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Neonatal phenobarbital-induced persistent alterations in plasma testosterone profiles and testicular function
J H Wani1, A K Agrawal, B H Shapiro
1School of Veterinary Medicine, University of Pennsylvania, Philadelphia 19104-6048, USA.
Insights
Neonatal exposure to phenobarbital permanently disrupts testosterone secretion patterns in rats, altering testicular steroidogenesis and hormone levels throughout development and adulthood. This early-life exposure impacts androgen profiles and responsiveness to hormonal regulation.
Area of Science:
- Endocrinology
- Neuropharmacology
- Developmental Biology
Background:
- Phenobarbital is a commonly used anticonvulsant medication.
- Early-life exposure to certain drugs can have long-term effects on hormonal systems.
- Testosterone plays a crucial role in male development and reproductive health.
Purpose of the Study:
- To investigate the long-term effects of neonatal phenobarbital exposure on serum testosterone levels and secretory profiles in rats.
- To examine alterations in testicular responsiveness to hormonal regulation following early-life phenobarbital exposure.
Main Methods:
- Rats received daily subcutaneous injections of phenobarbital (40 mg/kg) during the first 7 days of life.
- Plasma testosterone levels were measured from birth through adulthood.
- Testosterone secretory profiles were analyzed using cluster analysis at 65 and 165 days of age.
- Testicular responsiveness to human chorionic gonadotropin (hCG) and challenge doses of phenobarbital was assessed.
Main Results:
- Neonatal phenobarbital exposure led to subnormal testosterone levels from birth to pre-puberty, normal levels during puberty, and supranormal levels in adulthood.
- A significant increase in testosterone peak amplitude and duration was observed in treated rats.
- Neonatal phenobarbital exposure enhanced testicular responsiveness to hCG.
- Phenobarbital-induced testosterone reduction was delayed in adult rats with neonatal exposure.
Conclusions:
- Postpartum exposure to therapeutic phenobarbital levels can permanently disrupt testosterone secretory profiles.
- Early-life phenobarbital exposure alters the pathways regulating testicular steroidogenesis.
- These findings highlight potential long-term endocrine consequences of neonatal barbiturate exposure.
Abstract:
Daily sc injections of phenobarbital at anticonvulsant therapeutic doses for the rat (40 mg/kg) for the first 7 days of life resulted in below normal levels of serum testosterone from around birth to before puberty, normal levels during puberty and above normal levels of the androgen after puberty and in adulthood. Cluster analysis of the plasma testosterone secretory profiles obtained at 15-min intervals from phenobarbital-treated rats at 65 and 165 days of age revealed a significant increase in both the peak amplitudes and their durations resulting in a 100% increase in the amount of hormone secreted during the peak periods. In general, most of the rats (control and experimental) secreted testosterone as two large peaks, each 3 to 4 hr in duration, during the 10-hr lights-on collection period. In addition to permanently disrupting the ultradian profiles of plasma testosterone, neonatal exposure to the barbiturate altered testicular responsiveness to steroidogenic regulatory agents. That is, neonatal exposure to phenobarbital enhanced the responsiveness to exogenous hCG as measured by an above-normal increase in testosterone concentration. Moreover, phenobarbital-induced reductions in serum testosterone levels were delayed in adult rats neonatally exposed to the barbiturate. Whereas a single challenge dose of phenobarbital (1 or 10 mg/kg) reduced serum testosterone concentrations in control animals by almost 80% within 3 hr, a decline in serum androgen levels in the neonatally phenobarbital exposed males was not observed until 12 hr after the challenge dose. These results indicate that postpartum exposure to therapeutic levels of phenobarbital can permanently disrupt testosterone secretory profiles and alter pathways regulating testicular steroidogenesis.