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      The Pollutant Diethylhexyl Phthalate Regulates Hepatic Energy Metabolism via Species-Specific PPARα-Dependent Mechanisms

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          Abstract

          Background

          The modulation of energetic homeostasis by pollutants has recently emerged as a potential contributor to the onset of metabolic disorders. Diethylhexyl phthalate (DEHP) is a widely used industrial plasticizer to which humans are widely exposed. Phthalates can activate the three peroxisome proliferator–activated receptor (PPAR) isotypes on cellular models and induce peroxisome proliferation in rodents.

          Objectives

          In this study, we aimed to evaluate the systemic and metabolic consequences of DEHP exposure that have remained so far unexplored and to characterize the underlying molecular mechanisms of action.

          Methods

          As a proof of concept and mechanism, genetically engineered mouse models of PPARs were exposed to high doses of DEHP, followed by metabolic and molecular analyses.

          Results

          DEHP-treated mice were protected from diet-induced obesity via PPARα-dependent activation of hepatic fatty acid catabolism, whereas the activity of neither PPARβ nor PPARγ was affected. However, the lean phenotype observed in response to DEHP in wild-type mice was surprisingly abolished in PPARα-humanized mice. These species differences are associated with a different pattern of coregulator recruitment.

          Conclusion

          These results demonstrate that DEHP exerts species-specific metabolic actions that rely to a large extent on PPARα signaling and highlight the metabolic importance of the species-specific activation of PPARα by xenobiotic compounds.

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          Most cited references31

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          From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions.

          Peroxisome proliferator-activated receptors (PPARs) compose a family of three nuclear receptors which act as lipid sensors to modulate gene expression. As such, PPARs are implicated in major metabolic and inflammatory regulations with far-reaching medical consequences, as well as in important processes controlling cellular fate. Throughout this review, we focus on the cellular functions of these receptors. The molecular mechanisms through which PPARs regulate transcription are thoroughly addressed with particular emphasis on the latest results on corepressor and coactivator action. Their implication in cellular metabolism and in the control of the balance between cell proliferation, differentiation and survival is then reviewed. Finally, we discuss how the integration of various intra-cellular signaling pathways allows PPARs to participate to whole-body homeostasis by mediating regulatory crosstalks between organs.
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            Concentrations of Urinary Phthalate Metabolites Are Associated with Increased Waist Circumference and Insulin Resistance in Adult U.S. Males

            Background Phthalates impair rodent testicular function and have been associated with anti-androgenic effects in humans, including decreased testosterone levels. Low testosterone in adult human males has been associated with increased prevalence of obesity, insulin resistance, and diabetes. Objectives Our objective in this study was to investigate phthalate exposure and its associations with abdominal obesity and insulin resistance. Methods Subjects were adult U.S. male participants in the National Health and Nutrition Examination Survey (NHANES) 1999–2002. We modeled six phthalate metabolites with prevalent exposure and known or suspected antiandrogenic activity as predictors of waist circumference and log-transformed homeostatic model assessment (HOMA; a measure of insulin resistance) using multiple linear regression, adjusted for age, race/ethnicity, fat and total calorie consumption, physical activity level, serum cotinine, and urine creatinine (model 1); and adjusted for model 1 covariates plus measures of renal and hepatic function (model 2). Metabolites were mono-butyl phthalates (MBP), mono-ethyl phthalate (MEP), mono-(2-ethyl)-hexyl phthalate (MEHP), mono-benzyl phthalate (MBzP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP). Results In model 1, four metabolites were associated with increased waist circumference (MBzP, MEHHP, MEOHP, and MEP; p-values ≤ 0.013) and three with increased HOMA (MBP, MBzP, and MEP; p-values ≤ 0.011). When we also adjusted for renal and hepatic function, parameter estimates declined but all significant results remained so except HOMA-MBP. Conclusions In this national cross-section of U.S. men, concentrations of several prevalent phthalate metabolites showed statistically significant correlations with abdominal obesity and insulin resistance. If confirmed by longitudinal studies, our findings would suggest that exposure to these phthalates may contribute to the population burden of obesity, insulin resistance, and related clinical disorders.
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              Endocrine-disrupting organotin compounds are potent inducers of adipogenesis in vertebrates.

              Dietary and xenobiotic compounds can disrupt endocrine signaling, particularly of steroid receptors and sexual differentiation. Evidence is also mounting that implicates environmental agents in the growing epidemic of obesity. Despite a long-standing interest in such compounds, their identity has remained elusive. Here we show that the persistent and ubiquitous environmental contaminant, tributyltin chloride (TBT), induces the differentiation of adipocytes in vitro and increases adipose mass in vivo. TBT is a dual, nanomolar affinity ligand for both the retinoid X receptor (RXR) and the peroxisome proliferator-activated receptor gamma (PPARgamma). TBT promotes adipogenesis in the murine 3T3-L1 cell model and perturbs key regulators of adipogenesis and lipogenic pathways in vivo. Moreover, in utero exposure to TBT leads to strikingly elevated lipid accumulation in adipose depots, liver, and testis of neonate mice and results in increased epididymal adipose mass in adults. In the amphibian Xenopus laevis, ectopic adipocytes form in and around gonadal tissues after organotin, RXR, or PPARgamma ligand exposure. TBT represents, to our knowledge, the first example of an environmental endocrine disrupter that promotes adipogenesis through RXR and PPARgamma activation. Developmental or chronic lifetime exposure to organotins may therefore act as a chemical stressor for obesity and related disorders.
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                Author and article information

                Journal
                Environ Health Perspect
                Environmental Health Perspectives
                National Institute of Environmental Health Sciences
                0091-6765
                1552-9924
                February 2010
                8 October 2009
                : 118
                : 2
                : 234-241
                Affiliations
                [1 ] Center for Integrative Genomics, National Research Center “Frontiers in Genetics,” University of Lausanne, Lausanne, Switzerland
                [2 ] Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA
                [3 ] Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
                Author notes
                Address correspondence to B. Desvergne, Center for Integrative Genomics, Le Génopode, Université de Lausanne, CH-1015 Lausanne, Switzerland. Telephone: 41-0-21-692-41-40. Fax: 41-0-21-692-41-15. E-mail: beatrice.desvergne@ 123456unil.ch

                The authors declare they have no competing financial interests.

                Article
                ehp-118-234
                10.1289/ehp.0901217
                2831923
                20123618
                394310e0-be86-42e0-8b1b-d707476854df
                This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.
                History
                : 18 July 2009
                : 8 October 2009
                Categories
                Research

                Public health
                ppar,metabolism,species specificity,endocrine disruptor,dehp
                Public health
                ppar, metabolism, species specificity, endocrine disruptor, dehp

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