The placental trophoblast is the cellular conduit for all substances transported between the maternal and fetal compartments. Chemotherapeutic agents which are administered to pregnant women are delivered via the uterine circulation to he placenta where they are transferred to the fetus based upon their physicochemical properties (i.e., molecular size, polarity, ionic stats, etc.). Thus, understanding the principles of drug transport kinetics is important for establishing parameters of therapeutic treatment in pregnant women. In addition, the trophoblast readily metabolizes a variety of agents which can influence their transport to the fetal circulation and their therapeutic efficacy and toxicity. Current models used to study placental transport and metabolism rely on static in vitro systems of short-term primary trophoblast cultures or transformed cells lines derived from choriocarcinomas. Animal models have been useful for organ level physiologic studies, but cannot address cellular or molecular questions of drug metabolism by the placental trophoblast. We have designed a fibrous-bed bioreactor in which an immortal human placental trophoblast cell line (ED27) is maintained in long-term culture and monitored for a variety of physiologic (02 and C02 exchange), metabolic (glucose consumption, lactate production, and LDH release), endocrine steroid hormone and hCG secretion), and molecular (changes in gene expression) events can be evaluated in a single preparation.
In aim 1 of this proposal, we will establish the validity of the model system in terms of the above biologic parameters.
Aim 2 will then employ this reactor system to study the effect of the anti-HIV drug AZT (Zidovudine) on trophoblast functions. This system should be useful for preclinical evaluation of drugs intended for use in treating maternal and/or fetal complications of pregnancy.
