Development of PPARγ Ligand Exposure Biomarker

EPA Grant Number: FP917798
Title: Development of PPARγ Ligand Exposure Biomarker
Investigators: Edwards, Lariah Marie
Institution: Boston University
EPA Project Officer: Lee, Sonja
Project Period: September 1, 2015 through August 31, 2018
Project Amount: $132,000
RFA: STAR Graduate Fellowships (2015) RFA Text |  Recipients Lists
Research Category: Academic Fellowships

Objective:

Metabolic and bone homeostasis are regulated by multiple hormones and nuclear receptors thus making them targets of endocrine disrupting chemicals (EDCs). Peroxisome proliferator activated receptor-gamma (PPARg) links metabolic and bone diseases due to its regulatory role in the balance between bone and fat formation and can be targeted by environmental PPARg ligands, a growing class of EDCs. This research will employ mice and previously collected human serum samples to develop a novel biomarker for exposure to mixtures of environmental chemicals implicated in obesity and osteoporosis by assessing cumulative PPARg activity.

Approach:

To validate the Serum PPARg Agonist Activity Assay as a biomarker of cumulative exposure to environmental PPARg ligands, this study will quantify PPARg agonist activity relative to rosiglitazone, the prototypic PPARg ligand and therapeutic drug, in sera from mice and humans with well-defined chemical exposure histories. Female mice will be exposed to known quantities of PPARg ligands, rosiglitazone and a GW9662 and rosiglitazone combination (agonist and antagonist), to generate serum samples. Human serum samples (previously collected) will be provided from an existing Danish cohort study investigating chemical exposures among female pregnancy planners. Both mice and human samples will be tested in a reporter bioassay for PPARg transactivation to validate the biomarker. From the bioassay data, a sigmoid 4-parameter Hill function will be used to fit a rosiglitazone standard curve. Serum PPARg Agonist Activity from the mice and human samples will be related to rosiglitazone-like PPARg activation by interpolation from the generated rosiglitazone standard curve. Data analyses will include regression analysis to correlate rosiglitazone doses with Serum PPARg Agonist Activity in mice. Additionally, Spearman correlations and principal components analysis will assess associations between Serum PPARg Agonist Activity and individual chemicals and chemical classes in human serum samples.

Expected Results:

In the proposed research, the objective is to develop a human biomarker for exposure to PPARg ligands. Environmental PPARg ligands are widespread, and cumulative exposure to these chemicals at low doses pose significant concerns to health. Rosiglitazone doses in mice will be correlated with the Serum PPARg Agonist Activity measured in the reporter bioassay. The use of four orders of magnitude of rosiglitazone will allow determination of both the limit of detection and the type of relationship (e.g. linear) between dose and Serum PPARg Agonist Activity. Furthermore, dose-dependent decrements in mice Serum PPARg Agonist Activity are expected reflecting the cumulative effect of multi-ligand exposure. Based on previous work, a range of detectable PPARg activities in the human serum samples is expected and should reflect the chemical exposure information pertaining to each sample. The concentrations of known PPARg ligands present in the human samples (e.g. phthalates, parabens) will be positively associated with PPARg Agonist Activity, whereas the chemicals that are not PPARg ligands (e.g. perfluoroalkyl substances, phytoestrogens, polybrominated diphenyl ethers) will not.

Supplemental Keywords:

biomarker, endocrine disrupting chemicals, peroxisome proliferator activated receptor

Progress and Final Reports:

  • 2016
  • 2017
  • Final