Abstract
Proopiomelanocortin (POMC) is a precursor gene of the neuropeptide β-endorphin in the hypothalamus and is known to regulate various physiological functions including stress response. Several recent reports showed that fetal alcohol exposure programs the hypothalamus to produce lower levels of POMC gene transcripts and to elevate the hypothalamic-pituitary-adrenal (HPA) axis response to stressful stimuli. We investigated the role of methyl CpG binding protein (MeCP2) in the effects of prenatal ethanol on POMC gene expression and hypothalamic-pituitary-adrenal (HPA) axis function. Pregnant Sprague Dawley rats were fed between GD 7 and 21 with a liquid diet containing 6.7% alcohol, pair-fed with isocaloric liquid diet, or fed ad libitum with rat chow, and their male offsprings were used at 60 days after birth in this study. Fetal alcohol exposure reduced the level of POMC mRNA, but increased the level of DNA methylation of this gene in the arcuate nucleus (ARC) of the hypothalamus where the POMC neuronal cell bodies are located. Fetal alcohol exposed rats showed a significant increase in MeCP2 protein levels in POMC cells, MeCP2 gene transcript levels as well as increased MeCP2 protein binding on the POMC promoter in the arcuate nucleus. Lentiviral delivery of MeCP2 shRNA into the third ventricle efficiently reduced MeCP2 expression and prevented the effect of prenatal ethanol on POMC gene expression in the arcuate nucleus. MeCP2-shRNA treatment also normalized the prenatal ethanol-induced increase in corticotropin releasing hormone (CRH) gene expression in the hypothalamus and elevated plasma adrenocorticotrophic hormone (ACTH) and corticosterone hormone responses to lipopolysaccharide (LPS) challenge. These results suggest that fetal alcohol programming of POMC gene may involve recruitment of MeCP2 on to the methylated promoter of the POMC gene to suppress POMC transcript levels and contribute to HPA axis dysregulation.
Highlights
Alcohol exposure during pregnancy causes fetal alcohol spectrum disorder in the offspring characterized by various neural developmental deficits, growth retardation and facial abnormalities
Bendorphin synthesis, primarily within the arcuate nucleus of the hypothalamus, is activated by corticotropin-releasing hormone (CRH) release from terminals emerging from the paraventricular nucleus (PVN) of the hypothalamus, which is in turn inhibited by b-endorphin release [3,6]
In our studies we found that MeCP2 mRNA expression and protein were significantly increased in the mediobasal hypothalamus (MBH) of AF rats compared to ad libitum (AD) and PF control rats (Fig. 2A,B)
Summary
Alcohol exposure during pregnancy causes fetal alcohol spectrum disorder in the offspring characterized by various neural developmental deficits, growth retardation and facial abnormalities. A common endophenotype of fetal alcohol exposed offspring is an elevated neuroendocrine response of the HPA axis [1,2,3], an increase in circulating ACTH and corticosterone, which has been suggested to be due, at least in part, to the deleterious effects of alcohol exposure on hypothalamic bendorphin producing neurons [4,5]. Hypothalamic peptides are released through several signaling cascades, such as the release of corticotropin-releasing hormone (CRH) followed by the release of various POMC-derived peptides. POMC is a relatively large peptide that is cleaved into multiple biologically active subunits, including b-endorphin and a-melanocyte stimulating hormone (a-MSH). POMC system abnormalities have been associated with stress dysregulation, metabolic diseases, cancer and alcohol drinking [10,11,12,13,14,15]
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