PROJECT 1 - Human Fetal Liver and the Metabolic Syndrome. The purpose of this project is to develop and employ a model for studying the effects of arsenic on fetal liver development. The project is predicated on the relationship between altered fetal liver development and risk for metabolic syndrome in the offspring. The role of the liver In metabolic regulation and insulin sensitivity is well established. The association between intrauterine growth retardation, fetal metabolic programming and metabolic syndrome in the offspring is also established, having been shown in recent years to involve epigenetic mechanisms. The goal of this project is to develop a model in which human fetal liver is xenografted to nude rats. We will use this model to test the hypothesis that, like alterations in the nutrient environment, fetal arsenic exposure induces epigenetic changes in fetal liver that predispose to metabolic syndrome in the adult The proposal is based on published evidence that fetal arsenic exposure induces epigenetic changes in fetal liver. The proposal also derives from our extensive characterization of growth-regulating signaling mechanisms in the fetal rat and our identification of novel biomarkers for the fetal hepatocyte phenotype. We have shown that late term fetal hepatocytes, unlike adult rat hepatocytes, show mitogenindependent proliferation and are resistance to the anti-proliferative effects of rapamycin, an inhibitor of the nutrient-sensing mTOR pathway. The aforementioned biomarkers include a number of proteins involved in growth factor signaling, cell cycle control and translation control. We have also observed that rapamycin-induced inhibition of mTOR modulates gene expression in a manner most consistent with epigenetic mechanisms. We have developed the following specific aims:
Specific Aim 1 will be to develop a model in which human fetal liver is transplanted into nude rats and the fetal liver phenotype (defined as above) is maintained.
In Specific Aim 2, we will demonstrate that manipulation of the host environment in the adult rat xenograft recipients will induce changes in fetal liver. We will examine the effects of host dietary restriction and rapamycin administration to examine the effect on fetal liver growth and gene expression.
Specific Aim 3 will be to characterize and contrast the epigenetic consequences of host dietary restriction and rapamycin with the effects of arsenic exposure. The significance of this project lies in its potential to develop a model system to study mechanisms for programming of human fetal liver, something that is not possible with available methodologies.

Public Health Relevance

This project is thematically linked to the Formative Center pilot projects and cores through its focus on the mechanisms by which alterations in the fetal environment, acting through epigenetic mechanisms, modify fetal development in a way that produces risk for adult disease. The project will use the model common to other components of the project, the xenotransplantation of human tissues into nude rats for the purpose of modifying the environment in which the human tissue develops.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory Grants (P20)
Project #
5P20ES018169-03
Application #
8375002
Study Section
Special Emphasis Panel (ZES1-LKB-G)
Project Start
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
3
Fiscal Year
2012
Total Cost
$86,964
Indirect Cost
Name
Brown University
Department
Type
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
Saffarini, Camelia M; McDonnell-Clark, Elizabeth V; Amin, Ali et al. (2015) Developmental exposure to estrogen alters differentiation and epigenetic programming in a human fetal prostate xenograft model. PLoS One 10:e0122290
Saffarini, Camelia M; McDonnell-Clark, Elizabeth V; Amin, Ali et al. (2015) A human fetal prostate xenograft model of developmental estrogenization. Int J Toxicol 34:119-28
De Paepe, Monique E; Chu, Sharon; Hall, Susan J et al. (2015) Intussusceptive-like angiogenesis in human fetal lung xenografts: Link with bronchopulmonary dysplasia-associated microvascular dysangiogenesis? Exp Lung Res 41:477-88
Huse, Susan M; Gruppuso, Philip A; Boekelheide, Kim et al. (2015) Patterns of gene expression and DNA methylation in human fetal and adult liver. BMC Genomics 16:981
Garcia, Briana; Francois-Vaughan, Heather; Onikoyi, Omobola et al. (2014) Xenotransplantation of human fetal adipose tissue: a model of in vivo adipose tissue expansion and adipogenesis. J Lipid Res 55:2685-91
Spade, Daniel J; McDonnell, Elizabeth V; Heger, Nicholas E et al. (2014) Xenotransplantation models to study the effects of toxicants on human fetal tissues. Birth Defects Res B Dev Reprod Toxicol 101:410-22
Saffarini, Camelia M; McDonnell, Elizabeth V; Amin, Ali et al. (2013) Maturation of the developing human fetal prostate in a rodent xenograft model. Prostate 73:1761-75
De Paepe, Monique E; Chu, Sharon; Heger, Nicholas et al. (2012) Resilience of the human fetal lung following stillbirth: potential relevance for pulmonary regenerative medicine. Exp Lung Res 38:43-54
Campion, Sarah; Catlin, Natasha; Heger, Nicholas et al. (2012) Male reprotoxicity and endocrine disruption. EXS 101:315-60
Panikkar, Bindu; Smith, Natasha; Brown, Phil (2012) Reflexive research ethics in fetal tissue xenotransplantation research. Account Res 19:344-69

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