Maternal obesity and hormonally-mediated markers of fetal development

项目摘要 产妇肥胖是一个重大的公共卫生危机，因为>50%的妇女在怀孕时超重或肥胖。这 是令人震惊的，因为肥胖妇女的孩子更有可能发展代谢疾病的危险因素（包括 肥胖和胰岛素抵抗）和生殖障碍（如女儿初潮早， 儿子的精子质量）。代谢性疾病的重要早期预测因子包括出生体重和体重指数。 指数（从出生体重和长度测量），而生殖功能的早期预测因素包括 第二手指与第四手指的长度之比（2：4D）和肛门与生殖器之间的距离（anogenital distance， AGD）。在人类中，改变的2：4D与各种生殖异常有关，而早期AGD， 具体而言，与长期生殖健康和能力相关。虽然胎儿的标准测量 发育，包括出生体重和体重指数，在肥胖妇女的新生儿中改变，尚不清楚 母体肥胖是否影响新生儿AGD或2：4D。因此，我们将利用一个正在进行的怀孕 已经测量AGD和2：4D的队列，以及具有各种母体测量的队列 组成，以调查母亲肥胖是否与这些早期生命标志物相关， 扰乱生殖发育根据以前的研究，我们假设， 超重/肥胖妇女将女性化（AGD较短，2：4 D较长），而肥胖妇女的女婴将女性化（AGD较短，2：4 D较长）， 女性将被男性化（年龄段较长，2：4 D较短）。 通过出生体重或体重指数测量的胎儿生长改变是晚年肥胖的危险因素， 而新生儿AGD和2：4D是生殖能力改变的危险因素。母体雌激素水平和 睾酮是妊娠期两种重要的类固醇激素，对胎儿的发育和生长至关重要。为 例如，雌激素控制胎盘血管生成，调节营养转移到胎儿，而升高 在绵羊妊娠模型中显示母体睾酮导致子宫内生长受限。AGD 和2：4D，这是与生殖能力，也是性类固醇激素介导的;在男性 和女性，两者都是子宫内睾酮或雌激素暴露的标志物，并且对激素敏感。 产妇环境因素的影响。我们的怀孕队列研究结果表明， 也是一种内分泌干扰物，因为超重/肥胖孕妇的雌激素和睾丸激素较低 与正常体重的女性相比， 男性。目前尚不清楚肥胖女性的这些荷尔蒙变化是否是导致肥胖的部分原因。 众所周知，母亲肥胖与胎儿发育结果（出生体重和 体重指数），或与2：4D比率和AGD的拟议关联。因此，我们将调查 这一重要的生物学机制。

PROJECT SUMMARY Maternal obesity is a major public health crisis, as >50% of women enter pregnancy overweight or obese. This is alarming, as children of obese women are more likely to develop risk factors for metabolic disease (including obesity and insulin resistance) and reproductive disorders (such as earlier menarche in daughters and poor sperm quality in sons). Important early-life predictors of metabolic disease include birth weight and ponderal index (measured from birth weight and length), while early-life predictors of reproductive function include the ratio of the 2nd-to-4th finger lengths (2:4D) and the distance between the anus and genitals (anogenital distance, AGD). In humans, altered 2:4D is associated with various reproductive abnormalities, while early-life AGD, specifically, correlates with long-term reproductive health and capacity. While standard measures of fetal development, including birth weight and ponderal index, are altered in newborns of obese women, it is not known whether maternal obesity affects neonatal AGD or 2:4D. Therefore, we will leverage an ongoing pregnancy cohort that has already measured AGD and 2:4D, and that has various measures of maternal body composition, to investigate whether maternal obesity is associated with these early-life markers of perturbed reproductive development. Based on previous studies, we hypothesize that male infants of overweight/obese women will be feminized (have shorter AGD and longer 2:4D), while female infants of obese women will be masculinized (have longer AGD and shorter 2:4D). Altered fetal growth, as measured by birth weight or ponderal index, is a risk factors for later-life obesity, while newborn AGD and 2:4D are risk factors for altered reproductive capacity. Maternal levels of estrogen and testosterone, two important steroid hormones in pregnancy, are critical for fetal development and growth. For example, estrogen controls placental angiogenesis, which regulates nutrient transfer to the fetus, while elevated maternal testosterone in a sheep model of pregnancy was shown to cause intrauterine growth restriction. AGD and 2:4D, which are associated with reproductive capacity, are also sex steroid hormone-mediated; in males and females, both are markers of in utero testosterone or estrogen exposures, and are sensitive to hormonal disruption by maternal environmental factors. Findings from our pregnancy cohort suggest that maternal obesity is also an endocrine disruptor, as estrogen and testosterone were lower in overweight/obese pregnant women compared to normal-weight women, and associations with testosterone were only seen in women carrying males. It is not known whether these hormonal shifts in obese women are partially responsible for the well-known associations of maternal obesity with fetal developmental outcomes (birth weight and ponderal index), or for the proposed associations with 2:4D ratio and AGD. Therefore, we will investigate this important biological mechanism in the current study.