Effects of maternal phenylketonuria on the rat fetus

Luse, Sarah A.; Rhys, A. Farrer; Lessey, Robert A.

doi:10.1016/0002-9378(70)90420-5

Cited by 13 publications

(5 citation statements)

References 12 publications

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“…Cockburn et al ( 1972) demonstrated excess serum phenylalanine in a foetus aborted from a PKU mother, and also showed that phenylalanine loading in 5 normal mothers prior to abortion led to the same result. These observations are supported by experimental animal work, such as that of Luse (1970), who loaded rats with phenylalanine to render them hyperphenylalaninaemic. Offspring of such rats showed intrauterine growth retardation, cataracts, and mental retardation in many cases.…”

Section: Discussionmentioning

confidence: 77%

The Problem of Maternal Phenylketonuria

Pitt

Gooch²

1974

J Paediatrics Child Health

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Section: Discussionmentioning

confidence: 77%

The Problem of Maternal Phenylketonuria

Pitt

Gooch²

1974

J Paediatrics Child Health

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“…Several workers have used dietary phenylalanine or a daily maternal injection of phenylalanine to mimic maternal phenylketonuria (4,35), but in doing so monitored plasma phenylalanine levels at one time only. Such treatments are ineffective in raising phenylalanine concentrations for any length of time (32).…”

Section: Discussionmentioning

confidence: 99%

The Effects of Hyperphenylalaninemia on Fetal Development: a New Animal Model of Maternal Phenylketonuria

et al. 1982

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SummaryA new model has been developed for the study of maternal phenylketonuria. Beginning on the 12th day of gestation the diet of pregnant rats was supplemented with 0.5% a-methylphenylalanine and 3% phenylalanine. This resulted in an 83% reduction of hepatic phenylalanine hydroxylase activity. The maternal plasma phenylalanine ;vas elevated 10-20-fold for two-thirds of the day, but the degree and persistence of the fetal hyperphenylalaninemia may have been even greater. The brain phenylalanine concentrations in the fetus were raised up to 2900 nmole/g brain, whereas the highest level observed in the dam was 382 nmole/g. Experimentally-treated fetuses showed small reductions in both body and brain weight when compared to age-matched controls; however, no differences were seen in crown to rump length, litter size, DNA and protein concentrations per g, or in postnatal survival. Initiation of the diet at conception rather than on the 12th day caused a significantly greater inhibition of fetal growth, and 21% mortality.The fetal cerebral concentrations of metbionine and the branched chain amino acids (valine, leucine and isoleucine) were decreased by hyperphenylalaninemia. From the 16th day on, the concentration of the inhibitor neurotransmitter glycine was elevated. Cerebral serotonin showed a 20-30% deficit and its primary metabolite 5-hydroxyindoleacetic acid a 71-77% deficit.Of twelve enzymes quantified in the brains of hyperphenylalaninemic fetuses only phosphoserine phosphatase showed any change. From the 20th to the 22nd day of gestation its activity was 46-67% higher in experimental than in normal fetuses. Measurement on the 22nd day of gestation showed that the increases in phosphoserine phosphatase activity and glycine content were present in brain stem, cerebellum, and forebrain. SpeculationThis new animal model of maternal phenylketonuria is suitable for elucidating the mechanisms of abnormal development of heterozygous children of phenylketonuric mothers. ~6 r~h e n~l a l aninemia in the dam is responsible for gross elevations in fetal brain phenylalanine content and the bioch'kmical consequences of this elevation, such as pertubations in the levels of glycine, serotonin and branched chain amino acids, which may be responsible for the lasting damage to cerebral function.Several studies have indicated that mental retardation is associated not only with phenylketonuria but also with the majority of heterozygous infants of phenylketonuric mothers (8,16,17,30,38). This indicates that permanent damage of cerebral functions can occur if severe hyperphenylalaninemia is restricted to intrauterine life. The common end result. mental retardation. does not necessarily imply a common pathogenic pathway: the &mediate impact of the same metabolic abnormality may well be different at different stages of ontogeny. Studies of phenylketonurics and rats subjected to experimental hyperphenylalaninemia have provided some insights into the postnatal biochemical changes; however, little is known about those occurring in ute...

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“…Andersen et al (1973) demonstrated that the pC1-Phe portion of the combined pC1-Phe + Phe injection does not contribute appreciably t o the total level of ineasured phenylalanines in rats injected with the same doses used in this experiment . Our experiments suggest that the fetal brain is less well protected against high circulating phenylalanine levels than the maternal brain (Luse, Rhys, and Lessey, 1970). While the fetal plasma phenylalanine is 1.6 to 3.2 times higher than the maternal plasma phenylalanine, the fetal brain tissue phenylalanine level is 2.5 to 3.8 times as high as maternal brain tissue phenylalanine, indicated by the hgher brain:blood ratio found in the fetus.…”

Section: Discussionmentioning

confidence: 56%

Maternal hyperphenylalaninemia: An experimental model in rats

Andersen

1976

Developmental Psychobiology

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Experimental maternal hyperphenylalaninemia produced in pregnant F344 rats by the combined use of p-Chloro-DL-phenylalanine and L-phenylalanine reduced fetal birth weight in comparison to saline-injected controls. Offspring who experiences hyperphenylalaninemia in utero died within 5 days after birth. Fetal plasma phenylalanine levels were several times higher than maternal plasma phenylalanine levels, indicating that the placenta actively concentrates maternal phenylalanine. Fetal brain phenylalanine levels rose in direct proportion to elevations in fetal plasma phenylanaline, whereas maternal brain phenylalanine levels remained low during maternal plasma phenylalanine elevation; the contrast suggests that the maternal brain is better able than the fetal brain to screen itself against high circulating plasma phenylalanine levels.

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Effects of maternal phenylketonuria on the rat fetus

Cited by 13 publications

References 12 publications

The Problem of Maternal Phenylketonuria

The Problem of Maternal Phenylketonuria

The Effects of Hyperphenylalaninemia on Fetal Development: a New Animal Model of Maternal Phenylketonuria

Maternal hyperphenylalaninemia: An experimental model in rats

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