Alcohol Delays the Onset of Puberty in the Female Rat by Altering Key Hypothalamic Events.
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BACKGROUND: Because alcohol (ALC) delays signs of pubertal development, we assessed the time course of events associated with the synthesis of critical hypothalamic peptides that regulate secretion of luteinizing hormone-releasing hormone (LHRH), the peptide that drives the pubertal process. METHODS: Immature female rats were administered either laboratory chow or BioServe isocaloric control or ALC-liquid diets from 27 through 33days of age. On days 28, 29, 31, and 33, animals were killed by decapitation and tissue blocks containing the medial basal hypothalamus (MBH) and the rostral hypothalamic area (RHA) were isolated and stored frozen until assessed by Western blot analysis. RESULTS: Synthesis of dynorphin (DYN), a prepubertal inhibitor of LHRH secretion, was increased (p<0.05) in the MBH of ALC-treated animals by day 29. DYN was further elevated (p<0.01) on day 33 and was associated with an increase (p<0.01) in DYN receptor expression. ALC did not affect synthesis of neurokinin B (NKB), a prepubertal stimulator of LHRH; however, it did suppress (p<0.05) NKB receptor expression in the MBH by day 31. The most potent stimulator of prepubertal LHRH secretion, kisspeptin (Kp), was also decreased (p<0.05) in the MBH as early as day 29, with continued suppression (p<0.01) through day 33. Similar timely suppressions of mammalian target of rapamycin (mTOR), an immediate upstream regulator of Kp, were also noted. These decreases in mTOR and Kp were consistent with ALC stimulating (p<0.05) the p-AMP-activated protein kinase/Raptor inhibitory pathway to mTOR on day 29, then later suppressing (p<0.001) an Akt-mediated induction pathway to mTOR by day 31. In the RHA, ALC affected the pathways regulating Kp in a manner similar to that described in the MBH; however, these effects were not noted until day 33. CONCLUSIONS: ALC acts within the MBH as early as 29days to induce inhibitor and repressor inputs to LHRH, while depressing stimulatory inputs to the peptide. Collectively, these events lead to delayed signs of pubertal development.
