Placental origins of phthalate-induced changes in fetal reproductive development

在怀孕期间，母亲的大脑和胎儿-胎盘单位通过一种未被研究的 2下丘脑-垂体-胎盘轴。这一轴可能有助于揭示压力的不同影响。 3关于母婴健康的暴露补充了我们对下丘脑的已知-- 4垂体-肾上腺轴。新冠肺炎疫情加剧了慢性孕产妇应激源 5防止美国的结构性种族主义和歧视，并加剧了粮食不安全和 6例SARS-CoV-2感染。怀孕期间的压力和逆境不仅会增加早产、生长发育的风险 7限制和婴儿死亡率，但它们也增加了产后孕产妇死亡和发病率的风险 8(即糖尿病、心脏病、抑郁症)。为了深入了解这些戏剧性变化的原因 9在人口层面的接触和易感性方面，我们建议由美国国立卫生研究院组织“参军” 10产妇死亡率工作队，由跨学科调查人员在种族和性别方面产生和分析数据 11个经济上不同的种群，处于不同的生殖阶段，具有不同的组织类型。我们会 12在以下方面扩展我们的R01(ES029336-03)研究：1)拓宽母体的定义 13在环境中暴露于内分泌干扰性化学品邻苯二甲酸酯，包括粮食不安全和 14不断变化的食品环境(与超加工和包装食品的消费相关， 15含有邻苯二甲酸盐)、产妇压力、结构性种族主义和歧视，以及接触SARS-CoV-2和 16母体-胎盘界面的相关免疫和炎症效应；2)检测一种新的内分泌 17轴，通过研究促性腺激素，连接母亲的下丘脑和垂体与胎儿的胎盘 18孕妇血清(产前/产后)和胎盘组织中；3)估计和比较直接和 母体产前暴露到母体的19条间接途径(通过胎盘-垂体促性腺激素) 20产后健康。产后健康将作为妊娠并发症(先兆子痫和 21高血压、妊娠期糖尿病和血糖调节、胎盘附着和早剥、早产和 22分娩时的胎龄)和产后第一年的随访措施(血糖水平， 23与体重增加和新陈代谢有关的人体测量，抑郁，焦虑，压力， 24歧视和粮食不安全)。我们将使用来自两个队列的现有R01数据(上行MPI Barrett， 25 O‘Connor和Magee CT Pi Simhan)来建立概念模型，并将该模型应用于 26匹兹堡的新冠肺炎大流行和SRD-收集了100例黑人和女性妊娠的新数据 27名白人女性，她们自2020年3月怀孕，自2020年6月分娩。总而言之，这项工作将 28洞察怀孕期间逆境的来源，这是黑人和/或怀孕期间独有的 29新冠肺炎大流行；并提供适用于97%的城市的公共卫生战略 30美国黑人妇女产后孕产妇死亡率

1 During pregnancy, the maternal brain and the fetal-placental unit are connected by way of an understudied 2 hypothalamic-pituitary-placental (HPP) axis. This axis may shed light on the differential effects of stress 3 exposure on maternal and fetal well-being complementing what we already know about the hypothalamic- 4 pituitary-adrenal (HPA) axis. The COVID-19 pandemic has aggravated the chronic maternal stressors arising 5 from structural racism and discrimination in the U.S., and has also heightened disparities in food insecurity and 6 SARS-CoV-2 infection. Stress and adversity in pregnancy not only increase risks of preterm birth, growth 7 restriction and infant mortality, but they also heighten risk of postpartum maternal mortality and morbidity too 8 (i.e., diabetes, heart disease, depression). To gain insight into the etiology of these dramatic changes in 9 exposure and susceptibility at the population level, we propose to ‘join the army’ organized by the NIH 10 Maternal Mortality Task Force, of interdisciplinary investigators generating and analyzing data in racially and 11 economically diverse populations, at different stages of reproduction, and in different tissue types. We will 12 extend our R01 (ES029336-03) research in the following ways: 1) to broaden the definition of maternal 13 environmental exposure to the endocrine disrupting chemicals phthalates to include food insecurity and 14 changing food environments (correlated with consumption of ultra-processed and packaged foods which 15 contain phthalates), maternal stress, structural racism and discrimination, and SARS-CoV-2 exposure and 16 related immune and inflammatory effects at the maternal-placental interface; 2) to examine a novel endocrine 17 axis that connects the maternal hypothalamus and pituitary with the fetal placenta by studying gonadotropins in 18 maternal serum (prenatal/postnatal) and in placental tissue; and 3) to estimate and compare the direct and 19 indirect pathways (through placental-pituitary gonadotropins) from maternal prenatal exposures to maternal 20 postpartum health. Postpartum health will be measured as pregnancy complications (preeclampsia and 21 hypertension, gestational diabetes and glucose regulation, placental accrete and abruptio, preterm labor and 22 gestational age at delivery) and by follow-up measures in the first year postpartum (glucose levels, 23 anthropometrics related to weight gain and metabolism, measures of depression, anxiety, stress, 24 discrimination and food insecurity). We will use existing R01 data from two cohorts (UPSIDE MPIs Barrett, 25 O’Connor and Magee CT PI Simhan) to establish a conceptual model, and apply this model to the context of 26 the COVID-19 pandemic and SRD in Pittsburgh with collection of new data from 100 pregnancies of Black and 27 White women, who conceived since March 2020 and delivered since June 2020. In sum, this work will 28 generate insight into sources of adversity in pregnancy, unique to being Black and/or pregnant during the 29 COVID-19 pandemic; and to offer a public health strategy applicable to a city at the 97th percentile of 30 postpartum maternal mortality among Black women in the U.S