (e.g. atherosclerosis) • neurological effects • birth outcomes • diabetes

  9. Health effects of arsenic: cancer and non cancer endpoints • Cancer (Group 1 IARC) • Liver, lung, bladder, kidney, prostate • Non-cancer • peripheral vascular disease • cardiovascular disease (e.g. atherosclerosis) • neurological effects • birth outcomes • diabetes

  10. Unraveling the complex mode of action of iAs • iAs is not a point mutagen • iAs is generally negative in standard animal carcinogenesis studies • Research supports complex mode of action

  11. in utero exposure to iAs in rodents-alarming findings In utero exposure is associated with adult onset disease CD1 mice, exposed to 85 ppm iAs increase in hepatocellular carcinomas Gene expression changes in livers of offspring exposed to arsenic in uterowhen reach adulthood DNA methylation changes in target tissues-(ER-α showed hypomethylation) Waalkes, M. P. et al ToxicolApplPharmacol, 198. 377-384 (2004). Waalkes, M. P., et al, Journal of the National Cancer Institute, 96. 466-474 (2004). Xie, Y., et al, Toxicology, 236. 7-15 (2007).

  12. Prenatal and early life iAs exposure in humans and mortality Cancer Non-Cancer Increased mortality from bladder, kidney, liver and lung cancer from prenatal and early childhood exposures (Smith et al 2012, Liawet al., 2008; Smith et al., 2006). Prenatal exposure in humans and adult disease: supporting epigenetic modifications

  13. What are biological mechanisms underlying the long-term health effects associated with early life arsenic exposure?

  14. Establishing a prospective maternal-child cohort: Gómez Palacio, Mexico Gómez Palacio, Mexico García Vargas • Study launched in 2010 (ONES NIEHS) • Concerns over iAs in water (LM Del Razo) • Research network (M Styblo) • Prenatal exposure to iAs has not been assessed • >200 mother-baby pairs recruited

  15. Various endpoints as biomarkers of exposure: Integrated view of systems-wide effects of iAs Collection and isolation of samples for protein, mRNA, DNA assessment Inform mechanism of disease

  16. Biomarkers of Exposure to Arsenic The BEAR Study Inform mechanism of disease

  17. Pregnant women are exposed to high levels of iAs through drinking water 53% % 28% Collected urine during third trimester of pregnancy and drinking water from the home

  18. Pregnant women are exposed to high levels of iAs through drinking water N=107 (53%) exposed to >10 ppb N=56 (28%) exposed to >25 ppb Range in water <1 ppb to 240 ppb UAs to WAs p<0.01 53% % 28% Collected urine during third trimester of pregnancy and drinking water from the home

  19. Pregnant women are exposed to high levels of iAs through drinking water N=107 (53%) exposed to >10 ppb N=56 (28%) exposed to >25 ppb Range in water <1 ppb to 240 ppb Pregnant women are being exposed to elevated levels of iAs in Mexico 53% % 28% Collected urine during third trimester of pregnancy and drinking water from the home Abstract #473: JE Laine: Prenatal exposure to inorganic arsenic

  20. National Academy of Sciences' 1999 risk estimates lifetime risks of dying of cancer from arsenic in tap water

  21. National Academy of Sciences' 1999 risk estimates lifetime risks of dying of cancer from arsenic in tap water

  22. National Academy of Sciences' 1999 risk estimates lifetime risks of dying of cancer from arsenic in tap water

  23. Concerns for the developing baby Are there proteins with altered expression levels in the cord blood of babies who experienced prenatal arsenic exposure?

  24. Subcohort of 50 newborns selected from BEAR: serum from cord blood analyzed 121 ppb 11 ppb Newborns with low prenatal iAs (wAs <5ppb) Newborns with high prenatal iAs (wAs >100ppb)

  25. Proteins assessed in cord blood using proteomics assay proteins are biotinylated at primary amines >500 proteins assessed Cytokines Chemokines Growth factors Angiogenic factors Soluble receptors protein-specific antibodies are on array For each protein, across the 50 samples, regression analysis of urinary iAs as a continuous variable related to protein expression, controlling for potential confounders

  26. 31 proteins with altered expression associated with prenatal iAs levels Interleukin 23 Fibrobast growth factor 20 Intensity units Intensity units 8 with decreased expression as iAs increases 23 withincreasedexpression as iAs increases

  27. Proteins interact in a common pathway 17 of 31 in highly significant network p< 10-41 Increased expression Decreased expression

