Chavira-Suárez Erika, Reyes-Castro Luis Antonio, López-Tenorio Itzel Ivonn, Vargas-Hernández Lilia, Rodríguez-González Guadalupe L, Chavira Roberto, Zárate-Segura Paola, Domínguez-López Aaron, Vadillo-Ortega Felipe, Zambrano Elena
Unidad de Vinculación Científica de la Facultad de Medicina, Universidad Nacional Autónoma de México en el Instituto Nacional de Medicina Genómica, Mexico City, México.
Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de Mexico, Mexico City, México.
Front Cell Dev Biol. 2022 Aug 16;10:892315. doi: 10.3389/fcell.2022.892315. eCollection 2022.
Maternal obesity (MO) induces negative consequences in the offspring development. Adiposity phenotype is associated with maternal diet at early pregnancy and DNA methylation marks in the RXRα promotor at birth. Glucocorticoids play an important role in the regulation of metabolism through the activation of nuclear hormone receptors such as the RXRα protein. The aim of the study was to analyze steroid hormone changes at the end of pregnancy in the obese mother and RXRα gene methylation in the umbilical cord. For this purpose, in a well-established MO model, female Wistar rats were fed either standard chow (controls: C) or high-fat obesogenic diet (MO) before and during pregnancy to evaluate at 19 days of gestation (19 dG): 1) maternal concentration of circulating steroid hormones in MO and C groups, 2) maternal and fetal weights, 3) analysis of correlation between hormones concentration and maternal and fetal weights, 4) DNA methylation status of a single locus of RXRα gene near the early growth response (EGR-1) protein DNA binding site, and 5) RXRα mRNA and protein expressions in umbilical cords. Our results demonstrate that at 19 dG, MO body weight before and during pregnancy was higher than C; MO progesterone and corticosterone serum concentrations were higher and estradiol lower than C. There were not differences in fetal weight between male and female per group, therefore averaged data was used; MO fetal weight was lower than C. Positive correlations were found between progesterone and corticosterone with maternal weight, and estradiol with fetal weight, while negative correlation was observed between corticosterone and fetal weight. Additionally, male umbilical cords from MO were hypermethylated in RXRα gene compared to male C group, without differences in the female groups; mRNA and protein expression of RXRα were decreased in F1 male but not in female MO compared to C. In conclusion, MO results in dysregulation of circulating steroid hormones of the obese mothers and low fetal weight in the F1, modifying DNA methylation of RXRα gene as well as RXRα mRNA and protein expression in the umbilical cord in a sex-dependent manner.
母体肥胖（MO）会在子代发育过程中引发负面后果。肥胖表型与孕早期的母体饮食以及出生时视黄酸X受体α（RXRα）启动子中的DNA甲基化标记有关。糖皮质激素通过激活核激素受体（如RXRα蛋白）在代谢调节中发挥重要作用。本研究的目的是分析肥胖母亲妊娠末期的类固醇激素变化以及脐带中RXRα基因的甲基化情况。为此，在一个成熟的MO模型中，雌性Wistar大鼠在怀孕前及怀孕期间分别喂食标准饲料（对照组：C）或高脂致肥胖饮食（MO），以在妊娠第19天（19 dG）评估：1）MO组和C组母体循环类固醇激素的浓度；2）母体和胎儿体重；3）激素浓度与母体和胎儿体重之间的相关性分析；4）早期生长反应（EGR-1）蛋白DNA结合位点附近RXRα基因单个位点的DNA甲基化状态；5）脐带中RXRα mRNA和蛋白表达。我们的结果表明，在19 dG时，MO组怀孕前及怀孕期间的体重高于C组；MO组孕酮和皮质酮血清浓度较高，雌二醇低于C组。每组中雄性和雌性胎儿体重无差异，因此使用平均数据；MO组胎儿体重低于C组。孕酮和皮质酮与母体体重呈正相关，雌二醇与胎儿体重呈正相关，而皮质酮与胎儿体重呈负相关。此外，与雄性C组相比，MO组雄性脐带中RXRα基因甲基化程度更高，雌性组之间无差异；与C组相比，F1代雄性MO组中RXRα的mRNA和蛋白表达降低，而雌性MO组中未降低。总之，MO导致肥胖母亲循环类固醇激素失调以及F1代胎儿体重降低，以性别依赖的方式改变了脐带中RXRα基因的DNA甲基化以及RXRα mRNA和蛋白表达。
