International Symposium of Environmental Medicine
Including Asthma, Rhinitis Eczema, Uti Urticaria i (hives) Drug, Food, and Insect allergy Asthma: ~3 3 10 8 patients in the world 250,000 asthma deaths occur in the world each year Rhinitis: i i 10% ~ 30 % of the population. Still steady increase in the prevalence ~30% 40% population affected WAO White Book on Allergy 2011 2012: Executive Summary
Taiwan Rhinitis = 30 40% Wheezing =10% Allergy 65: 152 167, 2010
Nat Rev Immunol 2008, 8: 205
Nat Med 2012, 18: 673
Hypothesis. Environmental EDCs Asthma To set up animal models relevant to human exposure To set up animal models relevant to human exposure To clarify immunological mechanisms of EDC effect
Akylphenol ethoxylate (APEs) Nonylphenol ethoxylate (NPE) Octylphenolethoxylate ethoxylate (OPE) Used as non ionic surfactants Industrial, household applications Personal care products NP and OP Detectable in many food products Lipophilic pollutant Long half life (bioaccumulation) Estrogen like activity Binding to estrogen receptors (ERs) or aryl hydrocarbon receptor (AhR) NPE
Sample Alkylphenol yp level N (%) * Location Human milk Adipose tissue Ui Urine NP Mean: 4.47±4.31 ng/g 59 (86%) OP Mean: 129±168 1.29±1.68 ng/g 59 (31%) NP Median: 57 (10 567) ng/g 20 (100% ) OP Median: 4.5 (nd 8.6) ng/g 20 (23.5%) NP Median: 0.1 (nd 1.6) mg/l 371 (51%) OP Median: 0.3 (nd 0.4) mg/l 2517 (57%) Taiwan Spain USA Mother plasma NP Median: 5.68 (nd 268) ng/g 42 (52.4%) Taiwan Umbilical cord plasma NP Median: 2.95 (nd 100) ng/g 42 (52.4%) Taiwan Tolerable daily intake of NP (Danish Environmental Agency) 5 g/kg B.W./day Suen JL et al. Kaohsiung J Med Sci. 28: S43 8, 2012
(Tolerable Daily Intake) Corn oil or NP (5 g/kg BW/day) Day 0 10 19 20 21 22 Sensitization OVA in alum i.p. Challenge OVA aerosol BALF Low dose and daily exposure Pre condition of immune systems Pi Priming i event Mild allergic inflammation
BALF (cell infiltration) Splenic DC homeostasis
Splenic DC function cdc+naïve CD4 + T cell+anti CD3 Th1: IFN γ Th2: IL 4, IL 5, IL 10 NP exposure alter DCs function to favor Th2 differentiation.
Nuclear receptor superfamily of transcription factors ligand dependentd bhlh PAS family Cyp1A1 Cyp1B2 Annu Rev Pharmacol Toxicol 2000, 40:519
Adaptive responses to environmental changes Modulating estrogen/androgen pathway positively and negatively Exerting both estrogen and androgen related effects Intrinsic i function largely l unknown AhR is critical in controlling mast cell homeostasis. (Zhou YF and Huang SK. Blood 2013;121(16):3195 3204) 3204) AhR activity regulated by dietary compounds present in vegetables promotes intestinal immune function. (Cell. 147: 489, 2011)
BALF (cell infiltration) Normal AhR Mutant AhR NP exposure disturbs the physiologic function in an AhRdependent manner, leading to the enhanced allergic lung inflammation.
Splenic DC function Bone marrow cells NP GM CSF Immature DCs LPS IL 6 Normal AhR (AhR b ) Mutant AhR (AhR d )
NP AhR IL 6 in DC ChIP (IL 6 promoter) Western NP exposure disturbs AhR regulated IL 6 expression. NP s effect is lost in AhR d mice
IFN α/β IL 10 TNF α Th1 Inflamma on Inflamma on J Allergy Clin Immunol 2012;129:889 901
Splenic pdc function Corn oil or NP (5 g/kg BW/day) Day 1 11 12 Splenic pdcs
Western blotting (Nuclear IRF7) NP exposure may affect the immune regulation through the altered cytokine pattern in pdcs.
epithelial cells AhR + DCs IL 6 MHC II CD4 + T TCR Th2 IL 4 IL 5 Eosinophils Allergic inflammation pdcs IFN α/β IL 10 TNF α Th1 Inflamma on Inflammation Suen JL and Huang SK. Allergy. 2013 Jun;68(6):780 7. Hung CH and Suen JL. PLoS One. 2013 Sep 11;8(9):e73534
Used as plasticizer for polyvinyl chloride plastics (PVC) Non covalent bond to PVC Wide distributionib i ~3 million metric tons/year Food is major source for human exposure. Biological half life < 24 hours http://www.taiwanwatch.org.tw/drupal/node/807 https://en.wikipedia.org/wiki/bis(2-ethylhexyl)_phthalate
Maternal urinary BBzP metabolites Early onset eczema in children (EHP, 2012) A prospectivecohort cohort of 407 women child pairs Settled dust DEHP/BBzP concentrations Childhood asthma, eczema, or rhinitis Three case control studies (Sweden 2004, Bulgaria 2008, Taiwan 2012) y Fractional exhaled NO in atopic children A cross sectional study (Am J Respir Crit Care Med. 2012 Nov 1;186(9):830 7) Children s urinary DEP/BBzP metabolites
DEHP maternal exposure Windows of susceptibility Altered epigenetic programming of somatic cells Increased susceptibility to asthma/allergy Transgeneration Development of Immune System Modified from J Steroid Biochem Mol Bio 127: 204, 2011
Chronic & low level exposure Prenatal & postnatal exposure DEHP Ingestion F0 Breast F1 10 days feeding TDI: 37 g/kg/day/ / Naïve F2 OVA PND7/14 Endpoint measurement F3
The causal relationship between transgenerational DEHP exposureandallergic allergic inflammation DC differentiation or function? Epigenetic mechanism DC differentiation and functional changes DEHP CH3 C G G Altered gene expression persists Abnormal immune system development Allergic inflammation/diseases Human transgenerational study
Grant support KMU NHRI NSC Cooperation Cooperation Dr. SK Huang Dr. CH Hung
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