Department of Pediatrics, University of Michigan, Ann Arbor, Michigan.
College of Human Medicine, California Northstate University, Elk Grove, California.
Am J Physiol Heart Circ Physiol. 2022 Apr 1;322(4):H607-H621. doi: 10.1152/ajpheart.00691.2021. Epub 2022 Feb 4.
Perturbed in utero hormone milieu leads to intrauterine growth retardation (IUGR), a known risk factor for left ventricular (LV) dysfunction later in life. Gestational testosterone (T) excess predisposes offspring to IUGR and leads to LV myocardial disarray and hypertension in adult females. However, the early impact of T excess on LV programming and if it is female specific is unknown. LV tissues were obtained at gestation from T-treated or control fetuses ( = 6/group/sex) and morphometric and molecular analyses were conducted. Gestational T treatment increased cardiomyocyte number only in female fetuses. T excess upregulated receptor expression of insulin and insulin-like growth factor. Furthermore, in a sex-specific manner, T increased expression of phosphatidylinositol 3-kinase () while downregulating phosphorylated mammalian target of rapamycin ()-to- ratio suggestive of compensatory response. T excess ) upregulated atrial natriuretic peptide () and brain natriuretic peptide (), markers of stress and cardiac hypertrophy and ) upregulated estrogen receptors1 (ESR1) and 2 (ESR2), but not in androgen receptor (). Thus, gestational T excess upregulated markers of cardiac stress and hypertrophy in both sexes while inducing cardiomyocyte hyperplasia only in females, likely mediated via insulin and estrogenic programming. The present study demonstrates sex-specific effects of gestational T excess between and of gestation on the cardiac phenotype. Furthermore, the sex-specific programming is likely secondary to perturbation in both estrogen and insulin signaling pathways collectively. These findings are supportive of the role of androgen excess to serve as early biomarkers of CVD and could be critical in identifying therapeutic targets for LV hypertrophy and predict long-term CVD.
子宫内环境激素紊乱可导致宫内生长迟缓（IUGR），这是导致成年后左心室（LV）功能障碍的已知危险因素。妊娠期睾酮（T）过多会使后代易发生 IUGR，并导致成年雌性动物的 LV 心肌排列紊乱和高血压。然而，T 过多对 LV 编程的早期影响以及是否具有性别特异性尚不清楚。从 T 处理或对照胎儿（每组/性别= 6）中获取 LV 组织，并进行形态计量学和分子分析。妊娠期 T 处理仅增加了雌性胎儿的心肌细胞数量。T 过多上调了胰岛素和胰岛素样生长因子的受体表达。此外，T 以性别特异性的方式增加了磷酸肌醇 3-激酶（）的表达，同时下调了磷酸化哺乳动物雷帕霉素靶蛋白（）与的比值，提示存在代偿反应。T 过多上调了心房利钠肽（）和脑利钠肽（），这是应激和心肌肥厚的标志物，并且上调了雌激素受体 1（ESR1）和 2（ESR2），但雄激素受体（）没有上调。因此，妊娠期 T 过多在两性中均上调了心脏应激和肥大的标志物，而仅在雌性中诱导心肌细胞增生，这可能是通过胰岛素和雌激素编程介导的。本研究表明，在妊娠第 10 至 16 天之间，T 过多对心脏表型具有性别特异性影响。此外，这种性别特异性编程可能是由于雌激素和胰岛素信号通路的共同干扰所致。这些发现支持雄激素过多作为 CVD 的早期生物标志物的作用，并且对于确定 LV 肥厚的治疗靶点和预测长期 CVD 可能至关重要。
