Placental origins of phthalate-induced changes in fetal reproductive development

1在怀孕期间，母体大脑和胎儿-胎盘单位通过未被研究的方式连接起来。 2下丘脑-垂体-胎盘轴（HPP）。这条轴线可以揭示应力的不同影响 3暴露于母体和胎儿的健康补充了我们已经知道的下丘脑- 4垂体-肾上腺轴（HPA轴）。COVID-19大流行加剧了孕产妇的慢性压力， 5来自美国的结构性种族主义和歧视，还加剧了粮食不安全方面的差距， 6例SARS-CoV-2感染。怀孕期间的压力和逆境不仅会增加早产的风险， 7限制和婴儿死亡率，但它们也增加了产后产妇死亡率和发病率的风险 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病因， 9暴露和易感性在人群水平上，我们建议'加入NIH组织的大军' 10.产妇死亡率问题工作队，由跨学科调查人员组成，编制和分析种族和族裔方面的数据， 11个经济上不同的群体，在不同的繁殖阶段，在不同的组织类型。我们将 12.在以下方面扩展我们的R 01（ES 029336 -03）研究：1）扩大孕产妇的定义 13环境暴露于内分泌干扰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含有邻苯二甲酸酯），孕产妇压力，结构性种族主义和歧视，以及SARS-CoV-2暴露和 母体-胎盘界面的16种相关免疫和炎症效应; 2）检查一种新型内分泌 17轴连接母体下丘脑和垂体与胎儿胎盘通过研究促性腺激素在 18母体血清（产前/产后）和胎盘组织中;和3）估计和比较直接和 19种间接途径（通过胎盘-垂体促性腺激素）从母体产前暴露到母体 20产后健康产后健康将作为妊娠并发症（先兆子痫和 21例高血压、妊娠期糖尿病及血糖调节、胎盘植入及胎盘早剥、早产及 分娩时胎龄22）和产后第一年的随访测量（葡萄糖水平， 23项与体重增加和新陈代谢有关的人体测量，抑郁、焦虑、压力的测量， 24歧视和粮食不安全）。我们将使用来自两个队列的现有R 01数据（UPSIDE MPI Barrett， 25奥康纳和Magee CT PI Simhan）建立了一个概念模型，并将此模型应用于 26匹兹堡的COVID-19大流行和SRD，从100名黑人和 27名白色女性，自2020年3月起怀孕，自2020年6月起分娩。总之，这项工作将 28深入了解怀孕期间的逆境来源，这是黑人和/或怀孕期间所独有的。 29 COVID-19大流行;并提供适用于城市第97百分位数的公共卫生战略， 30美国黑人妇女的产后孕产妇死亡率

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