The incidence of obesity has risen dramatically over the last few decades. In addition to high caloric food intake and sedentary life style, the role of environmental factors is gaining credence. Bisphenol A (BPA) is a monomer of polycarbonate plastics used in many consumer products. BPA exerts multiple estrogenic-like actions and is detectable at H 1-20 nM in serum from the majority of tested individuals worldwide. We found that BPA at low nM doses suppresses adiponectin release from human adipose explants, with visceral explants from morbidly obese patients showing the highest sensitivity to the suppressive effect of BPA. Adiponectin is an adipocyte-specific hormone which plays a key role in metabolic homeostasis. Lower serum adiponectin levels are associated with the manifestation of the metabolic syndrome. Thus, any factor which suppresses adiponectin should subject the exposed individuals to increased risks of developing diabetes or cardiovascular disease. To support the premise that endocrine disruptors increase the risk of obesity-associated diseases, studies with human adipose tissue are critically needed. Our first objective is to establish that BPA, at environmentally relevant doses, inhibits adiponectin production and release from human Adipose tissue. Our second objective is to explore whether BPA rapidly inhibits adiponectin release and suppresses adiponectin expression by interacting with classical and non-classical estrogen receptors.
Specific aim 1 will compare the suppressive effects of BPA and estradiol on adiponectin gene expression and release from visceral and subcutaneous adipose explants from obese and non-obese patients.
Specific aim 2 will examine the mechanisms underlying acute and chronic effects of BPA, focusing on the roles of estrogen receptors (ER1 and/or ER2), G-protein-coupled receptor 30 (GPR30) and peroxisome proliferator- activated receptor 3 (PPAR3).
The second aim will be accomplished using primary human adipocytes or LS14, our novel human adipocyte cell line. Our long term goal is to establish the metabolic effects of BPA in human adipocytes and generate solid evidence that can be used by regulatory agencies to determine whether BPA in the environment is hazardous to human health.

Public Health Relevance

This study examines the effects of bisphenol A, an endocrine disruptor that is common in the environment, on the production and release of adiponectin from human adipose tissue and adipocytes. Adiponectin is an adipose-specific cytokine that plays a critical role in metabolic homeostasis and its suppression is associated with increased risk of developing diabetes and cardiovascular diseases that are associated with the metabolic syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
3R21ES016803-02S1
Application #
7924375
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Heindel, Jerrold
Project Start
2009-09-17
Project End
2010-08-31
Budget Start
2009-09-17
Budget End
2010-08-31
Support Year
2
Fiscal Year
2009
Total Cost
$113,868
Indirect Cost
Name
University of Cincinnati
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Jacobson, Eric M; Hugo, Eric R; Tuttle, Traci R et al. (2010) Unexploited therapies in breast and prostate cancer: blockade of the prolactin receptor. Trends Endocrinol Metab 21:691-8
LaPensee, Elizabeth W; Schwemberger, Sandy J; LaPensee, Christopher R et al. (2009) Prolactin confers resistance against cisplatin in breast cancer cells by activating glutathione-S-transferase. Carcinogenesis 30:1298-304
Ben-Jonathan, Nira; Hugo, Eric R; Brandebourg, Terry D (2009) Effects of bisphenol A on adipokine release from human adipose tissue: Implications for the metabolic syndrome. Mol Cell Endocrinol 304:49-54
Hugo, Eric R; Brandebourg, Terry D; Woo, Jessica G et al. (2008) Bisphenol A at environmentally relevant doses inhibits adiponectin release from human adipose tissue explants and adipocytes. Environ Health Perspect 116:1642-7