Metabolism disrupting chemicals and metabolic disorders

Abstract

The recent epidemics of metabolic diseases, obesity, type 2 diabetes(T2D), liver lipid disorders and metabolic syndrome have largely been attributed to genetic background and changes in diet, exercise and aging. However, there is now considerable evidence that other environmental factors may contribute to the rapid increase in the incidence of these metabolic diseases. This review will examine changes to the incidence of obesity, T2D and non-alcoholic fatty liver disease (NAFLD), the contribution of genetics to these disorders and describe the role of the endocrine system in these metabolic disorders. It will then specifically focus on the role of endocrine disrupting chemicals (EDCs) in the etiology of obesity, T2D and NAFLD while finally integrating the information on EDCs on multiple metabolic disorders that could lead to metabolic syndrome. We will specifically examine evidence linking EDC exposures during critical periods of development with metabolic diseases that manifest later in life and across generations.

Keywords: Developmental origins of health and disease; Diabetes; Endocrine disruptors; Lipid disorders; Metabolism disruptors; Obesity; Obesogens.

Published by Elsevier Inc.

Figures

Figure 1. Schematic illustrating the neuroendocrine control of energy balance (modified from Schwartz et al Nature 404, 661-71, 2000)

Peripheral signals reach the central nervous system through two main routes: Adiposity Signals (leptin, insulin and others) and hunger (Ghrelin, Orexin A, and others) signals bypass the blood brain barrier and target the hypothalamus (transparent blue circle), in particular the arcuate nucleus (ARC). b) Peripheral hunger and satiety signals that control meal processing, gastrointestinal activity and changes in energy stores reach the brainstem (nucleus of the solitary tract, NST) through vagal and other sensory nerve fibers. NPY and MSH neurons located within the ARC (stimulated or inhibited by adiposity and hunger signals) project to other hypothalamic nuclei (paraventricular nucleus, PVN, lateral hypothalamic nucleus, LH, and others). In particular, within the PVN they control CRH and TRH neurons, regulating (via the adenohypophysis) the hypophysis-adrenal and hypophysis-thyroid axes. From the hypothalamus, catabolic and anabolic pathways reach the brainstem where their data are integrated with the peripheral signals carried by the sensory system. There are also ascending projections from the NST that may reach the hypothalamus, through the lemniscus visceralis, contributing to adaptative changes in food intake and energy expenditure.

Figure 2. Mechanisms of Adipocyte Formation and Sites of Action of Metabolism Disruptors

1. Mesenchymal stem cells commit to the adipogenic lineage and become preadipocytes. Commitment to the adipocyte lineage is mediated by transcription factors Zfp423, Zfp467, Schnurri2, Tcf7l1 and the mTORC1 effector S6K1. 2. Adipocyte differentiation is primarily controlled by PPARγ and CCAAT-enchancer binding proteins (C/EBP)α, β and δ which establish a sustained feedback loop. Numerous chemicals are capable of differentiating pre-adipocytes into mature adipocytes. Adipocyte number and size can be increased in vivo under hormonal control and can also be influenced by chemical exposure. 3. Adipocyte hyperplasia has been shown in rodents to be caused by perinatal exposure to a variety of chemicals. 4. Adipocyte hypertrophy in rodents due to permanent upregulation of genes involved in lipid uptake is also caused by exposure during perinatal life to a number of chemicals.

Figure 3. Regulation of pancreas beta cell control of blood glucose and sites of action of metabolism disruptors

Glucose enters pancreatic beta-cells through glucose transporters (GLUT2 in mice and GLUT1 in humans) where it is metabolized in mitochondria resulting in an increase in the ATP/ADP ratio; this results in closure of membrane ATP-sensitive K+ channels (KATP) that are responsible for the resting membrane potential. KATP channel closure results in cellular depolarization that opens voltage-gated calcium channels, triggering Ca2+ signals that induce insulin granule exocytosis and a subsequent rise in circulating insulin levels. This secretory pathway is disrupted by EDCs at different points: 1) Bisphenol-A, nonylphenol, octylphenol and triphenyltin impair mitochondrial function. 2) Bisphenol-A blocks KATP channels after binding ERbeta. 3) Calcium signaling is altered by Bisphenol-A, Arsenic, PCBs and Triphenyltin. 4) disruption of insulin secretion has been described for Bisphenol-A, dioxins, PCBs, DDT, Arsenic, and Cadmium . Beta-cells have a low antioxidant capacity and are very sensitive to oxidative stress mediated by reactive oxygen and nitrogen species that impair their function by altering metabolism and/or KATP activity while inducing apoptosis. Mercury and Cadmium (5) are EDCs that produce oxidative stress in beta-cells. 6) Insulin gene expression is regulated by BPA via ERα, while DEHP and Cadmium provoke cell death and decrease in beta-cell mass.

Figure 4. Regulation of hepatic lipid metabolism and sites of action of metabolism disruptors

Hepatic steatosis occurs due to a combination of increased fatty acid (FA) synthesis or uptake and decrease FA oxidation or efflux. FA synthesis occurs as a consequence of liver X receptor (LXR) target gene activation which may occur following receptor activation by myriad environmental chemicals or via nuclear receptor cross talk. FA synthesis is upregulated by BPA, metals, PFCs, POPs, and tributyltin. BPA and POPs also upregulate scavenger receptors (e.g. CD36) to increase FA uptake into hepatocytes. Decreased FA oxidation is a consequence of mitochondrial dysfunction which may be mediated by BPA, chlorinated solvents POPs and metals. Liver also mediates xenobiotic metabolism which may increase oxidative stress. Endoplasmic reticulum (ER) stress is a consequence of exposures to aldehydes and metals. ER stress, in turn, impacts FA metabolism. Steatohepatitis occurs due to increased hepatic inflammation and cytokines. Proinflammatory cytokines are induced by many exposures including POPs, vinyl chloride, VOCs, and metals. More data are needed on the impact of MDCs on FA efflux in hepatic steatosis.