Review
PPAR-mediated activity of phthalates: A link to the obesity epidemic?

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Abstract

The endocrine disruption hypothesis asserts that exposure to small amounts of some chemicals in the environment may interfere with the endocrine system and lead to harmful effects in wildlife and humans. Many of these chemicals may interact with members of the nuclear receptor superfamily. Peroxisome proliferator-activated receptors (PPARs) are such candidate members, which interact with many different endogenous and exogenous lipophilic compounds. More particularly, the roles of PPARs in lipid and carbohydrate metabolism raise the question of their activation by a sub-class of pollutants, tentatively named “metabolic disrupters”. Phthalates are abundant environmental micro-pollutants in Europe and North America and may belong to this class. Mono-ethyl-hexyl-phthalate (MEHP), a metabolite of the widespread plasticizer di-ethyl-hexyl-phthalate (DEHP), has been found in exposed organisms and interacts with all three PPARs. A thorough analysis of its interactions with PPARγ identified MEHP as a selective PPARγ modulator, and thus a possible contributor 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.

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    Present address: Novartis Institute for Biomedical Research, CH-4056 Basel, Switzerland.

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