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AR 22b-387~ Diabetes Care Publish Ahead of Print, published online December 29, 2008 Perfluorvalkvl chemicals, glucose homeosJasis andmeJabolic syrTdrome Association Among Serum Perfluoroalkyl Chemicals, Glucose Homeostasis and Ntetabolic Syndrome in Adolescents and Adults Running title : Perfluor-c,7lkyl chemicals, glucose homeostasis and metabolic syndrome Chien-Yu Lin 1' Z' 3, MD, MPH; Pau-Chung Chen`, MD, PhD; Yu-Chuan Lin2' 4, MD; Lian-Yu Lin, MD, PhDs 1, Department of Internal Adedicine of ivephrology, En Chu Kong Hospital, Taipei County, Taiwan 2, Institute of Occupational NICdici:ie and Industrial Hygiene, National Taiwan University College of Public Health, Taipei, Taiwan 3, School of Medicine, Fu Jen Catholi: University, Taipei County, Taiwan 4, Department of Pediatrics, Taipei City Ho spital, Zhongxiao Branch, Taipei Taiwan 5, Department of Internal Medicine of Cardiology, ,'`htional Taiwan University Hospital, Taipei, - Taiwan Corresponding author : Lian-Yu Lip, E-mail : hspenos(q-)yahoo .com tw Submitted 3 October 2008 and accepted 17 December 2008. This is an uncopyedited electronic version of an article accepted for publication in Dabetes are. The American Diabetes Association, publisher of Diabetes Care, is in this version of the manuscript or any version derived from not responsible for any it by third parties. The errors or definitive or,'iissions publisher- ahtuttph:e/n/tciacraet.eddiabveetressijoonurwniallIs.boreg. available in a future issue of Diabetes Care in print and onlin'e at Copyright American Diabetes Association, Inc., 2008 Diabetes Care Publish Ahead of Print, published online December 29, 2008 Perfluoroallcyl chemicals, gluco.se homeostasis andmetabolic syndrome Association Among Serum Perfluoroalkyl Chemicals, Glucose Homeostasis and llrTetabolic Syndrome in Adolescents and Adults Running title : Per,fluo1?1ky1 chemicals, glucose homeostasis andmetabolic syndrome Chien-Yu Lin''2'3, MD, MPH; Pau-Chung Chen`, MD, PhD; Yu-Chuan LinZ'4, MD; Lian-Yu Lin, MD, PhDs I, Department of Internal P4edicine of lNephrology, En Chu Kong Hospital, Taipei County, ~ Taiwan 2, Institute of Occupational McAdick;e an&-Industrial Hygiene, National Taiwan University College of Public Health, Taipei, Taiwan 3, School of Medicine, Fu Jen Cthofl~= University, Taipei County, Taiwan 4, Department of Pediatrics, Taipei City Haspital, Zhongxiao Branch, Taipei Taiwan 5, Department of Internal Medicine of Cardiology; i'`fw tional Taiwan University Hospital, Taipei, Taiwan Corresponding author: Lian-Yu Lip. E-mail: hspenos r.(,yahoo.com.tw Submitted 3 October 2008 and accepted 17 December 2008. This is an uncopyedited electronic version of an article accepted for publication in Chabetes are. The American Diabetes Association, publisher of Diabetes Care, is not responsible for any errors or or,,nissins in this version of the manuscript or any version derived from it by third parties . The definitive publ~'isherauthenticated version will be available in a future issue o Drabetes Care in print and onlin ~e at http://care .diabetesjournals.org. Copyright American Diabetes Association, Inc., 2008 Perfluoroalkyl chemicals, glucose homeostasis and metabolic syndrome Objective : Perfluoroalkyl chemicals (PFCs) have been used worldwide in a variety of consumer products- The effect ofPFCs on glucose homeostasis is not known. Research design and methods: We examined 474 adolescents and 969 adults with reliable serum measures of metabolic syndrome (MS) profile from the National Health and Nutrition Examination Survey 1999-2000 and 2003-2004. Results: In adolescents, increased serum perfluorononanoic acid (PFNA) concentrations were associated with hyperglycemia (OR = 3.16, 95lo CI = 1 .39-7.16, P < 0.05). Increased serum PFNA concentrations also have favorable associations with serum HDL-C (OR = 0.67, 95% CI = 0.45-0.99, P < 0.05). Overall, increased serum PFNA concentrations were inversely correlated with the prevalence of the MS (OR = 0.37, 95% CI = 0.21-0 .64, P < 0.005) . In