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Persistent organic pollutants and metabolic syndrome; Clinical implications

June 2010, KSMRM, Korea. Persistent organic pollutants and metabolic syndrome; Clinical implications. Hong Kyu Lee, M.D. Bumsuk Prof. of Medicine, Eulji University Prof. Emeritus, Seoul National University. Lee HK et al. BBA General Subject 2010

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Persistent organic pollutants and metabolic syndrome; Clinical implications

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  1. June 2010, KSMRM, Korea Persistent organic pollutants and metabolic syndrome; Clinical implications Hong Kyu Lee, M.D. Bumsuk Prof. of Medicine, Eulji University Prof. Emeritus, Seoul National University Lee HK et al. BBA General Subject 2010 Kwak SH et al. J Diab Invest 2010 (in press)

  2. Diabetes epidemic in Korea Diabetes Infection IHD Death rate per 100,000 population 30 20 100,000 population Death Rate per 10 0 Year 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 Data source: Korea National Statistical Office http://www.nso.go.kr

  3. Obesity and Diabetes in the Developing World — A Growing Challenge. Why? Hossain P, Kawar, B, and Nahas ME. NEJM 356:213-215 2007

  4. Short history of search for cause 1. Yallow and Berson found high serum insulin in type 2 diabetes, thus insulin resistance : common underlying biochemical abnormality 2. Molecular approach (insulin receptor and post-receptor mechanisms) was not successful 3. Epidemiologic approach by establishing a disease entity (syndrome X) proposed by Reaven (1988) 4. WHO experts gave new name; metabolic syndrome (1998)

  5. Obesity Hypertension Atherosclerosis Diabetes Dyslipidemia Underlying cause(s) Concept of metabolic syndrome Syndrome X = Metabolic syndrome Cause(s)

  6. Theories on the causes of insulin resistance • Genetic cause (thrifty genotype hypothesis. Neel JV, 1962) • Fetal malnutrition (thrifty phenotype hypothesis. Barker DJP and Hales CN, 1992) 3 Mitochondrial dysfunction (Lee HK et al, 2006) • Environmental chemicals (Baillie-Hamilton PF, 2002) and POPs (Lee DH et al, 2006)

  7. Mitotoxins Mitochondrial dysfunction Kadowaki T et al. J Clin Invest 116:1784-1792, 2006

  8. Why mitochondria in diabetes?(KDA autumn meeting, 1994) • As genes did not change, something in the environment should have caused it • Causative agent(s) should be not infectious • Introduced by industrialization/ westernization/ coca-cola-rization? • Diabetogenic drug, streptozotocin damaged cell as NO donor • Mitochondrion is most vulnerable target of free radicals

  9. MH Chung studied OGG at JCC and told me free radical damage is 10 times higher in mtDNA Richter C, Park JW, Ames BN PNAS USA, 1988 • mtDNA 0.41 +/- 0.06 (n = 12) pmol of 8-OHdG per ug • nDNA 0.025+/- 0.004 (n = 4) • 16 times lower level of 8-OHdG in nuclear DNA • Oxidative damage should leave clue in mtDNA • What the hell is mitochondria and its DNA?

  10. Our studies linking insulin resistance and mitochondrial dysfunction • mtDNA density decrease precede the development of diabetes in Yochon cohort, 1998 • Medical student cohort (KU Lee et al) • Birth weight and mtDNA density (YY Lee, YA Sung): thrifty phenotype hypothesis • mtDNA variations and insulin resistance (Asians) 16189 T>C, haplogroups N9a (resistant) haplogroups B and F (sensitive) (In collaboration with M Tanaka et al, K Nanjo et al)

  11. Science, 2003 The association of mitochondrial dysfunction and insulin resistance is established, but the cause–effect relationship is not. See http://videocast.nih.gov/PastEvent.asp?c=998

  12. Maternal malnutrition Nutr Biochem Review, 2004, NYAS 2005, Revised 2009 Fetal malnutrition ncDNA, mtDNA • Low taurine level • Low level of methyl-donors • Depletion of nucleotide pool • Increased oxidative stress • Genomic imprinting Poor initial condition of mitochondrial function • Environment • Westernized life style • Aging • Drugs, toxins CNS/ANS Muscle/Liver Beta-cell Cognitive function Sympathetic overactivity? Poor response to insulin action Impaired insulin secretion Neurodegenerative diseases Hypertension Insulin resistance/obesity Diabetes Cancers

  13. Environmental factors causing mitochondrial dysfunction

  14. We looked for a clue in United States • Obesity epidemic is most rampant in Mississippi valley; agriculture • Mitochondrial toxin(s) in agriculture? • Corn is used in coca cola and fast foods

  15. Herbicides inhibit photosystem II Q binding site of chloroplast thylakoid membrane (photosynthesis) Known to inhibit respiration of gill of a shellfish

  16. A B Control Control Atrazine 3 mg/L Atrazine 3 mg/L Muscle Hepatocyte Effect of Chronic Exposure of Atrazine on the Mitochondrial Function and Insulin Resistance in Rats Lim S, Park KS, Cho YM, Lee KU, KimPak YM, Lee HK, (PLoS One, April 13, 2009).

