Interference of pollutants with PPARs: endocrine disruption meets metabolism

Abstract

The concept of endocrine disruption emerged over a decade ago with the observation that several natural or industrial compounds can interfere with estrogen and androgen signaling, and thereby affect both male and female reproductive functions. Since then, many endocrine-disrupting chemicals (EDCs) have been identified and the concept has been broadened to receptors regulating other aspects of endocrine pathways. In that context, interference of EDCs with receptors regulating metabolism has been proposed as a factor that could contribute to metabolic diseases such as obesity and diabetes. We review recent studies showing that several pollutants, including phthalates and organotins, interfere with PPAR (peroxisome proliferator-activated receptors) nuclear receptors and may thereby affect metabolic homeostasis. Particular emphasis is given on the mechanisms of action of these compounds. However, unlike what has been suspected, we provide evidence from mouse models suggesting that in utero exposure to the phthalate ester di-ethyl-hexyl-phthalate most likely does not predispose to obesity. Collectively, these studies define a subclass of EDCs that perturb metabolic signaling and that we propose to define as metabolic disruptors.

In utero exposure to di-(2-ethylhexyl) phthalate induces metabolic disorder and increases fat accumulation in visceral depots of C57BL/6J mice offspring

“…Environmental obesogens are chemical compounds that promote or exacerbate the development of obesity and its associated health outcomes (2) by disrupting or interfering with critical pathways associated with energy balance, adipogenesis and lipid metabolism (3). Phthalates are a class of candidate obesogens that are ingested in food.…”

Obesity: genome and environment interactions

“…Obesogens ( Figure 1) are foreign endocrine disrupting chemicals (EDCs) that inappropriately alter normal development and/or homeostasis of lipid metabolism, adipogenesis, fat storage, obesity, and type 2 diabetes (4,(45)(46)(47)(48). EDCs can interfere with normal functions of the endocrine system by disrupting the balanced system of hormones that regulate vital body functions such as growth, stress response, sex development, behaviour, ability to reproduce, production and utilisation of insulin, and metabolic rate.…”

The Role of Endocrine Disruptors on Metabolic Dysfunction

“…A number of other master transcriptional regulators critical to the regulation metabolic pathways leading to obesity has also been demonstrated as possible EDC targets, including peroxisome proliferator activated receptors (PPARs), liver X receptor (LXR), farnesoid X receptor (FXR), estrogen-related receptors (ERRs) and retinoid X receptors (RXRs) [42,72]. The activation of nuclear receptors such as PPAR and LXR by EDCs interferes with the expression of an array of genes involved in lipid metabolism and inflammation [72][73][74].…”

“…The activation of nuclear receptors such as PPAR and LXR by EDCs interferes with the expression of an array of genes involved in lipid metabolism and inflammation [72][73][74]. Several other mechanisms such as oxidative stress, mitochondrial dysfunction and epigenetic modifications are possible pathways of EDCs interference in the inflammatory processes [42,75].…”