Organochlorine compound-induced alterations in adipocyte/macrophage crosstalk and effects on wound healing

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Project Summary: The prevalence of obesity and type 2 diabetes are increasing at an alarming rate both within the United States and worldwide. One of the most prevalent sequalae associated with type 2 diabetes is alterations in wound healing which predispose the diabetic patient to diabetic foot ulceration and other soft tissue infections. Within these infections, Staphylococcus aureus is the most commonly isolated bacterial species and is thought to exacerbate diabetes-induced deficits in wound healing. While hyperglycemia and decreased peripheral circulation have been implicated in diabetes-induced deficits in wound healing, the role of environmental exposures remains unexplored. Recent studies have demonstrated environmental exposures to persistent organic pollutants (POPs), including legacy organochlorine (OC) pesticides, may promote type 2 diabetes pathogenesis and that these compounds may have immunomodulatory effects such as altering macrophage polarization and adipocyte secretion of adipokines. Additionally, POPs and especially OC pesticide based POPs bioaccumulate in the subcutaneous adipose tissue where they may exert a localized effect to alter the adipose tissue microenvironment. Our current preliminary data demonstrate exposure to the prevalent OC pesticide metabolites dichlorodiphenyldichloroethylene (DDE) and oxychlordane have opposing effects on macrophage phagocytic activity. However, when DDE and oxychlordane exposure is in the context of an environmentally relevant mixture, there is a significant mixture based effect which potentiates phagocytic activity at low concentrations but decreases phagocytic activity with increasing concentrations. Therefore, the possibility arises that OC pesticide increased POPs exposure may alter macrophage/adipocyte cross-talk in the adipose tissue microenvironment which could alter wound healing kinetics. Our current hypothesis is exposure to the highly prevalent POPs, DDE, trans-nonachlor, and oxychlordane will change the adipose tissue microenvironment leading to altered macrophage function/plasticity which may have a deleterious effect on wound healing. This hypothesis will be tested in the following specific aims: 1. Determine the effects of OC pesticide POPs exposure on adipocyte/macrophage cross-talk and subsequent function to evaluate alterations in adipose tissue microenvironment. 2. Determine the effects of exposure to OC pesticide POPs on the ability of S. aureus to cause localized skin and soft tissue infection in normal and obese/type 2 diabetic mice. This will be the first study to our knowledge to examine the effects of OC pesticide POPs exposure on the adipocyte/macrophage cross-talk in the adipose tissue microenvironment with an emphasis on alterations in wound healing. Should POPs significantly alter the adipose tissue microenvironment and wound healing, these compounds could be used as biomarkers to identify patients which are at increased risk for chronic wounds such as diabetic foot ulcers and other soft tissue infections.