  17. ATZ PBS DMSO - - - + + + ins pAKT(Thr308) pAKT(Ser473) AKT β-actin B ATZ DMSO Glu/Mal O2 Concentration (nmol/ml) TMPD/Asc Suc/G3P Rot Anti-A KCN Time Atrazine inhibited respiration of mouse liver A. Respiration D C Figure S1. Lim S, KimPak Y et. al. PLoS One, 2009

  18. Visceral fat - High fat diet group - Atrazine (3mg/l) Control Weight = 559 g Weight = 564 g

  19. Theories on the causes of insulin resistance • Genetic cause (thrifty genotype hypothesis. Neel JV, 1962) • Fetal malnutrition (thrifty phenotype hypothesis. Barker DJP and Hales CN, 1992) 3 Mitochondrial dysfunction (Lee HK et al, 2006) • Environmental chemicals (Baillie-Hamilton PF, 2002) and POPs (Lee DH et al, 2006)

  20. BAILLIE-HAMILTON PF. J ALTERNAT COMPLEMENT MED. 8:185–192, 2002

  21. Duk Hee Lee, an epidemiologist was looking for environmental factor(s) becauseof elevated gamma glutaryl transferase (GGT) was predictive of diabetes development. Reasoned environmental toxins would cause this elevation. Special thanks for letting me use her slides.

  22. Cross-sectional association between serum GGT and CVD risk factors II (CARDIA data) Insulin, uU/L SBP(mmHg) TG (mg/dl) GGT GGT GGT HDL-C (mg/dl) WBC(109/L) LCL-C (mg/dl) GGT GGT GGT Lee DH, et al. Clin Chem 2003;49:1358-66

  23. Pesticides • aldrin, chlordane, DDT, dieldrin, endrin, heptachlor, hexachlorobenzene, mirex, toxaphene, chlordecone, alpha -hexachlorocyclohexane, beta hexachlorocyclohexane, lindane, pentachlorobenzene), • Industrial chemicals • hexachlorobenzene, polychlorinated biphenyls (PCBs), hexabromobiphenyl, hexabromodiphenyl ether and • heptabromodiphenyl ether, pentachlorobenzene, perfluorooctane • sulfonic acid, its salts and perfluorooctane sulfonyl fluoride, • tetrabromodiphenyl ether and pentabromodiphenyl ether • 3. By-products • hexachlorobenzene; polychlorinated dibenzo-p-dioxins • polychlorinated dibenzofurans (PCDD/PCDF), and PCBs, • alpha hexachlorocyclohexane, beta hexachlorocyclohexane • and pentachlorobenzene].

  24. NHANES 1999-2002 had measured about 50 POPs in a random sample of US population • Polychlorinated Dibenzo-p-dioxins (PCDDs) • Polychlorinated Dibenzofurans (PCDFs) • Dioxin-like PCBs • Non-dioxin-like PCBs • Organochlorine Pesticides • POPs which were detected among  80% of subjects • 2,2’,4,4’,5,5’-hexachlorobiphenyl (PCB153) : banned • 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin • 1,2,3,4,6,7,8,9-octachlorodibenzo-p-dioxin • oxychlordane : banned • p,p’-DDE : banned • trans-nonachlor : banned

  25. Adjusted odds ratios of prevalent diabetes according to categories of sum of 6 POPs Lee DH, et al. Diabetes Care 2006

  26. Interaction between obesity and POPs on the risk of prevalent diabetes Lee DH, et al. Diabetes Care 2006

  27. Association between POPs and HOMA-IR among non-diabetics OC pesticides / some PCBs Lee DH et al. Diabetes Care 2007;30:622-8

  28. Association between POPs and 5 components of metabolic syndrome among non-diabetics Waist circumference Elevated triglyceride High blood pressure Dioxins Furans OC pesticides PCBs High fasting glucose Low HDL-cholesterol Lee DH, et al. Diabetologia (2007)

  29. Diabetes Care 31:1574–1579, 2008 Environmental Research 108: 63– 68, 2008 Diabetologia 51:1416-22, 2008 Diabetologia 53:899-906, 2010

  30. This association was confirmed in Greenland (Inuit), Taiwan, Japan, Native American, Slovakia and Belgium (Dirink E et al. Obesity, 2010). • An environment-wide association study (EWAS) on type 2 diabetes mellitus supported (Chirag J et al, PLoS One 2010) • Confirmed in experimental studies (Lim S, PLoS One, 2009; Ruzzin J et al, Environ Health Persp, 2009)

  31. Association between POPs (causative agent) and metabolic syndrome (disease phenotype) is established. Does exposure to POPs cause insulin resistance?

