Maternal phenylketonuria: Embryotoxicity in vitro of PKU-related metabolites and of human PKU-sera 199001003

Maternal phenylketonuria: Embryotoxicity in vitro of PKU-related metabolites and of human PKU-sera

[ [Maternale phenylketonurie: Embryotoxiciteit in vitro van PKU bevattende metabolieten en menselijk PKU-sera.] ]

Piersma AH, Verhoef A, Hamers AM, van den Ham WA, Jansen EHJM

35 p in English 1993

RIVM Rapport 199001003

Toon Nederlands

English Abstract
Mothers with untreated phenylketonuria (PKU) have an increased risk of bearing children with congenital malformations. PKU causes accumulation of phenylalanine (PHE) and its metabolites in urine and blood, and this condition may contribute to the developmental problems. In the present study we investigated the embryotoxicity of these compounds in the rat postimplantation embryo culture system. Whereas PHE was ineffective, phenylpyruvic acid and phenylacetic acid induced general growth retardation. Phenylacetic acid and O-hydroxyphenylacetic acid were also growth retarding and in addition affected yolk sac circulation. Phenylethylamine was the most embryotoxic compound tested, with a lowest effective concentration of 0.03 g/l. It induced various anomalies including incomplete flexion and neural tube defects. The effects of a mixture of phenylketones in culture did not reveal synergism between compounds. In the presence of maternal hepatocytes PHE was metabolized in culture without leading to embryotoxic effects. Extending culture duration from 26 to 48 hours did not increase sensitivity to phenylpyruvic acid. No changes in osmolarity or pH of media were observed that might have been responsible for the embryotoxicity observed. Analysis with HPLC of media after culture revealed no biotransformation of added compounds into other metabolites, except for phenylpyruvic acid. In addition, in the presence of maternal hepatocytes, metabolism was observed that was not accompanied with embryotoxic effects. Embryo culture in human PKU sera, either or not supplemented with 5% (v/v) rat serum, was not detrimental to development. Rather, embryo's tended to thrive better on PKU sera versus control sera. Analysis of human PKU sera revaled lower glucose levels and increased levels of PHE and PKU-related metabolites. The results suggest that the embryotoxicity of PKU-related phenylketones may contribute to teratogenicity of maternal PKU in man. However, in view of the relatively high concentrations necessary for embryotoxicity to occur in vitro, other factors yet unknown may play a significant role. Alternatively, the absence of embryotoxicity of human PKU sera in culture may be interpreted to suggest that the rat postimplantation embryo culture technique may not contain the developmental en points that are most vulnerable in maternal PKU.

RIVM - Bilthoven - the Netherlands - www.rivm.nl

Rijksinstituut voor Volksgezondheid en Milieu RIVM
_{( 1993-11-30 )}