Project 3

Environmental PPARγ agonist-mediated toxicity in the developing immune system

Emberley et al; Figure 5B

Determining the molecular mechanism by which individual and complex mixtures of environmental chemicals impair the development of the mammalian immune system and accelerate bone aging.

Project Leader

Jennifer Schlezinger
Boston University School of Public Health

Project Description

Aging is associated with development of fatty bone marrow, the site of immune cell development, and an impaired immune response to infection. Exposure to “environmental obesogens,” chemicals suspected to promote obesity via disruption of metabolic homeostasis pathways, may mimic these phenomena. A key signaling molecule in the pathway of fat cell formation is a protein called peroxisome proliferator activated receptor gamma (PPARγ). When this protein is active in the bone marrow, it binds to DNA and turns on fat cell forming signals, but turns off bone cell forming signals. It remains unclear how turning on PPARγ in the bone marrow may alter the microenvironment that supports life-long immune cell development. This is an important problem, as a growing number of environmental contaminants, including Superfund chemicals such as phthalates and organotins (widely used in industry and agriculture), are being recognized for their ability to activate PPARγ. The objective of Project 3 is to determine how phthalates and organotins may change bone marrow physiology through PPARγ activation.

Our data using in vitro and in vivo models suggest that contaminant-induced fat formation in bone results not only in loss of bone quality but also adverse changes to the microenvironment required to support immune cell development, similar to the effects of aging. Results from these studies will provide fundamental information on the interaction of the bone marrow environment and immune cell development and targets for intervention. Our long-term goal is to understand the molecular mechanisms by which individual and complex mixtures of Superfund chemicals impair the development of the mammalian immune system, a system that requires ongoing development in the face of continuing pathogen exposures.

Summer 2016 State of the Science Update

Project 3 focuses on chemicals commonly found in consumer products (organotins, phthalates, parabens, flame retardants) that act as endocrine disruptors, chemicals that promote or inhibit the production, elimination or action of hormones or hormone-like chemicals. The contaminants studied in Project 3  are recognized for their ability to activate a protein called PPARγ, the master regulator of fat formation, which plays an important role not only in metabolic health but also bone health. Our current work shows that tributyltin and triphenyl phosphate increase weight gain by regulating lipid and glucose homeostasis in adults and disrupt bone homeostasis by acting on both bone forming and bone resorbing cells.  Dr. Schlezinger’s new focus is investigating how early life exposures to these chemicals programs metabolic homeostasis and peak bone mass in adulthood.

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