Exposure to Zearalenone and its Impact on Maternal and Fetal Health

项目总结/摘要 真菌毒素食品污染可能因气候变化而加剧，这是一个日益受到国际关注的问题。 真菌代谢产物玉米赤霉烯酮（ZEN）是一种内分泌干扰真菌毒素，通常存在于植物中， 如生长在温带气候区的玉米和谷物。此外，虽然在欧盟被禁止， 在美国，这种合成衍生物玉米赤霉醇被用于牲畜，使肉类消费增加了 美国曝光的来源。人类暴露于ZEN和玉米赤霉醇通过ingredient污染的谷物衍生物 产品或产品从动物喂养污染的饮食。有大量证据表明 食品和人体生物体液中的ZEN及其代谢物的含量预计将增加， 气候变化进一步导致更温暖，更潮湿的栖息地。这种广泛的曝光是令人担忧的， 其化学结构与17β-雌二醇（E2）非常相似，可直接与核雌激素结合 受体α（ER-α）和受体β（ER-β）。ZEN及其代谢产物与雌激素受体结合的能力， 它们被称为“真菌雌激素”。在体内，大量证据表明，真菌雌激素破坏了 大鼠、小鼠、牛和猪的内分泌和生殖系统，导致不良后果，如 雌激素过多、不孕、流产、妊娠期体重增加减少和胎儿体积减小。体外证据 进一步证明ZEN破坏性类固醇激素的生物合成。鉴于其广泛的影响， 内分泌干扰作用在体内和体外模型系统和普遍暴露于真菌雌激素 在世界范围内，人类研究是迫切需要的。该项目利用了一项前瞻性出生队列研究 （n=326），在每个妊娠期收集生物标本，以检查真菌雌激素暴露对 母亲和胎儿的健康结果。实验室测定，以定量在每个母体尿液中的真菌雌激素 妊娠期和足月胎盘正在进行中。我们将用这些数据来翻译体外和动物 有证据表明，真菌雌激素暴露导致妊娠期体重增加减少，循环激素改变， 水平和胎盘性类固醇的表达，以及人类出生时较小的尺寸。我们将拟合纵向回归 模型来检验这一假设，即较高的真菌雌激素浓度与循环减少有关， 雌激素和减少妊娠期体重增加。线性模型将说明 ZEN对胎盘类固醇生成标志物表达的影响，包括雌激素受体1（ESR 1）的表达。 最后，我们将研究ZEN对婴儿出生时尺寸的影响。这些研究将对风险评估有价值 并将为公共政策提供信息，以减少弱势群体（婴儿、儿童）或 敏感期，如妊娠期。

Project Summary/Abstract Mycotoxin food contamination, potentially exacerbated by climate change, is a growing international concern. The fungal metabolite, zearalenone (ZEN), is an endocrine-disrupting mycotoxin commonly found on plants such as corn and grains grown in the temperate climate zone. Additionally, although banned in the European Union, the synthetic derivative, zeranol, is administered to livestock in the U.S. making meat consumption an additional source of U.S. exposure. Humans are exposed to ZEN and zeranol by ingesting contaminated grain-derived products or products from animals fed contaminated diets. There is a large body of evidence on the prevalence of ZEN and its metabolites in food products and in human biological fluids and exposure is expected to rise further with climate change leading to warmer, wetter habitats. This widespread exposure is concerning given that its chemical structure closely resembles 17β-estradiol (E2) which enables direct binding to nuclear estrogen receptors α (ER-α) and β (ER-β). The ability of ZEN and its metabolites to bind to estrogen receptors earned their designation as `mycoestrogens'. In vivo, substantial evidence demonstrates that mycoestrogens disrupt the endocrine and reproductive systems in rats, mice, cows, and pigs, leading to adverse outcomes such as hyperestrogenism, infertility, miscarriage, lower gestational weight gain, and reduced fetal size. In vitro evidence further demonstrates that ZEN disrupts sex steroid hormone biosynthesis. Given the wide-ranging impact of endocrine-disrupting effects in vivo and in vitro model systems and ubiquitous exposure to mycoestrogens worldwide, humans studies are urgently needed. This project capitalizes on a prospective birth cohort study (n=326) with biospecimen collection at each trimester, to examine the impact of mycoestrogen exposure on maternal and fetal health outcomes. Laboratory assays to quantify mycoestrogens in maternal urine in each trimester as well as term placenta are ongoing. We will use those data to translate the in vitro and animal evidence that mycoestrogen exposure leads to reduced gestational weight gain, altered circulating hormone levels and placental sex steroid expression, and smaller size at birth in humans. We will fit longitudinal regression models to test the hypothesis that higher mycoestrogen concentrations are associated with decreased circulating estrogens during pregnancy and reduced gestational weight gain. Linear models will inform on the impact of ZEN on placental expression of steroidogenic markers including expression of estrogen receptor 1 (ESR1). Finally, we will examine impacts of ZEN on infant size at birth. These studies will be valuable for risk assessment and will inform public policy to reduce exposure among vulnerable populations (infants, children) or during sensitive periods such as gestation.