adults, increased serum perfluorooctanoic acid (PFOA) concentrations were significantly associated with increased f3 cell function (Pcoeff = 0.07t0.03, P < 0.05). Increased serum perfluorooctane sulfate (PFOS) concentrations were associated with increased blood insulin ((3coeff = 0.14t0.05, P < 0.01), HOMA-IR ((3coeff = 0.140.05, P < 0.01) and R cell function (Pcoeff = 0.15t0.05, P < 0.01). Serum PFOS concentrations were also unfavorably correlated with serum HDL-C (OR = 1 .61, 95% CI = 1 .15-2 .26, P < 0.05). Conclusions : Serum PFCs were associated with glucose homeostasis and indicators ofMS. Further clinical and animal studies are warranted to clarify putative causal relationships . Perftuoroatkyt chemicaLv, glucose homeostasis and metabolic syndrome he perfluoroalkyl chemicals (PFCs) are a family of Tperfluorinated chemicals that consist of a carbon backbone typically 4-14 in length and a charged functional moiety [I]. PFCs have been used extensively since the 1950s in commercial applications, including as a component in surfactants, lubricants, paper and textile coatings, polishes, food packaging, and fire-retardant foams [2]. Some of these PFCs, including the most widely known examples of perfluorooctanoic acid (PFOA) and perfluorooctane sulfate (PFOS), persisted in humans and the environment and have been detected worldwide in wildlife [2]. The routes of human exposure to PFCs are currently being investigated . Possible exposure pathways that are being examined include drinking water, dust in homes, and food or migration from food packaging and cookware. Animal studies have shown that they are well absorbed orally, but poorly eliminated; they are not metabolized, and undergo extensive uptake from enterohepatic circulation and are distributed mainly to the serum, kidney and liver [1]. Although some PFCs have been voluntarily removed from the market by manufacturers, PFOA and PFOS and their derivatives are still produced commercially and its potential risk to humans continues to be evaluated . In animal studies, exposure to PFOS and PFOA is associated with adverse health effects, including carcinogenicity [3, 4], hepatotoxicity [4, 5], and developmental and reproductive toxicity [4]. For human beings, PFC exposure has been shown to be associated with certain types of cancers [6]. Maternal exposure to PFOS and PFOA also has been linked to low birth weight [7]. The causal biochemical mechanisms leading to the adverse health outcomes after exposure to PFCs are largely unknown . However, recent studies using advanced technologies in genomics and bioinformatics have shown that several categories of genes are commonly altered by some PFCs including peroxisome proliferation, fatty acid metabolism, lipid transport, cholesterol synthesis, proteosome activation and proteolysis, cell communication, and inflammation [1] . The agonistic properties of PFCs on PPAR-a (peroxisome proliferator- activated receptors-a) are well supported and are thought to be a major mechanism leading to PFC-mediated liver damage [8, 91. Since activation of PPAR-a can decrease serum triglycerides, normalize low-density lipoprotein cholesterol and increase HDL-C, we hypothesized that PFCs might have favorable effects on lipid homeostasis and may also be associated with reduced insulin resistance, improved serum lipid profile and lower prevalence of the metabolic syndrome (MS). The goal of the present study is to test this hypothesis by examining data from the National Health and Nutrition Examination Survey (NHANES) collected from 1999-2000 and 2003-2004. RESEARCH DESIGN AND METHODS Study design and population : Data were from NHANES 1999-2000 and 20032004. The NHANES is a population-based survey designed to collect information on the health and nutrition of the U.S. household population, and to obtain a representative sample of the non-institutionalized civilian US population. The survey data are released every 2 years . Detailed survey operations manuals, consent documents, and brochures of the NHANES 1999-2000 and 2003-2004 are available on the NHANES