Alcohol alters insulin-like growth factor-1-induced transforming growth factor 1 synthesis in the medial basal hypothalamus of the prepubertal female rat.
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BACKGROUND: Insulin-like growth factor-1 (IGF-1) and transforming growth factor 1 (TGF1) are produced in hypothalamic astrocytes and facilitate luteinizing hormone-releasing hormone (LHRH) secretion. IGF-1 stimulates release by acting directly on the LHRH nerve terminals and both peptides act indirectly through specific plastic changes on glial/tanycyte processes that further support LHRH secretion. Because the relationship between these growth factors in the hypothalamus is not known, we assessed the ability of IGF-1 to induce TGF1 synthesis and release and the actions of alcohol (ALC) on this mechanism prior to the onset of puberty. METHODS: Hypothalamic astrocytes were exposed to medium only, medium plus IGF-1 (200ng/ml), or medium plus IGF-1 with 50mM ALC. After 18hours, media were collected and assayed for TGF1. For the in vivo experiment, prepubertal female rats were administered either ALC (3g/kg) or water via gastric gavage at 07:30hours and at 11:30hours. At 09:00hours, saline or IGF-1 was administered into the third ventricle. Rats were killed at 15:00hours and the medial basal hypothalamus (MBH) was collected for assessment of TGF1, IGF-1 receptor (IGF-1R), and Akt. RESULTS: IGF-1 induced TGF1 release (p<0.01) from hypothalamic astrocytes in culture, an action blocked by ALC. In vivo, IGF-1 administration caused an increase in TGF1 protein compared with controls (p<0.05), an action blocked by ALC as well as a phosphatidylinositol 3 kinase/Akt inhibitor. IGF-1 stimulation also increased both total (p<0.01) and phosphorylated (p)-IGF-1R (p<0.05) protein levels, and phosphorylated (p)-Akt levels (p<0.01), which were also blocked by ALC. CONCLUSIONS: This study shows that ALC blocks IGF-1 actions to stimulate synthesis and release of hypothalamic TGF1, total and p-IGF-1R, and p-Akt levels further demonstrating the inhibitory actions of ALC on puberty-related events associated with hypothalamic LHRH release.
author list (cited authors)
Hiney, J. K., Srivastava, V. K., Volz, C. E., & Dees, W. L