Project 3

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

Emberley et al; Figure 5B

Determining the molecular mechanism by which individual and complex mixtures of environmental chemicals impact adipose and bone homeostasis.

Project Leader

Jennifer Schlezinger
Boston University School of Public Health

Project Description

Obesity and low bone quality (osteopenia/osteoporosis) are significant public health threats worldwide, as each contributes substantially to morbidity. Certainly, modern lifestyle factors have contributed to the prevalence of obesity, and aging has contributed to the prevalence of low bone quality; however, environmental exposures, particularly early in life, also are likely playing a significant role. While a strong physiological coupling of obesity and osteoporosis may seem unlikely, the recent discoveries of fat and bone regulatory crosstalk suggest that they share common origins. Adipose and bone tissue each contain multipotent cells whose differentiation and fate are regulated by common nuclear receptors, well known for their role in regulating both adipose and bone homeostasis and their propensity to be hijacked by environmental toxicants. One such nuclear receptor is the peroxisome proliferator activated receptor γ (PPARγ), which is an essential regulator of adipocyte differentiation and function and a negative regulator of bone homeostasis.

Both legacy Superfund chemicals (organotins, polychlorinated biphenyls (PCB)) and Superfund chemicals of emerging concern (organophosphate flame retardants) have been recognized as adipose and bone disruptors. Indeed, the organotin tributyltin (TBT) is an environmental PPARγ ligand and was the first identified member of the metabolic disruptor class of endocrine disruptors. This study will investigate the hypothesis that TBT and triphenyl phosphate (TPhP) selectively modulate PPARγ’s transcriptome to compromise adipose and bone homeostasis. In this study, we will (1) determine how early life exposures to TPhP impact adipose and bone homeostasis in adulthood; (2) define how selective activation of PPARγ by TPhP and TBT modifies the adipocyte transcriptome; and (3) define the roles of PPARγ and RXR in disruption of osteoclast function by TPhP and TBT.

Our findings will enhance knowledge of the physiological processes driving adipose and bone dyshomeostasis and how early life toxicant exposures increase risk of disease will enhance our understanding of the intersection of environmental and consumer product exposures.

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