Prepubertal ethanol exposure alters hypothalamic transforming growth factor-α and erbB1 receptor signaling in the female rat

Abstract

Glial derived transforming growth factor-α (TGFα) activates the erbB1/erbB2 receptor complex on adjacent glial cells in the medial basal hypothalamus (MBH). This receptor activation stimulates the synthesis and release of prostaglandin-E 2 (PGE 2 ) from the glial cells, which then induces the release of prepubertal luteinizing hormone releasing hormone (LHRH) secretion from nearby nerve terminals; thus, showing the importance of glial-neuronal communications at the time of puberty. Ethanol (EtOH) is known to cause depressed prepubertal LHRH secretion and delayed pubertal development. In this study, we assessed whether short-term EtOH exposure could alter the hypothalamic glial to glial signaling components involved in prepubertal PGE 2 secretion. Immature female rats began receiving control or EtOH diets beginning when 27 days old. The animals were killed by decapitation after 4 and 6 days of treatment and confirmed to be in the late juvenile stage of development. Blood and brain tissues were collected for gene, protein and hormonal assessments. Real-time PCR analysis demonstrated that EtOH did not affect basal levels of erbB1 gene expression in the MBH. Expression of total erbB1 protein was also unaffected; however, the EtOH caused suppressed phosphorylation of erbB1 protein in the MBH at both 4 and 6 days (p<0.01) as revealed by Western blotting. Phosphorylation and totaql protein levels of erbB2 receptor were not affected by EtOH exposure. Because this receptor is critical for PGE 2 synthesis/release, which mediates the secretion of LHRH, we assessed whether in vivo EtOH exposure could affect the release of PGE 2 . EtOH exposure for 6 days suppressed (p<0.01) basal levels of PGE 2 released into the medium. The effects of 4 and 6 day EtOH exposure on gene and protein expressions of TGFα, an upstream component in the activation of erbB1/erbB2, were also studied. The levels of TGFα mRNA were increased markedly at 4 days (p<0.001), but declined to near basal levels by 6 days in the EtOH-treated animals. The EtOH caused increases in TGFα protein expression at both 4 (p<0.001) and 6 (p<0.01) days; hence, suggesting that the EtOH inhibited release of the peptide. We confirmed this inhibition by showing decreased (p<0.01) TGFα released from MBHs incubated in vitro following 6 days of EtOH exposure in vivo. Thus, these results demonstrate that EtOH is capable of interfering with hypothalamic glial to glial signaling processes involved in prepubertal PGE 2 secretion.

Manganese protects against the effects of alcohol on hypothalamic puberty-related hormones

“…This is in agreement with previous reports using this feeding regimen and showing similar animal weights and hormone levels, as well as gene and protein expressions between these two CON groups of prepubertal, growing animals [10, 17, 20]. Similarly, no differences were detected between the two diet-fed CON groups supplemented with Mn.…”

“…PGE 2 is a critical component in the glial regulation of LHRH secretion, since once it is released it binds to its receptor on nearby LHRH nerve terminals in the ME, causing the release of this peptide [33, 41, 45]. Because ALC can suppress both TGFα and PGE 2 secretions [20], we also investigated in this study whether Mn supplementation could antagonize the actions of ALC on PGE 2, synthesis since it represents a critical pathway to LHRH neuronal secretion [33, 41, 45]. In support of this rational, previous studies have indicated Mn supplementation can up-regulate COX 2 expression in vivo and can stimulate PGE 2 and LHRH release from MEs incubated in vitro [26].…”

Alcohol alters hypothalamic glial-neuronal communications involved in the neuroendocrine control of puberty: In vivo and in vitro assessments

“…Collectively, these results demonstrate the inhibitory effects of alcohol on the glial TGFα/erbB1 pathway contributing to the production and secretion of PGE 2 within the MBH, hence, indicating that this is one of the mechanisms by which alcohol suppresses PGE 2 and subsequently, LHRH secretion (Hiney & Dees, 1991; Lomniczi et al, 2000; Srivastava et al, 2011). The fact that alcohol can negatively affect the erbB1 receptor is important since it is known that an alteration in the function of this receptor is associated with delayed puberty (Apostolakis, Garai, Lohmann, Clark, & O’Malley, 2000).…”

“…Specifically, it was shown in immature female rats that short-term alcohol exposure via a liquid diet feeding regimen for 4 and 6 days caused an increase in hypothalamic TGFα gene and protein expressions. TGFα gene expression was increased markedly at 4 days and was still elevated after 6 days (see Srivastava et al, 2011). This effect paralleled the increased TGFα protein expressions on both days (Fig.…”

“…1). Only recently, however, have the mechanisms of alcohol actions on the TGFα-PGE 2 pathway been critically assessed with regard to prepubertal hypothalamic glial-neuronal communications (Srivastava, Hiney, & Dees, 2011). Specifically, it was shown in immature female rats that short-term alcohol exposure via a liquid diet feeding regimen for 4 and 6 days caused an increase in hypothalamic TGFα gene and protein expressions.…”