Gangisetty Omkaram, Mead Edward A, Sarkar Dipak K
Rutgers Endocrine Research Program, Department of Animal Sciences, Rutgers University, New Brunswick, NJ, United States.
Front Neurosci. 2021 Mar 16;15:608102. doi: 10.3389/fnins.2021.608102. eCollection 2021.
Fetal alcohol exposure (FAE) causes various neurodevelopmental deficits in offspring, including reduced expression of the stress regulatory proopiomelanocortin () gene and an elevated stress response for multiple generations via the male germline. Male germline-specific effects of FAE on the gene raises the question if the sex-determining region Y (SRY) may have a role in regulating gene expression. Using a transgenerational model of FAE in Fischer 344 rats, we determined the role of SRY in the regulation of the gene. FAEs, like on the gene, reduced gene expression in sperm and the mediobasal hypothalamus (MBH) in male adult offspring. Fetal alcohol-induced inhibition of gene expression was associated with increased promoter DNA methylation. Additionally, fetal alcohol effects on the gene persisted for three generations in the male germline but not in the female germline. gene knockdown reduced the gene expression. recruitment onto the promoter was found to be reduced in the hypothalamus of fetal alcohol-exposed rats compared to control rats. promoter luciferase activity was increased following overexpression. A site-directed mutagenesis study revealed that binding sites are required for promoter transcription activity. Overall, these findings suggest that SRY plays a stimulatory role in the regulation of gene expression and may potentially contribute to the fetal alcohol-induced changes in the level of gene expression for multiple generations.
胎儿酒精暴露（FAE）会导致后代出现各种神经发育缺陷，包括应激调节阿片促黑皮质素（POMC）基因表达降低，以及通过雄性生殖系导致多代应激反应增强。FAE对POMC基因的雄性生殖系特异性影响引发了一个问题，即Y染色体性别决定区（SRY）是否可能在调节POMC基因表达中发挥作用。利用Fischer 344大鼠的FAE跨代模型，我们确定了SRY在POMC基因调控中的作用。与对POMC基因的影响一样，FAE降低了成年雄性后代精子和中基底下丘脑（MBH）中POMC基因的表达。胎儿酒精诱导的POMC基因表达抑制与POMC启动子DNA甲基化增加有关。此外，胎儿酒精对POMC基因的影响在雄性生殖系中持续了三代，但在雌性生殖系中没有。POMC基因敲低降低了POMC基因的表达。与对照大鼠相比，在胎儿酒精暴露大鼠的下丘脑中发现SRY募集到POMC启动子上的情况减少。SRY过表达后，POMC启动子荧光素酶活性增加。一项定点诱变研究表明，SRY结合位点是POMC启动子转录活性所必需的。总体而言，这些发现表明SRY在POMC基因表达调控中起刺激作用，并且可能潜在地导致多代胎儿酒精诱导的POMC基因表达水平变化。
