Reproductive Medicine Group

Early Reproductive Events

Carmen J. Williams, M.D., Ph.D.
Principal Investigator

Tel (919) 541-2158
Fax (919) 541-0696
williamsc5@niehs.nih.gov

Curriculum Vitae (http://www.niehs.nih.gov/research/atniehs/labs/lrdt/reproductive/docs/williams-cv.pdf)   (63KB) P.O. Box 12233
Mail Drop E4-05
Research Triangle Park, North Carolina 27709
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Research Summary

The Reproductive Medicine Group focuses on basic reproductive biology of early mammalian embryogenesis including gametes, fertilization, preimplantation embryo development, and implantation. The basic bench science is focused on specific areas that have direct relevance to human reproduction and human infertility, and how the environment influences these areas.

Mechanisms underlying effects of environmental chemical exposures on early reproduction

Naturally occurring phytoestrogens (estrogenic chemicals found in plants) are readily available in the diet, particularly in soy products. Depending on the dose and timing of exposure, these chemicals can have both beneficial and detrimental effects on health. We use a mouse model to study the effects on female reproductive health of neonatal exposure to the phytoestrogen genistein. Female mice treated neonatally with genistein have multi-oocyte follicles, lack regular estrous cyclicity, and are completely infertile even after superovulation. Despite the multioocyte follicle phenotype observed in the ovaries, eggs from genistein-treated females are competent to support full term development. However, defects in both the oviduct and uterus contribute to the observed complete infertility. We are currently examining how genistein exposure leads to these defects in the reproductive tract environment. Overall, this project has direct relevance to understanding how endocrine disrupting chemicals or other environmental factors can impact early reproductive events and potentially lead to reproductive failure in women.

Signal transduction mechanisms of egg activation and preimplantation embryo development

Successful fertilization depends on appropriate interactions between the egg and fertilizing sperm such that the sperm and egg plasma membranes fuse to form a single one-cell embryo. Similarly, successful implantation depends on appropriate interactions between the trophectoderm cells of the blastocyst stage embryo and the endometrial epithelial cells. Each of these interactions are facilitated by proteins on the surfaces of both cell types, but little is known regarding the identity of the proteins required or how expression of these interacting proteins is regulated. EMP2, a four-transmembrane protein related to tetraspanins and connexins, regulates the surface display of membrane proteins in somatic cells. Modulation of EMP2 expression and localization causes pleiotrophic changes on the plasma membrane of several classes of molecules, including integrins, MHC class I molecules, and GPI-linked membrane proteins. EMP2 is highly expressed in the egg and preimplantation embryo, and we hypothesize that it regulates the ability of the egg to bind sperm at fertilization and the trophectoderm cells to interact with the endometrium at implantation. We plan to use a conditional knockout allele of EMP2 to generate eggs and embryos deficient in this protein. We will then determine how EMP2 regulates surface molecules on the egg and embryo and if this regulation controls aspects of cell adhesion important for fertilization and embryo development.

A universal feature of fertilization in mammals is that the fertilizing sperm evokes a series of repetitive calcium oscillations in the egg that persist for several hours and terminate with pronucleus formation. This pattern of calcium oscillations in mice is essential for events of egg activation (e.g., resumption of meiosis, reprogramming of the maternal and paternal DNA, onset of transcription from the new embryonic genome) and full term development. The factor within sperm responsible for inducing these calcium oscillations is a testis-specific phospholipase C, PLCζ, that is released from the sperm head after sperm-egg plasma membrane fusion.

Continuation of these oscillations requires calcium entry into the egg from the extracellular medium to replenish calcium stores and strict regulation of intracellular calcium levels that likely depends on the activity of endogenous egg PLC to complement the sperm PLCζ activity. We hypothesize that inadequate calcium oscillatory patterns at fertilization could explain a spectrum of failure for the infertile couple, including failed fertilization, poor preimplantation embryo development, and even clinical pregnancy followed by miscarriage.

Major areas of research:

• Effects of the environment on gamete and embryo quality and reproductive tract function
• Signal transduction mechanisms of egg activation and preimplantation embryo development

Current projects:

• Effects of neonatal genistein exposure on reproductive tract function in the mouse model
• EMP2 as a modulator of cell adhesion in the egg and preimplantation embryo
• PLCζ activity as a marker of human sperm function
• Modulators of chromatin organization at fertilization and early embryo development

Carmen J. Williams, M.D., Ph.D, leads the Reproductive Medicine Group within the Laboratory of Reproductive and Developmental Toxicology. She received an M.D. from Duke University School of Medicine in 1986, 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 subsequent 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/index.cfm)

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