website [10]. We limited our analyses to the 3685 participants at least 12 years of age who had a blood test for PFCs. Among these subjects, only 1788 subjects had a morning examination and had fasting plasma glucose, insulin and triglyceride (TG) data available. Of these 1788 participants, we included the Perfluoroalkyl chemicals, glucose homeostasis and metabolic syndrome 1443 subjects without missing data for further analyses . Anthropometric and biochemical data: According to the statements on the NHANES website, data were collected at all study sites by trained personnel according to standardized procedures . Sociodemographic information such as age, gender, and race/ethnicity, education level and household income was collected during the household interview . Alcohol intake was determined by the questionnaire "in any one year, have you had at least 12 drinks of any type of alcohol beverage?" and was dichotomized . For adolescents, since there were too many missing data, alcohol intake was not entered for analysis. Smoking status was categorized as active smoker, former/passive smoker and non-smoker by smoking questionnaire and serum cotinine levels as previously described [11]. Laboratory measurements were performed in a mobile examination center. Weight and height were measured using standard methods and digitally recorded. Three and sometimes 4 blood pressure (BP) determinations were collected by a physician using a mercury sphygmomanometer. BP was measured in the right arm unless otherwise specified . Averaged systolic BP (SBP) and diastolic BP (DBP) were obtained . Blood specimens were processed locally, and then stored and shipped to central laboratories for analysis . Levels of serum total cholesterol (TC) and TG were measured enzymatically . Levels of HDL-C were measured after precipitation of other lipoproteins on a Hitachi model 704 analyzer (Roche Diagnostics, Indianapolis, Ind). Serum CRP levels were measured by latex-enhanced nephelometry. Plasma insulin was determined by immunoenzymornetric assay . Insulin resistance status (HOMA-IR) and (3-cell function were estimated by the updated homeostasis model assessment (HOMA2) [12]. Definition of metabolic syndrome: For subjects above 18 years old, presence of the metabolic syndrome was calculated by sex as defined by the National Cholesterol Education Program Third Adult Treatment Panel (NCEP/ATP 111) [13j guideline of presenting with at least 3 of the following qualifications : waist measurement greater than 88cm for women and greater than 102 cm for men; serum TG ? 1 .69mmol/L ; serum HDL-C <1 .03 mmol/L in men and <1 .29 mmol/L in women ; SBP ? 130 mmHg or DBP ~ 85 mmHg or a self report of taking anti-hypertensive medications ; and fasting glucose >-_ 6.10 mmoUL or a self report of taking anti-hyperglycemic medications . To define the MS among the young participants aged between 12 to 17 years, we used a previously proposed modification of the definition proposed in the NCEP/ATP 111 . The participants had to meet 3 of the following 5 criteria: serum concentration of TG? 1 .24 mmol/L, HDL-C~1 .04 mmol/L, WC >sex specific 90th percentile [14j, glucose concentration? 5.55 mmol/L or a self report of taking anti-hyperglycemic medications [15], and SBP or DBP? age, height and sexspecific 90th percentile or a self-report of taking anti-hypertensive medications [161 . Assessment of serum PFCs: As part of NHANES, serum samples of PFOA, PFOS, perfluorohexane sulfonic acid (PFHS) and perfluorononanoic acid (PFNA) were collected for analysis. The analytical method has been described in detail j17J. Briefly, without protein precipitation, only dilution with 0.1 M formic acid, one aliquot of 100 kL serum was injected into a commercial column switching system allowing for concentration of the analytes on a C18 solid-phase extraction column. This column was placed automatically in front of a C8 analytical highperformance liquid chromatography column for chromatographic separation of the analytes. Detection and quantification were Perfluaroalkyl chemicals, glucose