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Human oocyte development and PAH exposure

Institution: University of California, San Francisco
Investigator(s): Renee Reijo Pera, Ph.D.
Award Cycle: 2005 (Cycle 14) Grant #: 14RT-0159 Award: $260,944
Subject Area: General Biomedical Science
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
To date, few factors that affect age at onset of menopause have been identified with the exception of a family history of relatives who experience menopause early in life and exposure to tobacco smoke. Yet, menopause is a reality for all women as they age and results in infertility; this can be devastating for women who enter menopause in their 20’s, 30’s or even 40’s. Menopause is a fact of life because women have a defined number of oocytes (eggs) and birth and these are lost through ovulation monthly and natural death (apoptosis). Over time, the number of oocytes is reduced from 100,000 or more at birth to fewer than 1000 when menopause is triggered. Recent findings have suggested that common chemicals in tobacco smoke may make oocytes more susceptible to apoptosis and loss.

In order to begin to develop a system to specifically address questions regarding human egg development, we recently explored whether human embryonic stem cells (hESCs) might be differentiated to human germ cells (immature cells that will ultimately form oocytes). Our studies demonstrated that germ cells can be derived from hESCs and evidence suggested that the differentiation was recapitulating native programs. Based on these findings, we proposed to test the hypothesis that hESCs can provide a useful and reliable system to probe egg formation and maintenance (viability) in response to exposure to toxins produced by tobacco smoke. Our specific aims are:

Specific Aim 1. Characterize differentiation of human oocytes from hESCs in vitro (in a dish). We recently published evidence that human germ cells can be derived from hESCs. We now seek to extend these results to produce the necessary tools and reagents to produce oocytes that are suitable for transplantation in a model system in order to track egg development via landmark events that naturally occur.

Specific Aim 2. Establish the utility of in vitro oocyte differentiation for studies of environmental exposure to chemicals in tobacco smoke. Previous studies have demonstrated that polycyclic aromatic hydrocarbons (PAHs) can trigger egg destruction in mice and in human tissue slices. Here we seek to assess the susceptibility to PAHs in vitro as oocytes are differentiated from hESCs.

Specific Aim 3. Characterize the development and maintenance of human oocytes in vivo in response to chemicals in tobacco smoke. In this aim, we will use a rodent transplant system to assess susceptibility of the female germline to PAHs in vivo (in the animal) as the germline is differentiated from hESCs.

We expect that with successful completion of the three aims of this research, we will have optimized our ability to differentiate hESCs to oocytes and we will have examined the usefulness of hESCs to specifically understand oocyte destruction in response to exposure to PAHs, commonly encountered in tobacco smoke. These studies will be invaluable for direct examination of the impact of chemicals encountered in tobacoo smoke on human reproduction, in particular the differentiation and maintenance of oocytes of women.
Publications

A method for single -cell soring and expansion of genetically modified human embryonic stem cells.
Periodical: Stem Cells Index Medicus:
Authors: Cory R. Nicholas, Meenakshi Gaur, Shaohui Wang ART
Yr: 2007 Vol: 16 Nbr: Abs: Pg: 109-117

Characterization of human embryonic stem cell lines by the international Stem Cell Initiative
Periodical: Nature Biotechnology Index Medicus:
Authors: Reijo Pera ART
Yr: 0 Vol: Nbr: Abs: Pg:

Modeling human germ cell development with embryonic stem cells
Periodical: Future medicine Index Medicus:
Authors: Reljo Pera ART
Yr: 0 Vol: Nbr: Abs: Pg:

Differentiation of germ cells from embryonic stem cells.
Periodical: Human Embryonic Stem Cells Index Medicus:
Authors: Reijo Pera ART
Yr: 0 Vol: Nbr: Abs: Pg: