Tobacco smoke and oocyte differentiation from human ES cells
Initial Award Abstract
Tobacco smoke is one of the few factors known to cause premature (or early) menopause in women, aside from family history and chemo or radiation cancer therapy, and yet its mechanism has not been studied in humans. Menopause occurs around age 52 when the ovaries run out of eggs, or oocytes, and the menstrual cycle ceases. It is believed that all of a woman’s oocytes are made before birth by the end of the second trimester, and that this finite pool of oocytes is not replenished after birth. At puberty, either these oocytes begin to be ovulated (once a month until menopause), or they die off through a normal process called atresia until the oocyte pool is exhausted and menopause ensues. Thus, the age at which a woman experiences menopause depends on how many oocytes are made before birth versus how many die off after birth (ovulation is constant). Any chemical agent or gene mutation that causes fewer oocytes to be made or more oocytes to die would result in premature menopause. Recently, a study showed that chemicals in tobacco smoke (polycyclic aromatic hydrocarbons) result in oocyte death in mice, suggesting a potential mechanism for tobacco smoke induced oocyte death and premature menopause in humans.
The effect of tobacco smoke on human oocytes clearly needs to be directly assessed; however, human oocyte development has been difficult to study due to ethical limitations. Human embryonic stem cell technology now provides an unprecedented opportunity to study human development in vitro (or outside of the human body) in a non-invasive manner. Human embryonic stem cells are derived from the early embryo and are able to form any adult cell type in vitro, including oocytes. In this research proposal, I aim to characterize the formation and development of oocytes from human embryonic stem cells in the absence or in the presence of polycyclic aromatic hydrocarbons. I hypothesize that mature human oocytes can develop from human embryonic stem cells, but that their development is impaired in the presence of chemicals found in tobacco smoke.
I anticipate that successful completion of this research project, which will form my dissertation, will result in a direct link between accelerated oocyte death and premature menopause in women who smoke or who are exposed to secondhand smoke. Notably, although menopause is most commonly associated with the cessation of fertility, women also encounter increased risks of heart defects, osteoporosis, cancer, and obesity upon menopause onset. It is therefore of utmost importance to increase our understanding of human oocyte development and exposure to tobacco smoke which could lead to the prevention and/or treatment of premature menopause and provide aid to the 10 – 15% of couples who are infertile due to poor germ cell development. In addition, the successful completion of this project and publication of results will immediately raise awareness and educate the public on yet another potentially fatal consequence of smoking. |
|A method for single-cell sorting and expansion of genetically modified human embryonic stem cells
|Periodical: Stem Cells
|Authors: Nicholas CR, Gaur M, Wang S, Reijo Pera RA, Leavitt AD