homeostasis and metabolic syndrome done using negative-ion TurbolonSpray ionization, tandem mass spectrometry. Isotope-labeled internal standards were used for quantification . Statistics : Data were expressed as the mean t standard error (S.E). Participants were divided into adolescents (12 to 20 years of age) and adult (greater than 20 years of age) groups for analysis. The strength of the associations between concentrations of various serum PFCs and blood glucose, insulin and HOMA-IR levels was tested using multiple linear regression models . Logistic regression analyses were conducted to examine the odds ratios of MS (yes or no for having at least 3 components of MS) and its components (yes/no for that component) associated with one unit increase in log-PFCs . Log transformation was performed for variables with significant deviation from normal distribution before further analyses . For linear regression, we used an extended model approach for covariates adjustment: Model I = age, gender, race; Model 2 = Model I + health behaviors (smoking status, alcohol intake and household income); Model 3 = Model 2 -I- measurement data (waist measurement, CRP, insulin/glucose/HOMA) -t- medications (anti-hypertensive, and current anti- hyperglycemic and anti-hyperlipidemic agents) . For logistic regression, the models for adjustment were Model 4 = age, gender, race, health behaviors (smoking status, alcohol intake and household income), measurement data (CRP, HOMA/insulin) and current medications (anti-hypertensive, anti- hyperglycemic and anti-hyperlipidemic agents). Model 5 = Model 4 + other components of the MS. A P<0.05 was considered statistically significant. To avoid "model dependent association", the association was considered significant only when it remained statistically significant in all models . Sampling weights that account for unequal probabilities of selection, oversampling, and nonresponse were applied for all analyses using the Complex Sample Survey module of SPSS Version 13.0 for Windows XP (SPSS Inc . Chicago, Illinois, U.S.A.). RESULTS The basic demography of the participants is summarized in Table 1 . The study sample consisted of 474 adolescents (age between 12 to 20 years) and 969 adults (age above 20 years). The serum PFHS levels were significantly higher in adolescents than in adults (log-PFHS ng/mL, 0.950.10 vs. 0.60t0.04 respectively, P < 0.001) while the serum PFNA concentrations were lower in adolescents than in adults (log-PFNA ng/mL, -0.35t0.07 vs. -0:210.07, P = 0.001) . The serum PFOA and PFOS concentrations were not different between these two groups. The associations between the serum PFCs levels and glucose homeostasis markers are shown in Table 2. In adolescents, increased serum PFNA concentrations were associated with decreased blood insulin ((ieoeff = -0.1Of0.05, P < 0.05) and 0 cell function (f~coeff -0.120.06, P < 0.05) with borderline significant (P = 0.05-0.09 in all models and < 0.05 in final model). Other PFCs were not associated with the serum markers for glucose homeostasis . In adults, increased serum PFOA concentrations were significantly associated with increased 0 cell function (0coeff = 0.07t0.03, P < 0.05). Increased serum PFOS concentrations were also associated with increased blood insulin (0coeff = 0.140.05, P < 0.01), HOMA-IR (0coeff = 0.14f0_05, P < 0.01) and P cell function (0coeff= 0.15f0.05, P < 0.01). The associations between the serum PFCs and the MS/MS components are summarized in Table 3 . In adolescents, increased serum PFNA concentrations were associated with lower prevalence of the MS (OR = 0.37, 95!o CI = 0.21-0 .64, P < 0.005) PerJluoroalkyl chemicals, glucose homeostasis andmetaholic syndrome and HDL-C below the MS criteria (OR = 0.67, 95% CI = 0.45-0.99, P < 0.05). Increased serum PFNA concentrations were also correlated with higher prevalence of blood glucose above the MS definition (OR = 3 .16, 95% CI = 1 .39-7.16, P < 0.05). We also found that the serum PFOS (OR = 0.37, 95% C1= 0.16-0.82, P < 0.05) concentrations were inversely correlated with a lower prevalence