Persistent organic pollutants (POPs) increase rage signaling to promote downstream cardiovascular remodeling.

George E Howell,Eun‐Ju Yang,Amber M Kay,James A Stewart,Barbara L F Kaplan,Stephanie S Burr,Jackson B Coole,Jaime A Singh,Sandeep Kondakala

doi:10.1002/tox.22817

Abstract

Exposure to environmental contaminants and consumption of a high, saturated fatty diet has been demonstrated to promote precursors for metabolic syndrome (hyperglycemia, hyperinsulinemia, and hypertriglyceridemia). The purpose of this study was to determine if exposure to the most prevalent environmental persistent organic pollutants (POPs) would act as causative agents to promote metabolic syndrome independent of dietary intake. We hypothesized that POPs will activate the advanced glycated end‐product (AGE)‐and receptor for AGE (RAGE) signaling cascade to promote downstream signaling modulators of cardiovascular remodeling and oxidative stress in the heart. At 5‐weeks of age nondiabetic (WT) and diabetic (ob/ob) mice were exposed POPs mixtures by oral gavage twice a week for 6‐weeks. At the end of 6‐weeks, animals were sacrificed and the hearts were taken for biochemical analysis. Increased activation of the AGE‐RAGE signaling cascade via POPs exposure resulted in elevated levels of fibroblast differentiation (α‐smooth muscle actin) and RAGE expression indicated maladaptive cardiac remodeling. Conversely, the observed decreased superoxide dismutase‐1 and ‐2 (SOD‐1 and SOD‐2) expression may exacerbate the adverse changes occurring as a result of POPs treatment to reduce innate cardioprotective mechanisms. In comparison, ventricular collagen levels were decreased in mice exposed to POPs. In conclusion, exposure to organic environmental pollutants may intensify oxidative and inflammatory stressors to overwhelm protective mechanisms allowing for adverse cardiac remodeling.

Highlights

There has been an increasing interest in investigating the effects of persistent organic pollutants (POPs) exposure and its association with the prevalence of type 2 diabetes mellitus (T2DM) and the metabolic syndrome
From previous studies, increased POPs exposure exacerbated hepatic steatosis and adipocyte dysfunction resulting in elevated production of proinflammatory and oxidative stressors.[24]
These changes in the inflammatory profile have been demonstrated to exacerbate type 2 diabetes mellitus (T2DM); the mechanism regulating this process is unknown.10Therefore, our present study aimed to determine if POPs exposure would act as a causative agent to promote metabolic syndrome outcomes in the heart independent of dietary intake

Summary

| INTRODUCTION

There has been an increasing interest in investigating the effects of persistent organic pollutants (POPs) exposure and its association with the prevalence of type 2 diabetes mellitus (T2DM) and the metabolic syndrome. In states of metabolic dysfunction such as obesity and diabetes, ROS levels become exceedingly high, and when compounded with POPs exposure, innate antioxidant defense mechanisms become overwhelmed with increased levels of ROS from the activation of RAGE/NF-κB signaling.[24,26] The following results demonstrate a potential role for AGE-RAGE signaling in the POPs-mediated remodeling

| MATERIALS AND METHODS

| RESULTS

Findings

| DISCUSSION