  28. Proteins interact in a common pathway 17 of 31 in highly significant network p< 10-41 ERK 1/2 signaling pathway: Extracellular-signal-regulated kinase Increased expression Decreased expression Mitogen-activated protein kinase pathway linked to cellular growth and proliferation Implicated in carcinogenesis, key mediator of inflammatory responses pathway modulated by arsenic

  29. Proteins interact in a common pathway: known links to iAs 17 of 31 in highly significant network p< 10-41 ERK2: Activated by iAsIII, MMAIII, DMAIII in vitro MIF and EGFR: Upregulatedby MMAIII in vitro TIMP2: Upregulatedby arsenite in the mouse liver EGFR: Upregulated in serum in humans exposed to iAs Increased expression Decreased expression Mitogen-activated protein kinases linked to cellular growth and proliferation Implicated in carcinogenesis, key mediator of inflammatory responses pathway modulated by arsenic

  30. Proteins are pro-inflammatory Macrophage inhibitory factor Interleukin 1 receptor like 2 Histidine-rich glycoprotein Epiregulin SMAD family member 4/5 Interleukin 27 receptor subunit alpha Environ Health Perspect. 2011 Feb;119(2):258-64. Arsenic-associated oxidative stress, inflammation, and immune disruption in human placenta and cord blood. Ahmed S, et al. International Centre for Diarrhoeal Disease Research, Bangladesh, Dhaka, Bangladesh, 18 cytokines

  31. Proteins play a role in carcinogenesis Lung/liver Macrophage inhibitory factor Interleukin 1 receptor like 2 Histidine-rich glycoprotein Epiregulin Liver SMAD family member 4/5 Interleukin 27 receptor subunit alpha Environ Health Perspect. 2011 Feb;119(2):258-64. Arsenic-associated oxidative stress, inflammation, and immune disruption in human placenta and cord blood. Ahmed S, et al. International Centre for Diarrhoeal Disease Research, Bangladesh, Dhaka, Bangladesh, 18 cytokines

  32. Proteins play a role in carcinogenesis Macrophage inhibitory factor Increased expression in lung and liver tumors (MIF, EGFR) Metastasis and invasion in tumors (MMP13, CXCL16, ICAM) Prognostic indicators for hepatocellular carcinoma (SMAD 4) Epiregulin Epidermal growth factor receptor Matrix metallopeptidase 13 Mothers against decapentaplegic homolog 4

  33. Generating a systems level view of the effects of iAs In utero exposure to iAs in Thailand: gene expression Fry et al., 2007

  34. Generating a systems level view of the effects of iAs Proteomic and genomic signaling enriched for inflammation and immune response In utero exposure to iAs in Thailand: gene expression Fry et al., 2007

  35. Generating a systems level view of the effects of iAs

  36. Generating a systems level view of the effects of iAs Changes in protein expression in cohort in Mexico

  37. Generating a systems level view of the effects of iAs Changes in protein expression in cohort in Mexico Changes in gene expression in cohort in Thailand

  38. Generating a systems level view of the effects of iAs Changes in protein expression in cohort in Mexico DNA methylation? Changes in gene expression in cohort in Thailand

  39. DNA methylation: a key component of the epigenetic machinery SAM SAM

  40. DNA methylation at promoter regions can impede target gene expression Target gene silenced TF Methyl Methyl CpG CpG X Promoter Target gene Target gene expressed TF Promoter Target gene

  41. Putative mechanisms for arsenic-induced changes to DNA methylation SAM SAM

  42. Putative mechanisms for arsenic-induced changes to DNA methylation SAM Zhou et al 1997 Reichard et al 2007

  43. Are there iAs-associated differences inDNA methylation of the genes encoding the protein biomarkers?

  44. Extensive differences in gene-specific DNA methylation patterns in adults exposed to iAs ~200 genes Smeester et al. 2011

  45. Proteomic changes correspond with DNA methylation profiles • 450,000 methylation sites /single-nucleotide resolution • 99% of RefSeqgenes • 48 cord blood samples, analyzed for DNA methylation associated with UAs

  46. Proteomic changes correspond with DNA methylation profiles (n=10/31) • 450,000 methylation sites /single-nucleotide resolution • 99% of RefSeqgenes • 48 cord blood samples, analyzed for DNA methylation associated with UAs

  47. Proteomic changes correspond with DNA methylation profiles (n=10/31) Some of proteomic response linked to inflammation and carcinogenesis in newborn cord blood may be mediated by DNA methylation • 450,000 methylation sites /single-nucleotide resolution • 99% of RefSeqgenes • 48 cord blood samples, analyzed for DNA methylation associated with UAs

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