Experimental Maternal Hyperphenylalaninemta: Disaggregation of Fetal Brain Ribosomes

Copenhaver, John H.; Vacanti, Joseph P.; Carver, Michael J.

doi:10.1111/j.1471-4159.1973.tb04248.x

Cited by 28 publications

(10 citation statements)

References 21 publications

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“…However, as the 5-day-old and older neonates are not hypoglycemic, other mechanisms must be involved. Although food restric tion of control mothers produced no real detrimental effect per se, it may play a role in the Tx mother who has many metabolic abnormalities and does not supply the fetus with normal amounts of substrate [16,17,20], Deficiencies of single amino acids in the mother such as asparagine [29] and taurine [14] during nursing, or maternal protein deficiency pre-and postnatally [11], result in impairment of brain devel opment in the offspring just as does hyperphenylalaninemia [5] which is a well documented disorder which leads to mental retardation.…”

Section: Discussionmentioning

confidence: 99%

Behavioral Testing of Progenies of Tx (Hypothyroid) and Growth Hormone-Treated Tx Rats: An Animal Model for Mental Retardation

Hendrich

Jackson

Porterfield³

1984

Neuroendocrinology

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Virgin Sprague-Dawley Holtzman rats were rendered Tx (hypothyroid) by radiothyroidectomy and maintained on 1.0 µg T4 (thyroxine) per 100 g BW until pregnant. One-half of these Tx animals were administered 0.5 IU of growth hormone (GH) during the last 10–11 days of gestation as GH secretion is especially deficient in Tx rats. Untreated, food restricted to the level consumed by the Tx-only rats, GH-treated euthyroid, and T4-treated until pregnant animals served as controls. The animals were allowed to go through parturition and each litter was reduced to no more than 6 pups by removing pups for tissue weights and protein analyses at 1 and 5 days of age. The pups were weaned at 22 days of age and 2 animals per litter were utilized for behavioral testing between 40 and 60 days of age. At the end of the behavioral testing period the 60-day-old offspring were sacrificed to obtain tissue weights and protein concentrations. The behavioral tests were based on the ability of the animals to learn a Lashley’s type 3 enclosed alley maze and their spontaneous activity was measured in stabilimeter cages. The animals were fasted overnight on alternate days and then given a food reward upon traversing the maze. This allowed for 10 separate trials in both the Lashley maze and the stabilimeters over the 20-day period from 40 to 60 days of age. Our previous studies have shown the fetuses and progenies of Tx-only mothers to have multiple metabolic defects including reduced rates of protein synthesis and tissue protein concentrations. The Tx mothers have poor reproductive performance and the surviving fetuses and early neonates are growth stunted. GH treatment of the Tx mother, during the latter part of gestation, corrects some of these parameters in their offspring. The progenies of Tx mothers used in this study were typical of those of our previous reports. The numbers of live 1 -day-old neonates, their body, brain, and liver weights were significantly reduced as compared to controls. Brain, liver, and serum protein concentrations were significantly depressed in 1, 5-, and 60-day-old offspring of Tx-only mothers as compared to those of GH-treated and offspring of the various control group mothers. These offspring of Tx-only mothers showed a total inability to learn the Lashley maze. None of the offspring of Tx-only mothers were able to traverse the maze on consecutive trials without committing errors as compared to 25–42% of the progenies of the control groups which learned the maze before the end of 10 trials. The time required, for the offspring of all maternal groups, to traverse the maze to obtain a food reward decreased significantly. However, the offspring of Tx-only mothers, even though they would try to traverse the maze rapidly, took significantly longer to traverse the maze than progenies of the control groups in trials 6–10 because of the errors committed. These same offspring of the Tx-only mothers had also significantly increased spontaneous movements in the stabilimeter cages as compared to progenies of control mothers...

