Endocrine Disruptors Leading to Obesity and Related Diseases

Abstract

The review aims to comprehensively present the impact of exposure to endocrine disruptors (EDs) in relation to the clinical manifestation of obesity and related diseases, including diabetes mellitus, metabolic syndrome, cardiovascular diseases, carcinogenesis and infertility. EDs are strong participants in the obesity epidemic scenery by interfering with cellular morphological and biochemical processes; by inducing inflammatory responses; and by presenting transcriptional and oncogenic activity. Obesity and lipotoxicity enhancement occur through reprogramming and/or remodeling of germline epigenome by exposure to EDs. Specific population groups are vulnerable to ED exposure due to current dietary and environmental conditions. Obesity, morbidity and carcinogenicity induced by ED exposure are an evolving reality. Therefore, a new collective strategic approach is deemed essential, for the reappraisal of current global conditions pertaining to energy management.

Keywords: carcinogenesis; cardiovascular diseases; diabetes mellitus; endocrine disruptors; infertility; metabolic syndrome; obesity; pesticides.

Figure 1

Inflammatory signaling pathways link nutrient excess to insulin resistance (modified from [67]). Cytoplasmic/nuclear responses via tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and IRS-2 are activated by the presence of insulin at the cell surface. However, insulin signaling is potentially inhibited by serine phosphorylation of these proteins by Jun N-terminal kinases (JNK) and inhibitor of nuclear factor κB (NF-κB) kinases (IKK). Various intra/extracellular sequelae of chronic nutrient excess activate these signaling pathways, linking overfeeding to insulin resistance. JNK and IKK activation triggers inflammatory cytokine production, activating JNK/IKK in an autocrine/paracrine manner further reinforcing insulin resistance. ER: endoplasmic reticulum; AP-1: activator protein-1).

Figure 2

Obesity-associated changes in the physiological function of adipose tissue, which can lead to insulin resistance, chronic inflammation, and altered secretion of adipokines (direct pathogenic factors), are speculated to be involved in carcinogenesis and cancer progression (modified from [120]). AdipoR1/R2: adiponectin receptor 1/2; AMPK: 5′-AMP activated protein kinase; IGF-1: insulin-like growth factor-1; IGF-1R: insulin-like growth factor-1 receptor; IKK: IκB kinase; IL-6: interleukin-6; IL-6R: interleukin-6 receptor; IR: insulin receptor; IRS-1: insulin receptor substrate-1; JAK: Janus kinase; MAPK: mitogen-activated-protein-kinase; mTOR: mammalian target of rapamycin; NF-κB: nuclear factor-κB; ObR: leptin receptor; PAI-1: plasminogen activator inhibitor-1; PI3-K: phosphatidylinositol 3-kinase; ROS: reactive oxygen species; STAT3: signal transducer and activator of transcription 3; TNF-α: tumor necrosis factor-α; TNF-R1: tumor necrosis factor-receptor 1; TSC2: tuberous sclerosis complex 2; uPA: urokinase-type plasminogen activator; uPAR: urokinase-type plasminogen activator receptor; VEGF: vascular endothelial growth factor; VEGFR: vascular endothelial growth factor receptor.

Figure 3

Regulation of cancer stem cells and epithelial plasticity by endocrine disruptors in low dose; potential pathways leading to malignant transformation and involvement of cancer stem-like cells (modified from [130]). EMT: epithelial–mesenchymal transition; Jak-STAT: Janus kinase/signal transducers and activators of transcription pathway; TGF-β: transforming growth factor-beta; Wnt: Wnt protein signaling pathways.