Description
The primary goal of this RFA is to promote basic research on epigenetic targets of environmental agents that can be translated to human populations to improve our understanding of how early life exposures to environmental agents impact disease outcome.
The Specific Aims of Research Core 4 are:
- Increase our understanding of the contribution of epigenetic influences on human disease caused by environmental exposures
- Identify epigenetic mechanisms that contribute to disease as a result of early life exposures to environmental agents
- Use environmental toxicants that target developing tissues to understand basic mechanisms of signal transduction and cellular response to damage.
These Specific Aims will be accomplished by integrating RFA members working in four main research areas. First, Experimental Model Systems (Drs. Gore, Richburg, Walker) are being utilized for mechanistic studies to understand how early life exposures to environmental agents such as xenoestrogens, phthalates, and PCBs contribute to the development of cancer and reproductive and neurodevelopmental dysfunction. As epigenetic changes are an important mechanism by which early life exposures "imprint" target tissues to predispose to disease later in life, basic research on epigenetic control of histone modifications is also being conducted by members of the Chromatin Remodeling group (Drs. Bedford, Richie, Shen). These basic research studies will be integrated with studies ongoing within the Population-based Studies group (Drs. Forman, Jones, Hernandez), where epidemiologic investigations are examining early life exposures in human populations and correlating these exposures with adverse health outcomes. Finally, Epigenetics of Human Disease (Dr. Amos) is the focus of population-based studies being conducted to identify the contribution of epigenetic regulation, such as classical imprinting (parent-of-origin specific gene expression) to environmental disease. Our goal is to integrate information gained from these four research areas to understand how developmental programming by environmental exposures early in life influences disease outcomes in human populations.
Research Significance
Environmental exposures adversely affect populations at risk due to many factors and we now appreciate that individuals may be particularly vulnerable to environmental exposures during development and early life. Cancer, reproductive function, cardiovascular disease and neurodevelopmental disorders are all known to be affected by adverse environmental exposures during these sensitive periods. Because environmental exposures may contribute as much or more than genetics to disease risk, understanding the interplay between environmental exposures and susceptible populations is critical for improving human health outcomes. This research component of the Center will focus on this particularly important period of susceptibility to environmental agents: development and early life.
Early life environmental exposures can have profound effects on adult disease outcome via an epigenetic process termed developmental programming. At critical times during development, exposure of developing tissues to an adverse stimulus or insult can permanently reprogram normal physiological responses, and so give rise to metabolic and hormonal disorders such as diabetes, obesity, cardiovascular disease and cancer later in life. The spectrum of adverse health outcomes caused by early life environmental exposures includes gross congenital abnormalities caused by in utero exposures to drugs or dietary deficiencies, cellular and structural defects in organs such as the kidney or cardiovascular system that can predispose to diabetes, hypertension and obesity and epigenetic alterations that modify patterns of gene expression to promote diseases such as obesity and cancer.
Epigenetics refers to heritable changes in gene expression not mediated by changes in DNA sequence. Epigenetic information can be classified into three categories: 1) cytosine methylation at CpG sites in the DNA, 2) genomic imprinting (parent-of-origin-specific allele silencing, which may also occur via cytosine methylation) and 3) histone modifications. In general, changes in CpG methylation and loss of imprinting (LOI) participate in diseases such as cancer via turning genes on or off, for example silencing of tumor suppressor genes via methylation of CpG islands (long stretches of DNA enriched for CpG sites), or via bi-allelic rather than monoallelic expression of imprinted genes. There is still much to learn about how aberrant histone modifications contribute to disease or how environmental agents may impact this type of epigenetic regulation. However, recent reports indicate that cell signaling pathways targeted by endocrine disruptors can alter the activity of chromatin remodeling proteins and induce heritable changes in histone modifications. This suggests the possibility that environmental agents that that modulate cell signaling could induce epigenetic changes in histone modifications. Importantly, although epigenetic alterations are heritable and stably maintained, they are potentially reversible pharmacologically (for example by 5-azacytadine which reduces cytosine methylation) or nutritionally (for example with folate supplementation which can increase levels of 5-methyl cytosine). Therefore, elucidating the epigenetic alterations induced by environmental agents not only broadens our understanding of the mechanisms of action of these agents but also potentially opens new avenues to reverse or prevent their adverse health effects.
Members
Walker, Cheryl Carcinogenesis, SPRD
Amos, Christopher Epidemiology, UTMDACC
Bedford, Mark Carcinogenesis, SPRD
Forman, Michele Epidemiology, UTMDACC
Gore, Andrea Pharmacology/Toxicology, UT Austin
Hernandez-Valero, Maria Epidemiology, UTMDACC
Jones, Lovell Health Disparities Research, UTMDACC
Richburg, John Pharmacology/Toxicology, UT Austin
Richie, Ellen Carcinogenesis, SPRD
Shen, Xuetong Carcinogenesis, SPRD