of waist circumference below the MS definition. In adult subjects, among all the PFCs and MS components, only serum PFOS concentrations were associated with higher prevalence of HDL-C below MS definition (OR= 1 .61, 95lo Ct = 1 .15-2.26, P < 0.05). DISCUSSION To our knowledge, this report is the first to systemically analyze the link among serum PFC concentration, glucose homeostasis, and the MS/MS components in a nationally representative sample. In this study, we showed that PFCs were differentially associated with glucose homeostasis in adolescents and adults . We should take into careful consideration about extrapolating and interpreting data between laboratory animal studies and the corresponding biological effects (at high ppm range) compared to general human populations (at low ppb range). We found that the concentrations reported for PFCs in the occupational studies have been two and three orders of magnitude higher than what has been measured in the general population. While there were several studies about the maternal exposure and child development, worker's exposure and health outcome, the relationship of serum PFCs levels to medical diseases and laboratory abnormality in a nationally representative survey has never been explored . Our results might suggest that low dose PFCs exposure might have effects on glucose metabolism in general population. Our analysis showed that the serum PFOA and PFOS concentrations were not different between adolescents and adults. Unlike other lipophilic persistent pollutants that display increasing serum concentrations as people age, the lack of this general trend in PFOS and PFOA could be explained by intrauterine transfer, exposure early in life, ongoing exposures being much higher than earlier historical exposures or a combination of these factors [18). By contrast, the mean concentrations of PFHS were higher for adolescents than for adults, as previously reported [2, 19] . The higher concentrations of PHFS in children and adolescents could be related to their increased contact with carpeted floors containing PFHS, which is used for specific postmarket carpet-treatment applications [2, 19]. We showed that in adolescents, increased serum PFNA concentrations were associated with decreased blood insulin, impaired P cell function (borderline significance) and clinical hyperglycemia. On the other hand, we found that increased serum PFNA had a favorable correlation with serum HDL . Overall, increased serum PFNA concentrations were inversely associated with the prevalence of MS in adolescents . In adults, serum PFOS concentrations were independently associated with increases in both blood insulin and insulin resistance status (HOMA-IR) . Interestingly, both serum PFOA and PFOS were also positively correlated withJ3 cell function. The balance between increased insulin resistance and P cell function has a neutral effect on blood glucose. Increased PFOS also showed an unfavorable association with serum HDL-C in adults. Overall, the PFCs in the present study had neutral effects on the prevalence of the MS in adults . There has been a great deal of progress in the last few years in understanding the toxicology and distribution of PFCs in the environment, in wildlife, and in humans. However, there is a paucity of information pertaining to many specific PFCs [1]. Thus Perfluoroalkyl chemicals, glucose homeostasis and metabolic syndrome far, there are no published reports of either in vitro or in vivo data pertaining to effects of PFCs on glucose homeostasis . The underlying mechanisms of this linkage are unknown and might partially be related to peroxisome activation. The liver toxicity of PFOS and PFOA has been linked to their PPAR-u agonist property [8, 91. PFNA also has been shown to be a strong peroxisomal P oxidation inducer in animals [20, 21] . Fibrates, amphipathic carboxylic acids that activate PPAR-et, can decrease TO, normalize the lowdensity lipoprotein cholesterol profile, and increase HDL-C [22]. However, our results are not entirely consistent with previous animal