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Section: Discussionmentioning

confidence: 99%

Behavioral Testing of Progenies of Tx (Hypothyroid) and Growth Hormone-Treated Tx Rats: An Animal Model for Mental Retardation

Hendrich

Jackson

Porterfield³

1984

Neuroendocrinology

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“…Loo et al [24] described a disruption in the normal brain ganglioside pattern and reduced sialoglycoproteins. Copenhaver et al [25] found that the polyribosomal structure in rat fetal brains was disaggregated, and Okano et al [26] supported this in observing reduced polysomes with increased numbers of disomes and monosomes in fetal brains. Taken Future Directions in Maternal PKU Maternal PKU represents an unusual ex ample of biochemical disequilibrium trans mitted across the placenta and producing fetal damage.…”

Section: Pathogenesis Of the Fetal Damagementioning

confidence: 61%

Maternal Phenylketonuria

Levy¹

1987

Enzyme

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Maternal phenylketonuria (PKU) refers to fetal damage from PKU in the pregnant woman. The progeny from such pregnancies are almost always microcéphalie and mentally subnormal and have an increased frequency of congenital heart disease and low birth weight. Treatment with a phenylalanine-restricted diet, if begun before conception, seems to protect the fetus. The degree of protection is much less if dietary treatment is delayed until the pregnancy is in progress. The origin of fetal damage in maternal PKU is not known. Due to placental concentration of amino acids, the fetus is exposed to a higher concentration of phenylalanine than that in the mother, but it is not certain that phenylalanine is the toxic agent. Animal models made hyperphenylalaninémie by the administration of phenylalanine, often accompanied by a phenylalanine hydroxylase inhibitor, do not reproduce the full maternal PKU syndrome; but fetuses and newborns from these models have had reduced growth of the body and brain, and offspring later may show evidence of impaired learning ability.

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“…Animal experiments studying maternal PKU in terms of brain damage have shown the behavioural abnormalities in the offspring (Kerr et al, 1968), amino acid imbalances (Carver et al, 1965), disaggregation of polysomes (Wong et al, 1972, Copenhaver et al, 1973, changes in the amounts of DNA, RNA and protein (Brass et al, 1982;Spero and Yu, 1983), low pyruvate kinase (Wapnir et al, 1977) and decreased transmitter levels (Brass et al, 1982). However, to our knowledge studies concerning congenital heart disease using animal models of maternal PKU have not been reported.…”

Section: Discussionmentioning

confidence: 91%

“…(The incidence inthe general population is 0.8%). Mental retardation due to maternal PKU may be associated with disturbances in MS received 26.4.85 Accepted 1.8.85 protein synthesis in the fetal brain during development (Wong et al, 1972;Copenhaver et al, 1973). However, there are few reports on the cause of congenital heart disease in maternal PKU.…”

mentioning

confidence: 96%

Effects of phenylalanine loading on protein synthesis in the fetal heart and brain of rat: an experimental approach to maternal phenylketonuria

Okano

Chow

Isshiki

et al. 1985

J of Inher Metab Disea

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Pregnant rats were loaded with L-phenylalanine, and the distributions of [14C]leucine and [14C]urea into fetal plasma and tissues were examined. Uptake of [14C]leucine into the supernatant and protein fractions of fetal plasma and tissues was low in the rats loaded with phenylalanine. In contrast, [14C]urea was distributed identically in both groups, indicating that maternal hyperphenylalaninemia did not affect blood flow across the placenta. Administration of phenylalanine and p-chlorophenylalanine produced amino acid imbalance in fetal tissues. Along with these changes, polysomes of the affected fetal heart and brain disaggregated without changes in the ribonuclease activity. These results indicate that high phenylalanine levels in maternal plasma disturb the active transport of amino acids across the placenta, causing an amino acid imbalance and disaggregation of polysomes in fetal heart and brain. These changes may contribute to the congenital heart disease and mental retardation of maternal phenylketonuria.

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Experimental Maternal Hyperphenylalaninemta: Disaggregation of Fetal Brain Ribosomes

Cited by 28 publications

References 21 publications

Behavioral Testing of Progenies of Tx (Hypothyroid) and Growth Hormone-Treated Tx Rats: An Animal Model for Mental Retardation

Behavioral Testing of Progenies of Tx (Hypothyroid) and Growth Hormone-Treated Tx Rats: An Animal Model for Mental Retardation

Maternal Phenylketonuria

Effects of phenylalanine loading on protein synthesis in the fetal heart and brain of rat: an experimental approach to maternal phenylketonuria

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