Early Reproductive Events
Carmen J. Williams, M.D., Ph.D.
Tel (919) 541-2158
Fax (919) 541-0696
P.O. Box 12233
Mail Drop E4-05
Research Triangle Park, North Carolina 27709
The Reproductive Medicine Group focuses on translating basic laboratory findings regarding the events surrounding the initiation of pregnancy to clinical problems of infertility and endometriosis, both of which are likely to be impacted by environmental toxins and/or endocrine disruptors.
Gamete Quality and Egg Activation
"Egg activation" is the term used to describe the complex series of events that occurs between the time of sperm-egg plasma membrane fusion and cleavage to the 2-cell stage. Successful egg activation accomplishes conversion of these two gametes into a single embryo capable of implantation and full term development. The quality of the gametes that together comprise the early embryo and the effectiveness of their interactions at fertilization are critical determinants not only of the developmental competence of the preimplantation embryo but also the health of the fetus and newborn individual.
The best-known factor affecting egg quality is age – older women tend to have eggs that when fertilized do not develop as well as eggs from younger women. There is also evidence that women with endometriosis or polycystic ovarian syndrome have lower quality eggs, but the reasons underlying this diminished egg quality are unknown. The Reproductive Medicine Group hypothesizes that environmental exposures to endocrine disrupting chemicals can decrease egg quality. Previous work led by Retha Newbold at NIEHS demonstrated that brief exposure of female mice in the neonatal period to the phytoestrogen genistein led to multi-oocyte ovarian follicles, malformed reproductive tracts and infertility after reaching adulthood. Although the explanation for infertility in these mice is, in part, due to the abnormalities in the reproductive tract, there also appears to be a defect in the quality of the eggs and embryos produced. Williams and colleagues are following up on these studies by performing experiments designed to determine how neonatal genistein exposure affects egg and embryo quality. This work may provide insights into the variability in egg quality observed in human infertility, for example, in cases of polycystic ovarian syndrome.
Less is known regarding factors that affect sperm quality; however, environmental exposures such as alcohol use and smoking clearly have a negative influence on sperm. Assessment of sperm quality depends largely on the standard semen analysis that provides information regarding the number of sperm, their motility and their appearance. This clinical assay is very difficult to interpret, however, because of relatively large variations in semen parameters within an individual over time and the substantial overlap in these parameters in populations of fertile and infertile men. New methods of identifying "low quality" sperm, i.e., those with low fertilization potential or resulting in low clinical pregnancy rates would be highly useful for improving reproductive capability. Furthermore, defining critical parameters for sperm function, beyond the semen analysis, would allow the design of clinical studies to determine the impact of environmental agents on sperm quality.
Two molecules have recently been shown in animal models to be critical for sperm function.
Both of these sperm molecules could be affected by environmental agents that diminish reproductive capacity.
Endometrial Biology and Endometriosis
Williams previously demonstrated that a tetraspan protein, epithelial membrane protein-2 (EMP2), is expressed in the endometrium during the window of implantation in rodents and primates, including humans, and is required for implantation in the mouse model system. Tetraspan proteins are thought to serve as "molecular facilitators" that organize other proteins into cell surface signaling complexes and in that way alter cell adhesiveness. EMP2 itself is regulated by progesterone, likely through indirect pathways, but the influence of other hormones/growth factors/endocrine disruptors on its expression has not been examined, and little is known regarding the control of EMP2 localization. Williams is currently generating a conditional knockout mouse null for EMP2, and plans to study the expression and function of EMP2 in the endometrium of normal and infertile women. Because EMP2 modulates cell adhesiveness, it may be involved in initiating development of endometriosis. This hypothesis will be tested in a nude mouse model of endometriosis that utilizes human endometrium.
Major areas of research:
Carmen J. Williams, M.D., Ph.D., leads the Reproductive Medicine Group within the Laboratory of Reproductive and Developmental Toxicology and the Clinical Research Program. She received an M.D. from Duke University School of Medicine in 1986, and then completed a Residency in Obstetrics & Gynecology at Pennsylvania Hospital in 1990 and a Fellowship in Reproductive Endocrinology & Infertility at the University of Pennsylvania in 1993. After her clinical training she went on to complete a Ph.D. in Cell and Molecular Biology at the University of Pennsylvania in 1997 and subsequently postdoctoral fellowship training at Penn. She became an Assistant Professor of Obstetrics & Gynecology at the University of Pennsylvania in 2000, where she served as an attending physician in the Division of Reproductive Endocrinology & Infertility while running an active basic research laboratory in the Center for Research on Reproduction & Women´’s Health. She moved to the NIEHS in September 2007.
For more information on Selected Publications and Scientists & Staff for the Reproductive Medicine Group, please see the other group page in the Clinical Research Program. (http://www.niehs.nih.gov/research/clinical/program/groups/rmgroup.cfm)