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Permanent alterations in the hypothalamic-pituitary-thyroid axis in the rat following phenytoin exposure in utero
T J Theodoropoulos1, M A Pappolla, O S Goussis
1Department of Medicine, VA Medical Center, Montrose, New York.
Insights
In utero phenytoin exposure permanently alters the rat
Area of Science:
- Endocrinology
- Developmental Toxicology
- Neuroendocrinology
Background:
- Prenatal exposure to antiepileptic drugs can impact offspring development.
- The hypothalamic-pituitary-thyroid (HPT) axis is crucial for growth and metabolism.
- Thyroid hormone levels are critical during fetal development.
Purpose of the Study:
- To investigate the long-term effects of in utero phenytoin exposure on the rat HPT axis.
- To determine if phenytoin alters thyroid hormone concentrations and pituitary responsiveness.
- To explore potential mechanisms for observed HPT axis alterations.
Main Methods:
- Pregnant rats were exposed to phenytoin during gestation.
- Offspring were assessed for weight gain, serum thyroid hormone levels (thyroxine and triiodothyronine), and thyroid-stimulating hormone (TSH) responses.
- TSH responses were evaluated following challenges with thyrotropin-releasing hormone, propylthiouracil, and thyroidectomy.
Main Results:
- Phenytoin-exposed (DPH) offspring exhibited decreased weight gain.
- DPH animals showed reduced serum thyroxine and triiodothyronine concentrations.
- A blunted TSH response to various stimuli was observed in DPH rats, indicating impaired pituitary function.
Conclusions:
- In utero phenytoin exposure causes permanent disruptions to the rat's HPT axis.
- The observed pituitary dysfunction in DPH rats resembles patterns seen in neonatal thyrotoxicosis.
- Structural similarities between phenytoin and thyroid hormones may contribute to these developmental effects.
Abstract:
Phenytoin exposure in utero results in permanent alterations of the hypothalamic-pituitary-thyroid axis in the rat. The DPH exposed animals have decreased weight gain, thyroxine and triiodothyronine concentrations. In addition, they have blunted thyroid-stimulating hormone responses to thyrotropin-releasing hormone, propylthiouracil challenge or thyroidectomy. The diminished pituitary response in these animals is similar to that reported in neonatal thyrotoxicosis in the rat. This may be due, in part, to structural similarities between phenytoin and the thyroid hormone.