ABI Research Summaries - Maha M Mahadevan, D.V.M, Ph.D, M.B.A.

Dr. Mahadevan's research interests are focused on factors influencing human in vitro fertilization and embryo transfer outcome and competency of oocytes. In collaboration with physicians and basic scientists at UAMS, my laboratory will attempt to correlate different cellular aspects of oocyte physiology with oocyte competence in women exposed to smoking and older women. We will specifically analyze 1) levels of Gonadotropin releasing hormone (GnRH) and estrogen receptors; 2) the ability to induce mRNA translation by determining endogenous Mos mRNA cytoplasmic polyadenylation; 3) the ability of oocytes to mediate calcium release. Smoking is known to be deleterious to reproductive health, both in women and men. Aging also significantly influence reproductive outcome. At present we ask our infertility and In vitro fertilization (IVF) patients to stop smoking and avoid second hand smoke exposure at home or work. However, the effect of second hand smoking on conception and pregnancy outcome is not known and we plan to study this. Exposure to smoking and aging may interact to decrease the oocyte competence. These studies will provide valuable information to more accurately assess and predict infertility treatment outcome and reduce the burden of infertility both financially and emotionally.

Determine the levels and subcellular localization of GnRH and estrogen receptors:
Oocyte competence is controlled by both intracellular signal transduction cascades, and circulating hormones that act on the oocyte. Several groups have investigated the correlation between the global humoral status of the patient and oocyte competence. We will determine the levels and subcellular localization of GnRH receptor and estrogen receptor in the oocytes obtained from high fertility control, low fertility smoking and low fertility non-smoking women. The effect of aging also will be investigated. There exists strong evidence arguing for an important role for both GnRH and estrogen in oocyte maturation. GnRH receptors are highly regulated, and may be needed for certain level of competence. These studies will be carried out in collaboration with Dr. Gwen Childs in her laboratory. These studies will determine whether any correlation exists between the levels of GnRH and estrogen receptors in oocytes and oocyte competence.

Characterize the ability of the oocytes to induce the mRNA translational program:
Oocyte maturation in vertebrates is regulated at the level of mRNA translation. Immature oocytes lack key proteins involved in meiotic cell cycle control (e.g. the Mos proto-oncogene). The primary mechanism of controlling maternal Mos mRNA translation in amphibians and mice is through regulated poly[A] tail elongation, a process termed cytoplasmic polyadenylation. Cytoplasmic polyadenylation is directed by a cis regulatory sequence (CPE) in the mRNA 3' untranslated region (3' UTR). CPE-directed polyadenylation and translational induction requires an evolutionarily conserved trans factor, CPE-binding protein (CPEB). A plausible cause for oocyte incompetence could be inadequate accumulation of mRNA encoding CPEB, the key regulator of maternal mRNA translational induction during oocyte maturation. We will assess the levels of CPEB mRNA expression in oocytes obtained from high fertility control, low fertility smoking and low fertility non-smoking women, by RT-PCR. In addition, low fertility may correlate with a reduced ability to undergo CPEB- and CPE-directed mRNA cytoplasmic polyadenylation. We will determine if the endogenous human Mos MRNA (which contains CPE sequence) is polyadenylated in mature oocytes from fertile women by comparing Germinal Vesicle (GV) stage immature oocytes and oocytes in metaphase I with mature oocytes through the use of a PCR based poly[A] assay. Following maturation under standard IVF protocols, we will determine if women with low fertility or older women have reduced ability to facilitate endogenous Mos mRNA polyadenylation. These studies will be done in collaboration with Dr. Angus MacNicol in his laboratory.

Characterize the ability and levels of IP3 -dependent Ca2+ release from oocytes
Fertilization in all species from plants to humans results in a dramatic rise in cytoplasmic Ca2+ levels. These Ca2+ signals are necessary and sufficient for egg activation in mammals. The initial phase of this Ca2+ signal is due to Ca2+ release from intracellular stores, which in most species including humans is IP3 -dependent. We will measure the ability and the levels of Ca2+ release from oocytes obtained from fertile control, low fertility smoking and low fertility non-smoking women. If indeed IP3 -dependent Ca2+ dynamics are affected by a history of smoking or age, this will provide an explanation of the decreased fertility since this pathway is essential for normal oocyte activation and early embryo development. These studies will be performed in collaboration with Dr. Khaled Machaca.

Selected Publications:

Schultz GA, Gifford DJ, Mahadevan MM, Fleetham J, Taylor PJ. Protein synthesis patterns in immature and mature human oocytes. Annals of New York Academy of Science 541:237-247,1988

Mahadevan MM. Fleetham J. Relationship of a human oocyte scoring system to oocyte maturity and fertilizing capacity. International J Fertility 35: 240-244, 1990

Bose R, Mahadevan MM. Embryo associated immunosuppressive factor (EASF) and serum estradiol synergism in preembryonic development after in vitro fertilization. Immunology Letters, 52:15-22, 1996.

Mahadevan MM, Miller MM, Moutos DM. Improved human zygote development in a modified Ham's F10 medium in vitro. J Assisted Reprod. Genetics, 13:722-725,1996

Mahadevan MM. Optimizing culture conditions for human in vitro fertilization. Seminars in Reproductive Endocrinology. 16:197-208,1998.

Contact Information

Maha M Mahadevan, D.V.M, Ph.D, M.B.A.
University of Arkansas for Medical Sciences
Associate Professor, Department of Obstetrics and Gynecology
Director, Arkansas Reproductive Technology Laboratory

University of Arkansas for Medical Sciences, Slot 631
4301 West Markham Street
Little Rock, AR 72205

Phone: (501) 296-1703
Fax: (501) 296-1722
E-mail: Mahadevanmahendran@uams.edu