The Impact of Transgenerational Racial Trauma on Epigenetic Modifications in the Mother-Infant Dyad during Pregnancy. Comparisons Between Caucasian and African American Populations

项目摘要 结构性种族主义和歧视(SRD)从一开始就是美国的历史遗产 1619年对非洲人的奴役进入种族隔离时代(《吉姆·克罗》)，这一时代以文人和 投票权法案。种族创伤的生物影响隐藏在人们的视线中。有越来越多的人 认识到SRD是一种突出的机制，在非裔美国人中延续种族健康差距。在……里面 特别是，研究记录了SRD对负面妊娠结局的影响，包括更高的发生率。 非裔美国人(AA)妇女的早产和黑人母亲较高的死亡率 婴儿。在母婴健康方面的这些种族差异是普遍存在的，即使在考虑到社会- 经济地位和受教育程度；并已被证明是代代相传的，可能是通过表观遗传 影响。在这项研究中，我们试图调查种族和跨代SRD相关创伤的影响。 在再生障碍性贫血妇女中，母亲-胎儿界面上的不同表观遗传改变与改变有关 胎盘和发育中胎儿中免疫细胞的发育、激活和信号传递。研究表明， 胎盘可能是母体跨代表观遗传的门户。越来越多的证据 表明子宫内表观遗传变化的影响不仅仅是影响母亲和孩子，而且是 通过成年期延续到生殖系，对后代不利。烦躁不安的胎盘 表观遗传学与宫内生长受限、早产和先兆子痫有关，这些都是 再生障碍性贫血中婴儿死亡率的驱动因素。研究表明种族与胎盘炎有关 病理学。此外，由于跨代创伤造成的高应激率与慢性 胎盘发炎和不良妊娠结局。然而，形成的生物特性 妊娠结局的差异仍不得而知。我们假设与SRD相关的创伤是通过 跨世代和表现为表观遗传模式，促进炎症和先天 胎盘和胎儿的免疫功能障碍。提出了三个具体目标：1)评估负担 SRD对AA孕妇的母体压力、全身炎症和表观遗传学特征的影响；2) 对AA和CA的胎盘进行转录、表观遗传学和免疫学比较分析 孕妇以确定与SRD相关压力相关的特定变化；以及3)在子宫内进行调查 再生障碍性贫血新生儿免疫反应的程序化和特定表观遗传特征的遗传 暴露在与SRD相关的母亲压力之下。SRD对胎盘表观遗传学改变的生物学影响 可能会增加早产和婴儿期不良后果的风险。 这些研究可能会为未来的干预措施提供信息，以应对此类健康风险，并可以促进健康和健康- 有风险的母婴配对。

Project Summary Structural racism and discrimination (SRD) have remained a historical legacy of the U.S. from the beginning of enslavement of African populations in 1619 to the era of apartheid (“Jim Crow”), which ended with the Civil and Voting Rights Acts. Hidden in plain sight is the biological impact of racial trauma. There is an increasing awareness that SRD is a salient mechanism perpetuating racial gaps in health among African Americans. In particular, studies have documented the impact of SRD on negative pregnancy outcomes, including higher rates of preterm birth among African American (AA) women and higher rates of mortality among Black mothers and infants. These racial disparities in maternal and infant health are pervasive even after accounting for socio- economic status and education; and have been shown to persist transgenerationally, possibly via epigenetic influences. In this study, we seek to investigate the impact of race and transgenerational SRD-related trauma among AA women on distinct epigenetic modifications at the maternal-fetal interface that are linked to altered immune cell development, activation, and signaling in the placenta and developing fetus. Studies suggest that the placenta may be the gateway of maternal transgenerational epigenetic inheritance. Mounting evidence suggests the effects of in utero epigenetic changes go beyond influencing the mother and the child, and are carried forward through adulthood into germline, to the detriment of successive generations. Perturbed placental epigenetics is associated with intrauterine growth restriction, preterm birth, and pre-eclampsia, which are the drivers of infant mortality among AA. Studies demonstrate race is associated with placental inflammatory pathology. In addition, high rates of stress due to transgenerational trauma have been associated with chronic inflammation at the placenta and poor pregnancy outcomes. However, the biological properties that shape disparities in pregnancy outcomes remain unknown. We hypothesize that SRD-related trauma is transmitted across generations and manifests with epigenetic inheritance patterns that promote inflammation and innate immune dysfunction in the placenta and fetus. Three specific aims have been proposed: 1) Evaluate the burden of SRD on maternal stress, systemic inflammation, and epigenetic signatures among AA pregnant women; 2) Perform comparative transcriptional, epigenetic, and immunological profiling of placentae from AA and CA pregnant women to identify specific alterations associated with SRD-related stress; and 3) Investigate in utero programming of immune responses and the inheritance of specific epigenetic signatures in AA neonates exposed to maternal SRD-related stress. The biological impact of SRD on epigenetic alterations at the placenta may contribute to increased vulnerability towards preterm birth and adverse outcomes in infancy and childhood. These studies may inform future interventions to address such health risks and can promote the health and well- being of at-risk mother-infant pairs.