Emerging Mycoestrogens: Impacts on Placental and Early Childhood Growth

项目总结 世界卫生组织称玉米赤霉烯酮(Zen)为 最令人担忧的真菌毒素。玉米赤霉醇(ZER)，一种用于促进牲畜生长的合成形式的禅宗， 已经在欧盟被禁止，因为已经确定的内分泌干扰特性。禅宗和禅宗 ZER与雌激素受体α和β结合的亲和力高于其他研究较好的内分泌干扰物 化学品(EDCs)，被指定为“霉菌雌激素”。动物在宫内暴露于Zen和ZER 会破坏后代的发育，导致胎儿和新生儿体重减轻。霉菌雌激素对婴儿的影响 随着胎盘发育的改变，健康可能很早就开始了。作为荷尔蒙和生长的主要来源 对于正在发育的胎儿来说，胎盘是环境化学物质破坏的敏感目标。我们的 来自小鼠模型的实验数据表明，胎盘重量和表面积减少 Zen暴露后合胞化途径的改变。尽管在动物模型中进行了这项引人注目的工作 以及人类广泛接触这些化合物的证据，到目前为止，还没有流行病学研究 研究了霉菌雌激素对儿童健康的影响。建议的总体假设 研究表明，子宫内暴露于霉菌雌激素会对胎盘发育产生不利影响，并损害 胎儿和婴儿的生长发育。我们将测试我们的中心假设，作为正在进行的上行研究的一部分，这是一项总部位于美国的研究 研究胎盘在调节产前关系中的作用的妊娠队列研究 儿童暴露与早期发育(n=326)。我们将对尿液和胎盘中的真菌雌激素进行定量。 组织跨越多个时间点(第一、第二和第三个三个月和出生)。然后我们会检查母体 霉菌雌激素浓度与Upside的全面胎盘数据相关，其中包括：(1)基本 胎盘大小特征(如重量、表面积、厚度、体积和直径)；(2)新颖的胎盘 终点(如血管表面积和血管分支点数量)和(3)免疫组织化学 滋养层细胞应激的标志物(如细胞凋亡和细胞增殖)。 围产期生长我们将比较新的霉菌雌激素数据和基于中期和晚期妊娠的胎儿生物测量。 在出生时、1、6、12、24和36个月龄时，纵向收集超声波和婴儿人体测量数据。 这将是第一个全面评估母婴结局的流行病学研究。 在暴露于霉菌雌激素后，并将向公共卫生政策通报与增加存在和 全球粮食供应中霉菌毒素的管理。

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.