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Ornithine decarboxylase and polyamines in developing rat brain and heart: Effects of perinatal hypothyroidism
T A Slotkin1, A Johnson, W L Whitmore
1Department of Pharmacology, Duke University Medical Center, Durham, NC 27710, U.S.A.
Insights
Perinatal hypothyroidism induced by propylthiouracil (PTU) significantly impacts heart growth and development by disrupting cardiac ornithine decarboxylase (ODC) and polyamine levels. These biochemical changes, crucial for cellular maturation, were more pronounced in the heart than the brain.
Area of Science:
- Developmental Biology
- Endocrinology
- Biochemistry
Background:
- Perinatal hypothyroidism can disrupt normal growth and development.
- Thyroid hormones play a critical role in cellular maturation and organ development.
- Ornithine decarboxylase (ODC) and polyamines are key regulators of cellular growth and differentiation.
Purpose of the Study:
- To investigate the effects of perinatal hypothyroidism on cardiac and brain growth.
- To examine the impact of hypothyroidism on the ornithine decarboxylase (ODC) and polyamine system in the heart and brain.
- To compare the effects of hypothyroidism with those of exogenous thyroid hormone administration.
Main Methods:
- Induction of hypothyroidism in perinatal subjects using propylthiouracil (PTU).
- Measurement of organ weights (heart and brain) to assess growth deficits.
- Assay of cardiac and brain ornithine decarboxylase (ODC) activity.
- Quantification of polyamine levels (putrescine, spermidine) in cardiac and brain tissues.
Main Results:
- Perinatal PTU-induced hypothyroidism caused significant and persistent deficits in heart weight.
- Cardiac ODC activity was depressed, and putrescine and spermidine levels were markedly reduced in PTU-treated subjects.
- Brain growth was affected but to a lesser extent than the heart.
- Brain ODC activity showed a slight elevation, and spermidine levels were only slightly depleted, indicating a less pronounced disruption of the ODC/polyamine system.
Conclusions:
- Perinatal hypothyroidism profoundly disrupts cardiac development, primarily through alterations in the ODC/polyamine pathway.
- The heart is more sensitive to the effects of perinatal hypothyroidism than the brain.
- The observed biochemical changes in hypothyroidism are opposite to those induced by exogenous thyroid hormones, reinforcing the critical role of endogenous thyroid hormone signaling in development.
Abstract:
Hypothyroidism induced by perinatal administration of propylthiouracil (PTU) had profound effects on growth of the heart, with major organ weight deficits persisting well beyond the termination of drug treatment. These effects were preceded by disruption of the developmental patterns of cardiac ornithine decarboxylase (ODC) and the polyamines, which are thought to be intracellular modulators of cellular maturation. Activity of cardiac ODC was depressed in the PTU-treated group and putrescine and spermidine levels were markedly subnormal. PTU administration also affected brain growth, but much less so than in the heart. The disruption of the brain ODC/polyamine system was also less pronounced, with relatively small degrees of spermidine depletion and a slight elevation of ODC. For both tissues, the biochemical effects of perinatal hypothyroidism were opposite to those found previously for administration of exogenous thyroid hormones. These results support the views that:
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