Project Summary/Abstract Polychlorinated biphenyls (PCBs) are a group of environmental toxins that has been linked to an increased risk of heart disease, stroke, and cancer, as well as the development of metabolic syndromes such as obesity, hyperlipidemia, and type II diabetes. Metabolic diseases are characterized by both systemic and local inflammation with adipose tissue, the primary site of PCB accumulation. Adipose tissue is comprised of many cell types including adipocytes, adipose mesenchymal stem cells (MSCs), endothelial cells, and immune cells such as macrophages. Adipose tissue macrophages (ATMs) play an integral role in regulating the inflammatory state of adipose tissue and influencing adipocyte function. During the pathological expansion of adipose tissue, adipocytes become inflamed beginning a cascade of immune cell activation starting with ATMs. The changing adipocyte secretion profile polarizes the macrophages from an anti-inflammatory phenotype toward an inflammatory phenotype and increases the infiltration of macrophage precursors into adipose tissue. Furthermore, these inflammatory ATMs communicate with local adipocytes through the release of soluble factors causing additional metabolic disruption and lipid accumulation in adipocytes. Despite the essential role of ATMs in the regulation of adipocyte function and the known accumulation of PCBs in adipose tissue, little is known about how PCBs affect adipose through ATMs. We have previously shown that PCB-exposed adipocytes have decreased adiponectin and increased IL-8 secretion, two cytokines implicated in macrophage phenotype switching. Additionally, we have shown that macrophages exposed to PCBs are polarized toward a more inflammatory phenotype. The objective of this proposed research is to determine how PCBs alter adipocyte- macrophage crosstalk to influence the development of endocrine and metabolic disruption. We hypothesize that adipocyte-macrophage communication will be altered by PCB exposure resulting in functional changes for both cell types. Our approach to testing this hypothesis is divided into two aims. In Aim 1, we will assess how PCB- exposed adipocytes affect macrophage recruitment and polarization. In Aim 2, we will investigate how PCB- exposed macrophages affect adipocyte phenotype and adipogenesis. Through the completion of these aims, we will uncover the systems-level mechanisms by which PCBs contribute to adipose dysfunction and inflammation through the disruption of adipocyte-macrophage crosstalk. More broadly, this fellowship will help me achieve my goals of gaining experience in medicine, toxicology, bioengineering, and environmental chemistry to prepare for a future career in treating and researching diseases impacted by endocrine-disrupting chemicals.

Project Narrative Polychlorinated biphenyls (PCBs) persist in the built and natural environment leading to human exposure and increased risk of metabolic diseases such as diabetes and obesity. The development of metabolic diseases often begins in adipose tissue, the lipid-rich depot also responsible for PCB accumulation. This project will uncover the systems-level mechanisms by which PCBs contribute to adipose dysfunction and inflammation through the disruption of cellular crosstalk between adipocytes and macrophages.