EFFECTS OF PMPA ADMINISTRATION ON FETAL MONKEYS

Significance Prior studies have indicated that PMPA readily crosses the placenta and significantly reduces viral load in SIV-infected fetuses. Thus, PMPA holds great promise for treatment of HIV-infected gravid patients. However, studies in SIV-infected rhesus monkeys have shown that when administered at 30 mg/kg/day (both transplacentally and in the postnatal period), bone-related toxicity can occur in approximately 25% of treated infants. Objectives The objective of this study was to determine if prenatal exposure to PMPA has a significant effect on fetal ossification and future bone development. If it can be shown that PMPA is not harmful to the fetus when exposed transplacentally, then this would suggest that treatment of gravid women is potentially safe for future offspring. Results Five gravid rhesus monkeys were treated with PMPA throughout the length of gestation and fetuses removed for extensive analyses near term. There were no growth-related or gross abnormalities observed during the treatment period or at necropsy. Fetal serum alkaline phosphatase levels were increased when compared to non-treated values, although phosphorus levels were within normal limits for the majority of treated fetuses. Mechanical properties of fetal specimens are currently under investigation; current data suggests that bone strength was not altered as a result of exposure. Morphologic evaluations of tibial specimens also appear similar when compared to control (non-treated) fetuses of comparable age, suggesting that ossification patterns were not significantly altered as a result of prenatal exposure. Future Directions The mechanical properties of the boney skeleton of fetal monkeys exposed to PMPA will continue to be explored, and further studies will focus on bone ashing to determine whether mineralization is within the normal range. Histomorphometry measurements are also under investigation in order to detect any subtle abnormalities as a result of prenatal exposure. KEY WORDS fetus, growth, PMPA, bone mineralization, ossification FUNDING NIH Grant AI32299