Two satisfactory rat models of maternal phenylketonuria (PKU) have been developed. Continuous subcutaneous infusion into pregnant rats from the 9th-20th day of gestation of either (1) phenylacetate (PA), to elevate plasma levels of unconjugated PA to 0.25-0.60 mumol/ml, or (2) a nontoxic dose (0.2 mumol/g/day) of p-chlorophenylalanine (pClPhe) with L-phenylalanine (Phe), to elevate plasma Phe levels at least 10-fold (1.7-2.3 mumol/ml) and unconjugated PA to at least 0.2 mumol/ml, produced the syndrome of untreated maternal PKU: spontaneous abortion, mortality rate greater than normal among the newborn, retarded growth of fetal body and brain, and a learning deficit among the progeny. From the plasma of rats infused with only pClPhe, a metabolite was isolated and identified as p-chlorophenylacetic acid. This compound, at a concentration greater than 0.15 mumol/ml plasma was found to retard fetal body and brain growth. In the pregnant rat, plasma levels of unconjugated PA, in the range observed in some PKU individuals on a normal diet, effectively induced a simulation of maternal PKU. The results of this investigation support our contention that PA, which is produced in excessive amounts in clinical PKU, is the primary cause of the brain dysfunction.

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PubMedDate not supplied

Biochemical indices of neuronal development in experimental phenylketonuria: high affinity transport systems and gangliosides.

High affinity transport systems and gangliosides were assessed in an animal model of experimental phenylketonuria, namely the rat injected with phenylacetate during the first 21 days of life. The velocity of synaptosomal high affinity uptake of [3H]-choline, [14C]-gamma-aminobutyric acid (GABA), and [14C]-glutamic acid served as a measure of the relative density of uptake sites of these specific types of terminals. A reduction of cholinergic (25-37%) and GABAergic (23-45%) functioning terminals was produced by phenylacetate in the hippocampal, occipital, and frontal cortices from 40- to 55- and 80- to 95-day-old rats. In contrast, glutamatergic terminals in these same areas of the cerebrum from animals of both ages were not affected. This selection effect of phenylacetate on synaptic junctions is discussed. Cerebral ganglioside content was reduced approximately 40% in experimental hyperphenylalaninemia induced with p-chlorophenylalanine and L-phenylalanine. A similar decrease was observed in the rat exposed to phenylacetate but not in the animal injected with phenylpyruvate. Short-term exposure to phenylacetate did not alter the capacity of the very young rat to utilize glucosamine for the biosynthesis and incorporation of sialic acid into gangliosides. The large decrease in cerebral ganglioside concentration and the significantly smaller percentage distribution of GM1, observed in the 19-day-old chronically exposed to phenylacetate, are apparently associated with deficient neuronal development.

Animals↗