The effect of maternal blood phenylalanine level on mouse maternal phenylketonuria offspring

Maternal phenylketonuria is a disease process caused by the adverse effects of high maternal blood phenylalanine (PHE) on the fetus. Unless treated, maternal PKU results in teratogenic effects on the fetus that can lead to mental retardation, microcephaly, intrauterine growth retardation, congenital cardiovascular defects, low birth weight, spontaneous abortion and fetal death. Although PKU has been recognized as a major challenge for many years, surprisingly little is known about the pathophysiologic mechanism(s) of PHE toward the fetus. To more thoroughly investigate the pathogenesis of this heritable disease and to explore potential therapeutic actions, the genetic mouse model Pahenu2 was used. The overall goals of this project were to use the Pah enu2 mouse to examine the effect of maternal blood PHE level on: (1) The pregnancy outcome of maternal PKU offspring as measured by the incidence of spontaneous abortion and certain key measures of development at birth (i.e., head circumference, weight, and crown-rump length of offspring); and (2) The fetal nutritional status of maternal PKU offspring as assessed by the levels of PHE, tyrosine (TYR), and other essential amino acids (EAA) at birth. In this study, we clearly observed that elevated maternal blood PHE levels, whether they were caused by the maternal diet or maternal genotype, were responsible for the fetal abnormalities in maternal PKU. With regard to fetal developmental outcomes, significant reductions in birth weight, crown-rump length, and head circumference were seen in offspring gestated under high maternal blood PHE conditions. The incidence of fetal loss was significantly different between treatment and control groups. Reductions in the levels of alanine, glutamine, and glutamic acid were observed in fetal blood among offspring born to mutant mothers with high blood PHE levels. None of the branched chain amino acids were reduced in maternal PKU offspring. These findings strongly suggest that there are important maternal genotype and dietary components but no fetal genotype component to this maternal PKU model. Given that these maternal factors also appear to be the most important components of human maternal PKU, this model seems certain to provide a valid animal model to overcome the difficulties of human studies