Superfund Research Program

Environmental PPARγ Pathway Activators: Multifaceted Metabolic Disruptors Impacting Adipose and Bone Homeostasis

Project Leader: Jennifer J. Schlezinger
Co-Investigator: James Hamilton
Grant Number: P42ES007381
Funding Period: 2005-2021

Project-Specific Links

Final Progress Reports

Year:   2019  2016 

Obesity and osteoporosis are public health issues worldwide, contributing significantly to metabolic diseases (e.g. type 2 diabetes) and fracture risk and thereby creating a substantial health care burden. Adipose and bone tissue each contain multipotent cells whose differentiation and function are regulated by common proteins, called nuclear receptors. These nuclear receptors are used by hormones to change how cells act and are well known for their propensity to be commandeered by environmental toxicants. One such nuclear receptor is the peroxisome proliferator activated receptor gamma (PPARg). In this project, the research team studied environmental chemicals that “turn on” PPARg and how these chemicals turn on fat cell formation and turn off bone cell formation. Research showed that Generalized Concentration Addition, a model of additivity, can predict the behavior of PPARg when it is exposed to a mixture of chemicals (Watt et al., 2016). Using mouse models, researchers studied the consequences of exposure to environmental PPARg ligands on fat tissue and bone tissue homeostasis. It was found that female mice are more susceptible to the effects of the organotin, tributyltin (TBT), than male mice. Surprisingly, while TBT suppressed the formation of cortical bone, as expected from this team’s previous studies showing that TBT inhibits bone formation in vitro, TBT increased trabecular bone (Watt et al., 2017). TBT not only changed the physiology of bone forming cells, but also bone resorbing cells. Research translation focused on enhancing knowledge of the bone as a target of toxicity and how toxicants may negatively impact achievement of peak bone mass in young adulthood, a critical risk factor for development of osteoporosis. To this end, the research team worked with the Collaborative on Health and the Environmental to develop a partnership phone call (Fatty Bones Make Bad Skeletons: Influence of Bone-disrupting Chemicals across the Lifespan).