findings, suggesting an alternative or even multiple pathways in association among PFCs, glucose and lipid metabolism. For example, Luebker et al. have demonstrated that both PFOS and PFOA can interfere with the binding affinity of L-FABP (liver-fatty acid binding protein) in rodents [23]_ Interestingly, they also found that among the tested PFCs, PFOS exhibited the highest level of inhibition of L-FABP binding, which might partially explain the unfavorable association between increased serum PFOS and HDL-C. CONCLUSION In conclusion, we present the first report of a relationship between serum PFCs, glucose homeostasis and metabolic syndrome. Since PFCs have been widely used worldwide in a variety of consumer products, further longitudinal clinical and in .vitro studies are urgently warranted to elucidate the putative casual relationships between PFCs and metabolism. Study limitation: Our study has several limitations . First, the cross-sectional design does not permit any causal inference . Second, due to a number of missing data, drinking status was not included in our analyses of adolescents . Perffuoroalkvl chemicals, glucose homeostasis and metaholic syndrome REFERENCES 1 . Lau C, Anitole K, Hodes C, Lai D, Pfahles-Hutchens A, Seed J: Perfluoroalkyl acids : A review of monitoring and toxicological findings . Toxicol Sci 99:366-394, 2007. . 2 . Calafat AM, Wong LY, Kuklenyik Z, Reidy JA, Needharn LL: PolyfIuoroalkyl chemicals in the US population : data from the National Health and Nutrition Examination Survey (NHANES) 2003-2004 and comparisons with NHANES 1999-2000. Health Perspect 115:1596-1602,2007 . 3. Kennedy GL Jr, Butenhoff JL, Olsen GW, O'Connor JC, Seacat AM, Perkins RG, Biegel LB, Murphy SR, Farrar DG: The toxicology ofperfluorooctanoate . Crit Rev Toxicol 34:351-384, 2004. 4. U.S. Environmental Protection Agency. 2005. Evaluating Human Health Risks from Exposure to Perfluorooctanoic Acid (PFOA) : Recommendations to the Science Advisory Board's PFOA Review Panel; Available: http://www.epa.gov/sab/pdflkropp-ewg .pdf [last retrieved on September 21, 20081. 5. Butenhoff J, Costa G, Elcombe C, Farrar D, Hansen K, Iwai H, Jung R, Kennedy G Jr, Lieder P, Olsen G, Thomford P: Toxicity of ammonium perfluorooctanoate in male cynomolgus monkeys after oral dosing for 6 months . Toxicol Sci 69:244-257, 2002. 6. Alexander BH, Olsen GW, Burris JM, Mandel JH, Mandel JS: Mortality of employees of a perfluorooctanesulphonyl fluoride manufacturing facility . Occup Environ Med 60:722-729, 2003. 7. Fei C, McLaughlin JK, Tarone RE, Olsen J: Perfluorinated chemicals and fetal growth: a study within the Danish National Birth Cohort. Envir Health Persp 115 :1677-1682, 2007 . 8. Intrasuksri U, Rangwala SM, O'Brien M, Noonan DJ, Feller DR: Mechanisms ofperoxisome proliferation by perfluorooctanoic acid and endogenous fatty acids . Gen Pharmaco131 :187197, 1998. 9. Sohlenius AK, Eriksson AM, Hogstrom C, Kimland M, DePierre JW: Perfluorooctane sulfonic acid is a potent inducer of peroxisomal fatty acid [3-oxidation and other activities known to be affected by peroxisome proliferators in mouse liver. Pharmacol Toxicol 72 :90- 93,2003 . 10. The national health and nutrition examination surveys (NAHNES) [online article]. http://www .ede.govlnchs/about/major/nhanes/eurrentnhanes .htm and http://www .edc .gov/nchs/about/major/nhanes/nhanes2003-2004/current_nhanes_03_04 .htm [last retrieved on September 219 2008]. 11 . Weitzman M, Cook S, Auinger P, Florin TA, Daniels S, Nguyen M, Winickoff JP. Tobacco smoke exposure is associated with the metabolic syndrome in adolescents . Circulation 112:862-869,2005 . 12. Diabetic Trial Unit, University of Oxford. HOMA calculator. University of Oxford Web site. http://www .dtu.ox .ac.uk/index .php?maindoc=/homa/.december 12, 2007. Accessibility verified October 1, 2008. 13. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection . Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)_ JAMA 285 :2486-2497, 2001 . 14.. Li C, Ford ES, Mokdad AH, Cook S: Recent trends in waist circumference and waist-height ratio among US children and adolescents . Pediatrics 118:e 1390-e1398, 2006. 