Emerging Mycoestrogens: Impacts on Placental and Early Childhood Growth

项目摘要 世界卫生组织称玉米赤霉烯酮（ZEN），通常在食品供应中发现， 最令人担忧的霉菌毒素。Zeranol（ZER）是ZEN的一种合成形式，用于促进牲畜的生长， 在欧盟已经被禁止，因为它具有内分泌干扰的特性。禅和 ZER与雌激素受体α和β的结合亲和力高于其他研究充分的内分泌干扰素， 化学品（内分泌干扰物），赢得了他们的指定为“真菌雌激素”。动物在子宫内暴露于ZEN和ZER 破坏后代的发育，导致胎儿和出生体重下降。真菌雌激素对婴儿的影响 随着胎盘发育的改变，健康可能开始得更早。作为激素和生长的主要来源 胎盘是胎儿生长的重要因素，是环境化学物质破坏的敏感目标。我们 来自小鼠模型的实验数据表明胎盘重量和表面积沿着减少 ZEN暴露后合胞途径的改变。尽管在动物模型上的研究引人注目 和广泛的人类接触这些化合物的证据，迄今为止，没有流行病学研究 研究真菌雌激素对儿童健康的影响。所提出的总体假设 研究表明，子宫内暴露于真菌雌激素会对胎盘发育产生不利影响， 胎儿和婴儿的生长。作为正在进行的UPSIDE研究的一部分，我们将测试我们的中心假设，基于 妊娠队列研究胎盘在调节产前 暴露和儿童早期发育（n=326）。我们将定量尿液和胎盘中的真菌雌激素 在多个时间点（妊娠早期、妊娠中期和妊娠晚期以及出生）的组织中。然后我们将检查产妇 真菌雌激素浓度与UPSIDE的全面胎盘数据相关，包括：（1）基础 胎盘大小特征（例如重量、表面积、厚度、体积和直径）;（2）新的胎盘 终点（例如血管表面积和血管分支点的数量）和（3）免疫组织化学 滋养层应激的标志物（例如，细胞凋亡和细胞增殖）。为了研究真菌雌激素对 围产期生长，我们将比较新的真菌雌激素数据，胎儿生物统计学的基础上，第二和第三个三个月 在出生时、1、6、12、24和36个月时纵向收集超声以及婴儿人体测量。 这将是第一个全面评估母亲、胎儿和婴儿结局的流行病学研究 在真菌雌激素暴露后，将告知与日益增加的存在相关的公共卫生政策， 全球食品供应中的真菌毒素管理。

PROJECT SUMMARY The World Health Organization has called zearalenone (ZEN), commonly found in the food supply, one the mycotoxins of greatest concern. Zeranol (ZER), a synthetic form of ZEN used to promote growth in livestock, has been banned in the European Union because of established endocrine-disrupting properties. Both ZEN and ZER bind to estrogen receptors α and β with higher affinity than other well-studied endocrine-disrupting chemicals (EDCs), earning their designation as ‘mycoestrogens’. In utero exposure of animals to ZEN and ZER disrupts offspring development, causing reduced fetal and birth weight. The impact of mycoestrogens on infant health may start early, with altered development of the placenta. As the principal source of hormones and growth factors for the growing fetus, the placenta is a sensitive target for disruption by environmental chemicals. Our experimental data from a mouse model indicates reduction in placental weights and surface area along with alteration of syncytialization pathways following ZEN exposure. Despite this compelling work in animal models and evidence of widespread human exposure to these compounds, to date, no epidemiological research has examined the impact of mycoestrogens on children’s health. The overarching hypothesis of the proposed research is that mycoestrogen exposure in utero adversely affects placental development and impairs fetal and infant growth. We will test our central hypothesis as part of the ongoing UPSIDE study, a U.S.-based pregnancy cohort that investigates the role of the placenta in mediating relationships between prenatal exposures and early development of children (n=326). We will quantify mycoestrogens in urine and placental tissue across multiple time points (1st, 2nd and 3rd trimesters and birth). We will then examine maternal mycoestrogen concentrations in relation to UPSIDE’s comprehensive placenta data, which includes: (1) basic placental size characteristics (e.g. weight, surface area, thickness, volume, and diameter); (2) novel placental endpoints (e.g. vascular surface area and number of vascular branch points) and (3) immunohistochemical markers of trophoblast stress (e.g., apoptosis and cell proliferation).To study the impact of mycoestrogens on perinatal growth we will compare novel mycoestrogen data to fetal biometry based on 2nd and 3rd trimester ultrasounds as well as infant anthropometric collected longitudinally at birth, 1, 6,12, 24 and 36 months of age. This will be the first epidemiological study to comprehensively assess maternal, fetal, and infant outcomes following mycoestrogen exposure and will inform public health policy related to the increasing presence and management of mycotoxins in the global food supply.