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Neonatal phenobarbital-induced defects in age- and sex-specific growth hormone profiles regulating monooxygenases
A K Agrawal1, N A Pampori, B H Shapiro
1Laboratories of Biochemistry, School of Veterinary Medicine, University of Pennsylvania, Philadelphia 19104-6048.
Insights
Neonatal phenobarbital exposure permanently alters growth hormone patterns in rats, leading to sustained induction of liver enzymes crucial for drug metabolism. This study reveals long-term effects of early-life medication on endocrine and metabolic systems.
Area of Science:
- Endocrinology
- Pharmacology
- Developmental Toxicology
Background:
- Growth hormone (GH) secretion exhibits sexually dimorphic patterns in rats, with higher mean concentrations in younger animals.
- Neonatal exposure to phenobarbital, an anticonvulsant, is known to induce hepatic monooxygenases transiently.
Purpose of the Study:
- To investigate the long-term effects of neonatal phenobarbital exposure on growth hormone secretion patterns.
- To determine if neonatal phenobarbital exposure causes persistent alterations in hepatic monooxygenase activity.
- To explore the link between altered growth hormone profiles and sustained hepatic enzyme induction.
Main Methods:
- Measurement of circulating growth hormone levels in male and female rats at 65 and 150 days of age following neonatal phenobarbital administration.
- Assessment of hepatic monooxygenase activity using hexobarbital metabolism.
- Analysis of sex-dependent differences in hepatic monooxygenases around sexual maturity.
Main Results:
- Neonatal phenobarbital reduced growth hormone pulse amplitudes in a sex- and age-dependent manner.
- While initial hepatic monooxygenase induction was transient, a second, persistent phase of induction was observed in both sexes.
- This persistent induction occurred around sexual maturity, coinciding with the appearance of gender-dependent differences in enzyme activity.
Conclusions:
- Neonatal phenobarbital exposure induces abnormal growth hormone profiles that persist into adulthood.
- These altered growth hormone patterns are proposed to be responsible for the permanent induction of hepatic monooxygenases.
- The findings highlight the critical role of growth hormone in regulating sex-dependent hepatic enzyme activity and the long-lasting consequences of early-life drug exposure.
Abstract:
Growth hormone was secreted in sexually dimorphic patterns in both 65- and 150-day-old rats (i.e., "on-off" pulsatile for males and "continuous" pulsatile for females), but as a result of a 200-400% increase in pulse levels the mean concentration of hormone in the circulation was about two times as great in the younger animals. Neonatal exposure to phenobarbital at anticonvulsant therapeutic doses for the rat reduced the pulse amplitudes of circulating growth hormone in both the 65- and 150-day-old males but only in the 65-day-old females. As expected, neonatal administration of the barbiturate produced an almost immediate increase in the activities of the hepatic monooxygenases, as measured by hexobarbital metabolism, which declined to noninduction levels after treatment ceased. Contrary to the well-known transient effects of phenobarbital, at around the time of sexual maturity when gender-dependent differences in hepatic monooxygenases appear (males > females), we observed a second "round" of enzyme induction that persisted in both sexes for the remainder of the study (180 days). Because growth hormone is the primary regulator of sex-dependent hepatic monooxygenases, we have proposed that the abnormal plasma growth hormone profiles produced by neonatal phenobarbital are responsible for the permanent induction of hepatic monooxygenases.