15.. Grundy SM, Brewer HB Jr, Cleeman Jl, Smith SC Jr, Lenfant C: American Heart p. 10 Perfluoroallcyl chemicals, ,glucose homeostasis and metabolic syndrome Association, National Heart, Lung, and Blood Institute : Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American heart Association conference on scientific issues related to definition . Circulation 109 :433-438, 2004. 16. National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents . The fourth report on the diagnosis, evaluation and treatment of high blood pressure in children and adolescents . Pediatrics 114 :555-576, 2004. 17. Kuklenyik Z, Needham LL, Calafat AM: Measurement of 18 perfluorinated organic acids and amides in human serum using on-line solid-phase extraction . Anal Chem 77:6085-6091, 2005. 18. Inoue K, Okada F, Ito R, Kato S, Sasaki S, Nakajima S, Llno A, Saijo Y, Sata F, Yoshimura Y, Kishi R, Nakazawa H. Perfluorooctane sulfonate (PFOS) and related perfluorinated compounds in human maternal and cord blood samples: Assessment of PFOS exposure in a susceptible population during pregnancy. Environ. Health Perspect 112:1204-1207, 2004. 19_ Olsen GW, Church TR, Hansen KJ, Burris JM, Butenhoff JL, Mandel JH. Quantitative evaluation o perfluorooctanesulfonate (PFOS) and other fluorochemicals in the serum of children . ,J Child Health 2 :53-76, 2004. 20. Kudo N, Bandi N, Suzuki E, Katakura M, Kawashima Y. Induction by perfluorinated fatty acids with different carbon chain length of peroxisomal (3-oxidation in the liver of rats. Chem. Biol. Interact 124 :119-132, 2007. 21 . Kudo, N., Suzuki-Nakajima, E., Mitsumoto, A., and Kawashima, Y. Responses of the liver to perfluorinated fatty acids with different carbon chain length in male and female mice: In relation to induction of hepatomegaly, peroxisomal (3-oxidation and microsomal 1acylglycerophosphocholine acyltransferase. Biol Pharm. Bull 29:1952-1957, 2006. 22. Cross-talk between statins and PPARalpha in cardiovascular diseases: clinical evidence and basic mechanisms. Trends Cardiovasc Med 18 :73-78,2008 . Luebker DJ, Hansen KJ, Bass NM, Butenhoff JL: Interactions of fluorochemicals with rat liver fatty acid-binding protein. Toxicology 176:175-185, 2002. p. 11 Perfluoroalkvl chemicals, glucose homeostasis and metabolic syndrome Table 1 Basic demography abd serum concentrations of PFCs of the sample subjects Age, years Gender, % Male Female Race, % Mexican American Non-Hispanic White Non-Hispanic Black Smoking, % Active smoker Former/passive smoker Non-smoker Alcohol drinking status, fo 112 drinks last year < 12 drinks last year Annual household income, % <25000 25000-55000 >55000 MS, Q/o MS waist, % MS glucose, % MS HDL-C, % MS triglyceride, % MS blood pressure, % DM medication Hypertension medication Hyperlipidemia medication Log-CRP, mg/dL Log-Insulin, pmol/L Log-PFHS, ng/mL Log-PFNA, ng/mL Log-PFOA, nglmL. Log-PFOS, ng/mL Unweighted No . adolescent/adult 474/969 266/476 208/493 182/273 123/510 169/I86 66/197 246/144 162/628 /659 /310 186/352 163/320 125/297 38/382 I24/786 35P212 96f313 86/364 49/470 0/79 0/245 0/118 474/969 474/969 474/969 474/969 474/969 474/969 Adolescents (2-! 12 yrs, <20 yrs) 15 .Sf0 .2 56.6t3 .1 43 .4-3 .1 11 .72.5 71 .7t3 .5 16.6f2 .6 19.If2 .1 49 .6f3 .6 31 .4f3.8 N/A N/A 27.3f3 .1 33.8+3.6 38 .9f3 .9 8 .6t2 .1 26 .4f2.7 7.3f2 .1 23.8f3 .1 2i .8f2 .8 8.3+1 .6 0 0 0 -2.94t0 .07 4 .05f0.04 0 .950.10 -0.35t0 .07 1 .51f0 .05 3 .11=0 .05 Adults 20 yrs 46.2t0 .8 50 .2t1 .7 49~813 8.71,7 80.8t2 .5 10.51 .7 25 .3t2.5 14 .5f 1 .4 60 .22 .5 73 .3f2 .3 26.7f2 .3 25 .2t2 .4 33 .4f2 .7 41 .4f2 .2 36.2f2 .0 81 .21 .8 15 .7t1 .5 32 .6+2.3 34 .6f2.2 42 .012.2 4.8f0 .7 19.51 .5 9 .71 .0 -1 .54t0 .05 3 .99f0 .04 0 .60f0 .04 -0.21t0.07 _ 1 .48f0.04 3 .1 9i0.04 Abbreviations . MS, metabolic syndrome ; HDL-C, high density lipoprotein cholesterol ; CRP, C-reactive protein ; PFHS, perfluorohexane sulfonic acid; PFNA, perfluorononanoic acid; PFOA, perfluorooctanoic acid; PFOS, perfluorooctane sulfate ; N/A, not assessment