Obesity and associated metabolic syndrome diseases have become an epidemic of global proportions. Excessive consumption of calorie-dense food and diminished physical activity are generally accepted causal factors for obesity. But can environmental factors expose preexisting genetic differences or exacerbate the root causes of diet and exercise? The """"""""obesogen hypothesis"""""""" proposes that environmental chemicals can perturb lipid homeostasis, adipocyte development and adipose tissue function. Exposure during sensitive developmental windows can induce imbalances resulting in permanent changes that result in increased fat storage. New work from our laboratory has identified organotins as a novel class of obesogen candidates. Organotins are a well-studied group of environmental endocrine disrupting agents demonstrated to cause pleiotropic effects on development, hormonal physiology and sex determination in vertebrates and invertebrates. We found that the ligand dependent retinoid X receptors (RXR) and peroxisome proliferator activated receptor gamma (PPARg) are novel high-affinity molecular targets of the organotins such as tributyltin (TBT). RXR-PPARg signaling is a critical component in vertebrate adipogenesis. RXR also serves a broader role as the common heterodimeric partner to many additional nuclear receptors involved in lipid, metabolic and developmental signaling pathways. We have proposed that the potent effects by TBT on these receptors occurs via a novel covalent modification and that inappropriate activation has the potential to strike at the heart of adipose tissue homeostasis. Initial results show that TBT promotes adipocyte differentiation in the murine 3T3-L1 adipogenic model, modulates known adipogenic genes in vivo, and increases adiposity in mice after in utero exposure, consistent with an obesogen model. We hypothesize that TBT acts as an environmental obesogen and that prenatal exposure can lead to long-term effects on metabolism, predisposing exposed individuals to obesity and related disorders. We propose three specific aims to test this hypothesis: 1) How does prenatal TBT exposure perturb adipose homeostasis, in vivo? 2) Which molecular interactions are critical for the organotin elicited adipogenic phenotype? 3) What are the molecular interactions between organotins and RXRs-PPARg? Validation of this hypothesis will provide a paradigm shift in our evaluation of obesity related gene-environment interactions from the molecular to the whole animal level. Since central adiposity plays a pivotal role in increasing the risk of metabolic syndrome diseases in human populations, the proposed research studying a novel contributing mechanism is highly relevant to current public health concerns.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES015849-04
Application #
7810625
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Heindel, Jerrold
Project Start
2007-08-03
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
4
Fiscal Year
2010
Total Cost
$319,159
Indirect Cost
Name
University of California Irvine
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Janesick, Amanda S; Dimastrogiovanni, Giorgio; Chamorro-Garcia, Raquel et al. (2017) Reply to ""Comment on 'On the Utility of ToxCast™ and ToxPi as Methods for Identifying New Obesogens'"". Environ Health Perspect 125:A12-A14
Janesick, Amanda Shaine; Dimastrogiovanni, Giorgio; Vanek, Lenka et al. (2016) On the Utility of ToxCast™ and ToxPi as Methods for Identifying New Obesogens. Environ Health Perspect 124:1214-26
Grün, Felix (2014) The obesogen tributyltin. Vitam Horm 94:277-325
Kamstra, Jorke H; Hruba, Eva; Blumberg, Bruce et al. (2014) Transcriptional and epigenetic mechanisms underlying enhanced in vitro adipocyte differentiation by the brominated flame retardant BDE-47. Environ Sci Technol 48:4110-9
Chamorro-García, Raquel; Blumberg, Bruce (2014) Transgenerational effects of obesogens and the obesity epidemic. Curr Opin Pharmacol 19:153-8
Goran, Michael I; Dumke, Kelly; Bouret, Sebastien G et al. (2013) The obesogenic effect of high fructose exposure during early development. Nat Rev Endocrinol 9:494-500
Chamorro-García, Raquel; Sahu, Margaret; Abbey, Rachelle J et al. (2013) Transgenerational inheritance of increased fat depot size, stem cell reprogramming, and hepatic steatosis elicited by prenatal exposure to the obesogen tributyltin in mice. Environ Health Perspect 121:359-66
Pueyo, Natalie C; Raub, Andrew G; Jackson, Sean et al. (2013) Oxidation of Ethidium using TAML Activators: A Model for High School Research Performed in Partnership with University Scientists. J Chem Educ 90:326-331
Ortiz, Laura; Nakamura, Brooke; Li, Xia et al. (2013) In utero exposure to benzo[a]pyrene increases adiposity and causes hepatic steatosis in female mice, and glutathione deficiency is protective. Toxicol Lett 223:260-7
Casey, Stephanie C; Blumberg, Bruce (2012) The steroid and xenobiotic receptor negatively regulates B-1 cell development in the fetal liver. Mol Endocrinol 26:916-25

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