  32. 1. National Institute of Nutrition and Seafood Research (NIFES), Norway. 2. Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark. 3. INSERM U-870, University, INSA Lyon and Hospices Civils, France. 4. Others

  33. METHODS: 1. Wistar rats exposed for 28 days to lipophilic POPs (high-fat diet containing crude fish oil obtained from farmed Atlantic salmon). 2. Measured body weight, whole-body insulin sensitivity, POP accumulation, lipid and glucose homeostasis, gene expression and performed microarray analysis. RESULTS: Rats exposed to crude, but not refined, salmon oil developed insulin resistance, abdominal obesity and hepatosteatosis.

  34. Ruzzin J et al. Environment Health Perspect. Nov. 2009

  35. Endocrine Disruptor, dioxin (TCDD)–Induced Mitochondrial Dysfunction and Apoptosis in Human Trophoblast-Like JAR Cells Su-Chee Chen et al.Hum Reprod, 2010 • 2.58x increase in lipid peroxides (2 nM TCDD, 4 hrs). • DNA damage marker, 8-OH-dG increased with and increase in mtDNA deletions. • Reduction in mtDNA copy number and ATP content • Increased apoptosis, p53 accumulation, Bax over-expression, cytochrome c release, and sequential caspase 3 activation after TCDD exposure.

  36. The Mitochondrion — A Trojan Horse That Kicks Off Inflammation? Manfredi, AA, Patrizia Rovere-Querini, P NEJM 362;2133, 2010 DAMP denotes damage-associated molecular pattern, PRR pattern-recognition receptor

  37. Mitochondrial damage cholesterol Lee HK et al. BBA General Subject Mar 2010. Ruzzin J et al. Environment Health Perspect. Nov. 2009

  38. Obesity Hypertension Atherosclerosis Diabetes Dyslipidemia POPs or Mitotoxs Concept of metabolic syndrome Syndrome X = Metabolic syndrome Cause(s)

  39. Chemical substances that persist in the environment, bio-accumulate through the food web, and pose a risk of health and the environment.

  40. What should we give to “chemical substances causing metabolic syndrome”?

  41. Dioxins and POPs are known as endocrine disruptors, but also affect mitochondria

  42. Endocrine disruptors Hypertensiongens Mitochondrial toxins vs Metabogens? Obesogens Carcinogens Xenobiotics Persistent organic pollutants Grun F, Blumberg B. Endocrine disrupters as obesogens. Mol Cell Endocrinol 2009;304:19–29.

  43. Works to be done • Establishing cause-effect relationship between xenobiotics exposure and MS • 3 Koch’s postulates • Etiologic treatment: drug development and clinical trials

  44. To establish cause-effect relationship between POPs and MS • POPs are very diverse, small, slowly act, dangerous to handle and --- • Current detecting methods are too expensive • Need cheap and valid method (for diagnosis): i.e. CALUX (chemically activated luciferase expression) assay • Best way to eliminate toxins (evidence-based detoxification therapy)

  45. How should we treat patients with metabolic syndrome? 1. Avoid and remove toxins (xenical, colestimide, activated charcoal, herbs?)2. Recover mitochondrion already damaged (stem cell therapy) 3. Current treatment methods- need re-evaluation

  46. Blood concentrations of POPs like p,p′-DDE increase with age. (a) New Zealand report conducted in 1996–97 (N=1834) and the Canary Islands study in 1997–1998 (N=682), (b) East & West Ger III conducted in 1998 (N=2290 for West Germany and N=534 for East Germany), Porta M et al. Environment International 34 (2008) 546–561

  47. Environment • Westernized life style • Aging • Drugs • Mito-toxins

  48. Acknowledgements • Park KS, Cho YM, Lim S, KimPak Y, Lee W, and many collaborators, Korea • Wei Y-H, Taiwan • Nanjo K, Tanaka M. Japan • Members of Molecular Diabetology in Asia

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