Superfund Research Program
Environmental PPARγ Pathway Activators: Multifaceted Metabolic Disruptors Impacting Adipose and Bone Homeostasis
Project Summary (2017-2021)
Obesity and low bone quality (osteopenia/osteoporosis) are prevalent public health issues worldwide, contributing significantly to metabolic disease and fracture risk. A growing body of evidence suggests that environmental exposures are contributing to the incidence and severity of these pathological conditions. Both legacy Superfund chemicals (organotins, polychlorinated biphenyls (PCB)) and Superfund chemicals of emerging concern (organophosphate flame retardants) have been recognized as metabolic and bone disruptors. 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. One such nuclear receptor is the peroxisome proliferator activated receptor γ (PPARγ), an essential regulator of adipocyte differentiation and function and a negative regulator of bone homeostasis.
Critical gaps in knowledge prevent the understanding of the potential for environmental PPARγ activators to contribute to development of disease, including: 1) how environmental PPARγ ligands disrupt metabolic health, whereas therapeutic PPARγ ligands used to treat type 2 diabetes improve metabolic health; 2) whether developmental exposures program both adipose and bone dysfunction in adulthood, and 3) how environmental PPARγ activators interact with other classes of adipose- and bone-disrupting chemicals (e.g. PCBs).
Novel and compelling preliminary data from the Boston University Superfund Research Program (BU SRP) team show that tributyltin (TBT) alters adipose and bone differentiation in vitro and adipose and bone homeostasis in vivo, through its interaction with PPARγ and with the retinoid X receptor (RXR). The researchers identified a novel PPARγ ligand, the common organophosphate flame retardant triphenyl phosphate (TPhP), which coordinately enhances adipocyte differentiation and suppresses bone formation in vitro. TPhP stimulates adipose accumulation and hepatic steatosis following adult exposures, and lipodystrophy and systemic inflammation following perinatal exposures. TPhP and TBT activate PPARγ, but also induce adipocyte transcriptomes that are distinct from those induced by a therapeutic PPARγ ligand.
To address a major theme of the BU SRP Center, early life exposures resulting in lifetime effects, researchers are investigating the hypothesis that TPhP and TBT selectively modulate PPARγ's activation and function to compromise adipose and bone homeostasis. This BU SRP Center project is addressing three Specific Aims:
- To determine how early life exposures to TPhP and TBT impact adipose and bone homeostasis in adulthood;
- To define how selective activation of PPARγ by TPhP and TBT modifies adipocyte function, and
- To define the roles of PPARγ and RXR in disruption of osteoclast function by TPhP and TBT.
Collectively, the work is enhancing knowledge of the physiological processes driving adipose and bone dyshomeostasis and of how early life toxicant exposures exacerbate risk of developing disease, contributing to the ability to minimize/prevent chronic disability caused by exposure to Superfund chemicals.