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dc.contributor.authorPiersma AH
dc.contributor.authorVerhoef A
dc.contributor.authorHamers AM
dc.contributor.authorvan den Ham WA
dc.contributor.authorJansen EHJM
dc.date.accessioned2014-01-17T13:38:03
dc.date.issued1993-11-30
dc.identifier199001003
dc.description.abstractMothers 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.<br>
dc.description.sponsorshipRIVM
dc.format.extent35 p
dc.language.isoen
dc.publisherRijksinstituut voor Volksgezondheid en Milieu RIVM
dc.relation.ispartofRIVM Rapport 199001003
dc.relation.urlhttp://www.rivm.nl/bibliotheek/rapporten/199001003.html
dc.subject06nl
dc.subjectphenylketonurienl
dc.subjectmaternaalnl
dc.subjectrisiconl
dc.subjectteratogeniciteitnl
dc.subjectcongenitale afwijkingennl
dc.subjectin vitronl
dc.subjectmetabolietennl
dc.subjectserumnl
dc.subjectphenylketonuriaen
dc.subjectmaternal-fetal exchangeen
dc.subjecthealth risksen
dc.subjectembryoen
dc.subjectteratogenicityen
dc.subjectabnormalitiesen
dc.subjectin vitro methodsen
dc.subjectmetabolitesen
dc.subjectimmune seraen
dc.subjectphenylalanineen
dc.titleMaternal phenylketonuria: Embryotoxicity in vitro of PKU-related metabolites and of human PKU-seraen
dc.title.alternative[Maternale phenylketonurie: Embryotoxiciteit in vitro van PKU bevattende metabolieten en menselijk PKU-sera.]nl
dc.typeOnderzoeksrapport
dc.date.updated2014-01-17T12:40:20Z
html.description.abstractMothers 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&apos;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.&lt;br&gt;


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