p. 12 Perluoroalky! chemicals, glucose homeostasis and metabolic syndrome Table 2 Linear regression coefficients with one unit increase in log-PFCs in adolescents and adults Adolescent Glucose Model l Model 2 Model 3 Log-insulin Model I Model 2 Model 3 Log-HOMA-IR Model 1 Model 2 Model 3 Log-(3 cell function Model l Model 2 Model 3 Adult Glucose Model 1 Model 2 Model 3 Log-insulin Model l Model 2 Model 3 Log-HOMA-IR Model l Model 2 Model 3 Log-P cell function Model l Model 2 Model 3 Log-PFHS (3coeff -0.02t0.03 -0.02f0.03 -0 .01t0.03 0.02t0.04 0.03f0.04 0.06t0.03 0.02t0 .04 0 .02t0 .05 0_05{1 .03 0 .030.04 0.03f0.04 0.050.03 -0 .07f0.09 -0.05f0 .09 -0.02t0 .06 -0.04t0 .05 -0 .04f0 .05 0.01f0 .03 -0_05f0.05 -0.04f0 .05 O.OOf0.04 -0 .02t0.04 -0 .020.04 0.01t0.03 Log-PFNA Pcoeff 0.04f0.04 0.05t0 .05 0 .07f0 .04 -0.090.05 -0.IOf0 .05 -0- 100 .05* -0 .09t0.05 -0.09t0.05 -0.08f0.04 -0.12f0.07 -0 .12f0 .06 -0.12t0 .06* -0 .OSf0.04 -0.02t0.05 O.OOf0 .04 -0 .060 .04 -0 .05t0 .04 -0.04t0.03 -0.06f0 .04 -0.06t0.05 -0.04f0 .04 -0.05f0.03 -0.05f0.04 -0.040.03 Log-PFOA (icoeff -0.04t0.05 -0.04=0.05 -0.03f0.05 0_OSf0.08 0.07f0.09 0.080.07 0 .04t0 .08 O.O6f0.09 0.08f0.05 0.06i0.10 0.08t0.10 0 .08f0 .08 -0.11t0 .10 -0 .IIt0.11 -0 .09f0.08 0 .08t0 .04 0 .08f0.04 0.07f0 .03* 0.06f0.05 0 .07f0 .05 0.06f0.04 0.09t0 .04* 0.09+0 .04* 0.070.03* Log-PFOS (icoeff -0.03t0.06 -0.04t0 .06 -0.03f0 .06 0.060 .07 0.07f0 .07 0.15t0 .08 0.05f0.07 0.07f0.07 0.15f0.07 0 .06t0 .08 0 .08t0 .08 0.13f0.09 -0 .03f0.08 -0.23f0.09 -0.03t0.07 0.13f0 .05* 0.13t0 .05* 0 . 140 .05t 0.12f0.05* 0.12t0 .05* 0.14f0.05t 0.14f0.06* 0.14t0.06* 0.15t0_05fi *, p<0.05; t, p<0.01 ; $, p<0 .005; Model I adjusted for age, gender, race; Model 2 adjusted for Model I + health behaviors (smoking status, alcohol intake and household income); Model 3 adjusted for Model 2 -= measurement data (waist circumference, CRP, and insulin/glucose/HOMA) + medications p. 13 Peifluoroalkyl chemicals, glucose homeostasis and metabolic syndrome Table 3 Odds ratios of metabolic syndrome and its components associated with one unit increase in log-PFCs in adolescents and adults Adolescent Log-PFHS OR (95% Cl) Log-PFNA OR (95% CI) Log-PFOA OR (95% Cl) Log-PFOS OR (95% CI) MS Model 4 MS Waist Model 4 Model 5 MS Gluocse Model 4 Model 5 MS HDL-C . 0.56 (0.22-1 .45) 0.37 (0 .21-0.64) $ 0.79 (0_30-2.12) 0.49(0 .18-1 .30) 0.72 (0 .48-1_09) 0.64 (0.45-0.91)* 0.99 (0.59-1 .63) 1 .09 (0.61-1 .95) 0.61 (0.32-1 .13) 0.58 (0.34-1 .00)* 0.41 (0 .21-0.83)* 0.37 (0.16-0.82)* 1 .10 (0.46-2.62) 0.98 (0.44-2.17) 3.15 (1 .39-7.12)* 3 .16 (1 .39-7.16)* 0.46 (0 .25-0.85)* 0.55(0-24-1 .25) 0.58 (0.31-1.10) 0.58 (0.28-1 .14) Model 4 Model 5 MS Triglyceride 0.93 (0.58-1 .47) 0.93 (0 .60-1 .43) 0.59 (0-42-0-83)f 0.67 (0.45-0.99)* 1 .20 (0.60-2.39) 1 .50(0.67-3.36) 0.89 (0 .51-1.55) 1 .38 (0 .61-3.14) Model 4 Model 5 Adult 1 .07 (0 .76-1 .52) 1 .08 (0 .83-1 .40) 0 .68 (0.40-1 .15) 0 .71 (0 .37-1 .34) 1 .64 (0.72-3 .73) 1 .15 (0 .54-2 .47) 0 .95 (0.50-1 .80) 0 .78 (0 .41-1 .49) MS Model 4 MS Waist 0 .93 (0.73-1 .19) 0.92 (0.69-1 .24) 1 .07 (0_73-1 .57) 1 .25 (0.86-1 .82) Model 4 Model 5 MS Gluocse Model 4 Model 5 MS HDL-C Model 4 Model 5 MS Triglyceride 0.73 (0 .53-0 .99)* 0.80 (0 .58-1 .10) 0.79 (0 .53-1.16) 0.76 (0 .54-1 .07) 0.90(0.69-1 .18) 1.00 (0 .73-1 .37) 1 .25 (0.88-1 .74) 1 .34 (0 .93-1 .92) 0.81 (0.62-1 .07) 0.86 (0.66-1 .12) 0.80 (0 .65-0.99)* 0.81 (0.65-1 .00) 0.95 (0.63-1 .45) 0 .97 (0.65-1 .46) 0.89 (0 .63-1 .26) 0.87 (0.61-1.26) 1 .14 (0.84-1 .55) 1 .22 (0 .86-1 .71) 0.89 (0.59-1 .34) 0 .91 (0 .59-1 .41) 0.83 (0.64-1 .08) 0.81 (0.62-1 .05) 1 .47 (1 .07-2.00)* 1.61 (1 .15-2.26)* Model 4 Model 5 0 .80 (0.64-0.99)* 0_78 (0.60-1 .02) 0 .98 (0.82-1 .16) 0.99 (0.81-1 .19) 0.91 (0 .69-1 .20) 0.86 (0 .65-1 .13) 0.97 (0.73-1 .27) 0.86(o .65-1-16) *, p<0 .05 ; t, p<0.01 ; $, p<0 .005 ; Model 4 adjusted for age, gender, race, health behaviors (smoking status, alcohol intake and household income), measurement data (CRP, HOMAJinsulin) and medications ; Model 5 adjusted for Model 4 + other components of the metabolic syndrome