ReviewPPAR-mediated activity of phthalates: A link to the obesity epidemic?
Section snippets
Introduction: endocrine disrupters and obesogens
Over a number of years now, anecdotal observations and scientific evidence have come to light that suggest that chemicals present in the environment may be exerting an adverse effect on the reproductive capacity of wild life and man. The types of pollutants shown to cause reproductive effects include polychlorinated hydroxybiphenyls such as OH-PCB, organochlorine pesticides (DDT) and industrial pollutants, organophosphate pesticides, petroleum hydrocarbons, heavy metals, certain plastic
Nuclear receptors, sensors of exposure to xenobiotics
A privileged mechanism for ED interference with metabolic pathways is their direct or indirect activity on nuclear receptors. Nuclear receptors are transcription factors characterised by three important properties: first, they share a common modular organization, with a DNA binding domain and ligand binding domain; second, they are activated by the binding of specific ligands; third, the activated receptors bind to specific response elements located in the vicinity of the promoter of their
PPARs as adaptive molecules for environmental chemicals
Three different PPAR isotypes (PPARα, β/δ or FAAR, and γ, respectively) were identified in the early 1990s in Xenopus laevis and in mice (Dreyer et al., 1992, Issemann et al., 1992). Since then, PPARα, β/δ and γ have also been identified in humans, rats, fish, hamsters and chickens. Various endogenous and exogenous PPAR ligands have been identified, including fatty acids, eicosanoids, synthetic hypolipidemic and antidiabetic agents. Most of the identified PPAR target genes are involved in
Phthalate interaction with PPARs: a model for studying endocrine disruption mediated by PPARs
Phthalates are widespread environmental micro-pollutants found in Europe and North America consisting of a ubiquitous class of compounds used most commonly as softeners for products made with polyvinyl chloride (PVC). Between 1985 and 1990, 300 million pounds worth of phthalates were manufactured annually. The primary route for release into soil of DEHP the most commonly used phthalate, is through disposal of industrial and municipal waste at landfills (ATSDR, 1993). Human exposure to
Phthalates are true ligands of PPARs
In addition to evidence that some of phthalate activities are PPARα dependent, several reports assessed these activities on the three PPAR isotypes, using transactivation assays and intact cellular systems with endogenous receptors and target genes (Hurst and Waxman, 2003, Bility et al., 2004, Feige et al., 2007). These studies determined the range of potency and efficacy of phthalate monoesters on PPARα, PPARβ and PPARγ activation. They showed that the three PPAR isotypes are activated by
Phthalate-mediated activation of PPARγ: functional consequences
The observation that MEHP acts similarly to rosiglitazone as a PPARγ agonist is well corroborated by functional studies in 3T3-L1 in which MEHP-induced adipogenesis, although the maximal effect of MEHP remained lower than that induced by Rosiglitazone. These effects of MEHP on adipocyte differentiation were indisputably mediated by PPARγ as demonstrated by PPARγ knock-down and by using specific inhibitors (Feige et al., 2007).
A recently developed concept, more particularly used in the context
PPARs and phthalate in the context of human exposure
As mentioned above, DEHP is among the phthalate esters most abundantly used as industrial plasticizers, and is also found in cosmetics, as well as in industrial paints and solvents. DEHP is found in flexible plastics used in manufacturing a wide variety of every-day products including medical devices and food packaging, and its propensity to leach can lead to high levels of human exposure (NTP-CERHRexpertpanel, 2006). The biological effects of exposure to DEHP are hence of major concern but
Conclusion
PPARs mediate the effects of hypolipidemic and antidiabetic drugs and are involved in illnesses such as atherosclerosis, hyperlipidemia, and obesity, which in general develop slowly over many years. Therefore, these diseases often reflect subtle deregulations of complex metabolic pathways that become manifest only after many years, and may even reflect a perturbation that occurred in utero (Grun and Blumberg, 2007). Therefore, it is of paramount importance to understand the molecular bases of
Acknowledgements
We thank Laurent Gelman, Walter Wahli, and all past members of our team worked for the PNR50 programme for lively discussion and help. The work of the authors was supported by the Swiss National Research Project 50, the Swiss National Science Foundation, and the Etat de Vaud.
References (50)
- et al.
Oral toxicity of bis(2-ethylhexyl) phthalate during pregnancy and suckling in the Long-Evans rat
Food Chem. Toxicol.
(1998) - et al.
Structure of the PPARalpha and -gamma ligand binding domain in complex with AZ 242; ligand selectivity and agonist activation in the PPAR family
Structure
(2001) - et al.
Control of the peroxisomal β-oxidation pathway by a novel family of nuclear hormone receptors
Cell
(1992) - et al.
Exposure of hemodialysis patients to di-2-ethylhexyl phthalate
Int. J. Pharm.
(1999) - et al.
From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions
Prog. Lipid Res.
(2006) - et al.
The endocrine disruptor monoethyl-hexyl-phthalate is a selective peroxisome proliferator-activated receptor gamma modulator that promotes adipogenesis
J. Biol. Chem.
(2007) - et al.
Fluorescence imaging reveals the nuclear behavior of peroxisome proliferator-activated receptor/retinoid X receptor heterodimers in the absence and presence of ligand
J. Biol. Chem.
(2005) - et al.
Molecular basis of selective PPARgamma modulation for the treatment of Type 2 diabetes
Biochim. Biophys. Acta
(2007) - et al.
Role of PPARalpha in mediating the effects of phthalates and metabolites in the liver
Toxicology
(2005) - et al.
Effects of relatively low levels of mono-(2-ethylhexyl) phthalate on cocultured Sertoli cells and gonocytes from neonatal rats
Toxicol. Appl. Pharmacol.
(1998)
The peroxisome proliferator-activated receptor mediates the induction of CYP4A6, a cytochrome P450 fatty acid omega-hydroxylase, by clofibric acid
J. Biol. Chem.
The repressed nuclear receptor CAR responds to phenobarbital in activating the human CYP2B6 gene
J. Biol. Chem.
Association with coregulators is the major determinant governing peroxisome proliferator-activated receptor mobility in living cells
J. Biol. Chem.
Imaging protein molecules using FRET and FLIM microscopy
Curr. Opin. Biotechnol.
Diethylhexylphthalate as an environmental contaminant—a review
Sci. Total Environ.
Imaging biochemistry inside cells
Trends Cell Biol.
Peroxisome proliferator-activated receptor structures: ligand specificity, molecular switch and interactions with regulators
Biochim. Biophys. Acta
Chemical toxins: a hypothesis to explain the global obesity epidemic
J. Altern. Complement. Med.
Activation of mouse and human peroxisome proliferator-activated receptors (PPARs) by phthalate monoesters
Toxicol. Sci.
Interference of pollutants with PPARs: endocrine disruption meets metabolism
Int. J. Obesity.
Central role of peroxisome proliferator-activated receptors in the actions of peroxisome proliferators
Annu. Rev. Pharmacol. Toxicol.
Sensors for metabolic control: a regulatory network of nuclear receptors
Peroxisome proliferator-activated receptors: nuclear control of metabolism
Endocr. Rev.
Estrogens from plastic—are we being exposed?
Endocrinology
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Present address: Novartis Institute for Biomedical Research, CH-4056 Basel, Switzerland.