Gender and perinatal origins of adult disease

许多人类研究表明，与较大的婴儿相比，出生较小的婴儿成年后患心血管疾病的风险更高，这表明影响胎儿生长的产前环境因素可能会使个人在晚年面临更高的心血管风险。其中一个因素是母亲的蛋白质摄入量。在大鼠中，母体蛋白质限制会导致成年后代肾功能障碍和高血压。在发育的关键时期抑制肾内肾素血管紧张素系统，以及随之而来的肾单位捐赠的减少，似乎在这一规划中发挥了重要作用。雌性后代相对受到保护，不受包括蛋白质限制在内的几种不利母亲饮食条件的编程影响。在其他模型中，性腺激素在发育和/或成年期的存在有助于高血压的性二型性模式，但女性通过母体饮食防止高血压编程的机制尚不清楚。本项目的目的是确定女性性别对围产期高血压的相对保护作用的机制。最重要的假设是，发育过程中的睾酮和/或发育过程中的睾酮和/或生命后期的睾酮或雌激素的存在或不存在是围产期编程的性别二型性的原因，具体地说，这些性腺激素至少部分地通过允许抑制胎儿/新生儿的肾素-血管紧张素系统而参与后代高血压的编程，从而损害肾脏发育，导致肾脏结构和功能的永久性变化。在这些研究中，正常和蛋白质限制的母亲的雌性后代的睾酮和雌激素水平将在发育期和/或成年生活中通过睾丸切除/卵巢切除和给予外源性激素或通过给予药物抑制物来操纵。将在新生期测量肾脏肾素-血管紧张素系统成分，并将测量幼年和成年动物的动脉压、肾功能、肾小球数量和体积。

Numerous human studies have shown that babies born smaller have an increased adult cardiovascular risk compared to larger babies, indicating that factors in the prenatal environment affecting fetal growth can program the individual for increased cardiovascular risk later in life. One of these factors is maternal protein intake. In rats, maternal protein restrict leads to renal dysfunction and hypertension in the adult offspring. Suppression of the intrarenal renin angiotensin system during a critical period in development, and a consequent reduction in nephron endowment, appear to play an important role in this programming. Female offspring are relative protected from the programming effects of several adverse maternal dietary conditions, including protein restriction. In other model, the presence of gonadal hormones during development and/or in adulthood contribute to the sexually dimorphic patterns of hypertension, but the mechanisms by which female gender protects against programming for hypertension by maternal diet are not known. The purpose of this project is to determine the mechanisms responsible for the relative protective effect of female gender on perinatal programming for hypertension. The overarching hypothesis is that the presence or absence of testosterone during development and/or testosterone during development and/or testosterone or estrogen later in life are responsible for the sexual dimorphism of perinatal programming, and specifically, that these gonadal hormones contribute to programming of offspring hypertension at least in part through permitting suppression of the fetal/newborn intrarenal renin-angiotensin system and consequent impairment of renal development, resulting in permanent changes in renal structure and function. In these studies, testosterone and estrogen levels in female offspring of normal and protein-restricted mothers will be manipulated during the developmental period and/or in adult life by orchiectomy/ovariectomy and administration of exogenous hormone or by administration of pharmacologic inhibitors. Renal renin-angiotensin system components will be measured in the neonatal period, and arterial pressure, renal function, and glomerular number and volume will be measured in juvenile and adult animals.