Department of Obstetrics and Gynecology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Department of Pharmacy, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Department of Nutrition and Food Hygiene, School of Public Health and Management, Chongqing Medical University, Chongqing 400016, China.
Department of Obstetrics and Gynecology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Biochim Biophys Acta Mol Basis Dis. 2019 Jan;1865(1):147-160. doi: 10.1016/j.bbadis.2018.10.040. Epub 2018 Nov 4.
Diabetes exerts adverse effects on the initiation or progression of diabetes and metabolic syndrome in the next generation. In past studies, limited attention has been given to the fathers' role in shaping the metabolic landscape of offspring. Our study was designed to investigate how paternal hyperglycemia exerts an intergenerational effect in mammals as well as the underlying mechanisms.
Hyperglycemia was introduced in male rats by intraperitoneally injected streptozotocin and these males were bred with healthy females to generate offspring. The metabolic profiles of the progeny were assessed; DNA methylation profiles and gene expression were investigated. Mutagenesis constructs of the Ppara promoter region, and a luciferase reporter assay were used to determine transcription factor binding sites (TFBSs) and the effects of hypermethylation on Ppara transcription.
Paternal hyperglycemia induced increased liver weight, and plasma TC, TG, LDL, accumulation of triglycerides in the liver. We discovered that CpG 13 in the amplified promoter region (-852 to -601) of Ppara was hypermethylated in adult offspring liver and expression of Ppara, Acox1, Cpt-1α, and Cd36 was down regulated. Hypermethylation of CpG site 13 in the Ppara promoter inhibited the gene transcription, probably through abrogation of SP1 binding. The same epigenetic alteration was discovered in the fetus (E16.5) liver of hyperglycemic father's progeny.
Paternal hyperglycemia may induce epigenetic modification of Ppara in offspring's liver, probably through interaction with SP1 binding, causing impaired lipid metabolism. Our investigation may have implications for the understanding of father-offspring interactions with the potential to account for metabolic syndromes.
糖尿病对下一代糖尿病和代谢综合征的发生或进展有不良影响。在过去的研究中，父亲在塑造后代代谢状态方面的作用受到的关注有限。我们的研究旨在探讨雄性亲代高血糖如何在哺乳动物中产生跨代效应，以及其潜在机制。
通过腹腔注射链脲佐菌素使雄性大鼠产生高血糖，并使这些雄性大鼠与健康雌性大鼠交配以产生后代。评估后代的代谢特征；研究 DNA 甲基化谱和基因表达。使用 Ppara 启动子区域的诱变构建体和荧光素酶报告基因检测，确定转录因子结合位点（TFBS）和高甲基化对 Ppara 转录的影响。
亲代高血糖导致雄性后代肝脏重量增加，血浆 TC、TG、LDL 升高，肝脏甘油三酯蓄积。我们发现 Ppara 扩增启动子区域（-852 至-601）的 CpG13 在成年后代肝脏中发生高甲基化，Ppara、Acox1、Cpt-1α 和 Cd36 的表达下调。Ppara 启动子 CpG 位点 13 的高甲基化抑制了基因转录，可能是通过 SP1 结合的缺失。在高血糖父亲后代的胎儿（E16.5）肝脏中也发现了同样的表观遗传改变。
亲代高血糖可能导致后代肝脏中 Ppara 的表观遗传修饰，可能是通过与 SP1 结合相互作用，导致脂质代谢受损。我们的研究可能有助于理解父代与子代的相互作用，并有可能解释代谢综合征。
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