Persistent organic pollutants and metabolic syndrome; Clinical implications Hong Kyu Lee, M.D. Hong Kyu Lee, M.D. Bumsuk Prof. of Medicine, Eulji Bumsuk Prof. of Medicine, Eulji University University Prof. Emeritus, Seoul National Prof. Emeritus, Seoul National University University June 2010, KSMRM, Korea Lee HK et al. BBA General Subject 2010 Kwak SH et al. J Diab Invest 2010
50
Embed
Persistent organic pollutants and metabolic syndrome; Clinical implications Hong Kyu Lee, M.D. Bumsuk Prof. of Medicine, Eulji University Prof. Emeritus,
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Persistent organic pollutants and metabolic syndrome;
Clinical implications
Hong Kyu Lee, M.D.Hong Kyu Lee, M.D.
Bumsuk Prof. of Medicine, Eulji UniversityBumsuk Prof. of Medicine, Eulji University
Prof. Emeritus, Seoul National UniversityProf. Emeritus, Seoul National University
June 2010, KSMRM, Korea
Lee HK et al. BBA General Subject 2010Kwak SH et al. J Diab Invest 2010 (in press)
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
Known to inhibit respiration of gill of a shellfish
Herbicides inhibit photosystem II Q binding site of chloroplast thylakoid membrane (photosynthesis)
A
BControl Atrazine 3 mg/L
Control Atrazine 3 mg/L
0 1 2 3 4 50
100
200
300
ATZ (0.3mg/L)
350
450
550
650
Control
ATZ (3mg/L)
Months
Bo
dy
wei
gh
t (g
)
High fat diet
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).
Basal I II & III IV0
100
200DMSOATZ
***
O2 c
on
su
mp
tio
n r
ate
(nm
ole
/min
/mg
pro
tein
)A. Respiration
O2
Co
nce
ntr
atio
n(n
mo
l/ml)
Time
Glu/Mal
Rot Suc/G3P
Anti-A
TMPD/Asc
KCN
DMSOATZ
B
C
II III0
25
50
75
100
125
150DMSOATZ
**
Co
mp
lex
ac
tiv
ity
% c
on
tro
l
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
Atrazine (3mg/l) Control
Visceral fat - High fat diet group -
Weight = 559 g Weight = 564 g
Theories on the causes of insulin resistance
1. Genetic cause (thrifty genotype hypothesis. Neel JV, 1962)
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.
109 109
111
112
114
10
11
12
14 14
5759
64
74
83SBP (mmHg) Insulin, uU/L TG (mg/dl)
103
107
110
116115
LCL-C (mg/dl)54
53 53
51
54HDL-C (mg/dl)
5.7
6
6.2
6.4 6.5WBC(109/L)
Cross-sectional association Cross-sectional association between serum GGT and CVD risk factors II (CARDIA data)between serum GGT and CVD risk factors II (CARDIA data)
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].
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].
NHANES 1999-2002 had measured about 50 POPs in a random sample of US population
• 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)
Association between POPs (causative agent) and metabolic syndrome (disease phenotype) is
established.
Does exposure to POPs cause insulin resistance?
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
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.
Ruzzin J et al. Environment Health Perspect. Nov. 2009
Endocrine Disruptor, dioxin (TCDD)–Induced Mitochondrial Dysfunction and Apoptosis
in Human Trophoblast-Like JAR CellsSu-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.
The Mitochondrion — A Trojan Horse That Kicks Off Inflammation?
Manfredi, AA, Patrizia Rovere-Querini, P NEJM 362;2133, 2010
Chemical substances that persist in the environment, bio-accumulate through the food
web, and pose a risk of health and the environment.
What should we give to “chemical substances causing
metabolic syndrome”?
Dioxins and POPs are known as endocrine disruptors, but also affect mitochondria
XenobioticsPersistent 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.
Works to be done
• Establishing cause-effect relationship between xenobiotics exposure and MS
• 3 Koch’s postulates
• Etiologic treatment: drug development and clinical trials
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)
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
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
Environment•Westernized
life style•Aging•Drugs
•Mito-toxins
Acknowledgements
• Park KS, Cho YM, Lim S, KimPak Y, Lee W, and many collaborators, Korea