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Persistent organic pollutants and metabolic syndrome; Clinical implications Hong Kyu Lee, M.D. Bumsuk Prof. of Medicine, Eulji University Prof. Emeritus,

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Presentation on theme: "Persistent organic pollutants and metabolic syndrome; Clinical implications Hong Kyu Lee, M.D. Bumsuk Prof. of Medicine, Eulji University Prof. Emeritus,"— Presentation transcript:

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

2 Diabetes Infection IHD Year Death Rate per 100,000 population Death rate per 100,000 population Data source: Korea National Statistical Office Diabetes epidemic in Korea

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

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 Syndrome X = Metabolic syndrome Cause(s) Concept of metabolic syndrome

6 Theories on the causes of insulin resistance 1.Genetic cause (thrifty genotype hypothesis. Neel JV, 1962) 2.Fetal malnutrition (thrifty phenotype hypothesis. Barker DJP and Hales CN, 1992) 3 Mitochondrial dysfunction (Lee HK et al, 2006) 4.Environmental chemicals (Baillie-Hamilton PF, 2002) and POPs (Lee DH et al, 2006)

7 Kadowaki T et al. J Clin Invest 116: , 2006 Mitochondrial dysfunctionMitotoxins

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9 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

10 mtDNA / (n = 12) pmol of 8-OHdG per ug nDNA / (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? 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

11 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) T>C, haplogroups N9a (resistant) haplogroups B and F (sensitive) (In collaboration with M Tanaka et al, K Nanjo et al)

12 Science, 2003 The association of mitochondrial dysfunction and insulin resistance is established, but the cause–effect relationship is not. See

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

14 Environmental factors causing mitochondrial dysfunction

15 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

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

17 A B ControlAtrazine 3 mg/L ControlAtrazine 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).

18 A. Respiration O 2 Concentration (nmol/ml) Time Glu/Mal Rot Suc/G3P Anti-A TMPD/Asc KCN DMSO ATZ B C pAKT(Thr308) β-actin pAKT(Ser473) AKT PBS DMSO ATZ ins D Figure S1. Lim S, KimPak Y et. al. PLoS One, 2009 Atrazine inhibited respiration of mouse liver

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

20 Theories on the causes of insulin resistance 1.Genetic cause (thrifty genotype hypothesis. Neel JV, 1962) 2.Fetal malnutrition (thrifty phenotype hypothesis. Barker DJP and Hales CN, 1992) 3 Mitochondrial dysfunction (Lee HK et al, 2006) 4.Environmental chemicals (Baillie-Hamilton PF, 2002) and POPs (Lee DH et al, 2006)

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

22 Duk Hee Lee, an epidemiologist was looking for environmental factor(s) because of 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.

23 SBP (mmHg) Insulin, uU/L TG (mg/dl) LCL-C (mg/dl) HDL-C (mg/dl) WBC(  10 9 /L) Cross-sectional association between serum GGT and CVD risk factors II (CARDIA data) GGT Lee DH, et al. Clin Chem 2003;49:

24 1.Pesticides aldrin, chlordane, DDT, dieldrin, endrin, heptachlor, hexachlorobenzene, mirex, toxaphene, chlordecone, alpha -hexachlorocyclohexane, beta hexachlorocyclohexane, lindane, pentachlorobenzene), 2.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].

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

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

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

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

29 Association between POPs and 5 components of metabolic syndrome among non-diabetics Waistcircumference Highbloodpressure Highfastingglucose Elevatedtriglyceride LowHDL-cholesterol OC pesticides PCBs DioxinsFurans Lee DH, et al. Diabetologia (2007)

30 Diabetes Care 31:1574–1579, 2008 Environmental Research 108: 63– 68, 2008 Diabetologia 51: , 2008 Diabetologia 53: , 2010

31 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)

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

33 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

34 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.

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

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37 Endocrine Disruptor, dioxin (TCDD)–Induced Mitochondrial Dysfunction and Apoptosis in Human Trophoblast-Like JAR Cells Su-Chee Chen et al. Hum Reprod, x 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.

38 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

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

40 Syndrome X = Metabolic syndrome Cause(s) Concept of metabolic syndrome

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

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

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

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

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

46 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)

47 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

48 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

49 Environment Westernized life style Aging Drugs Mito-toxins

50 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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