A model system to study the inheritability of structural racism and discrimination through epigenomics

ABSTRACT Structural racism and discrimination (SRD) is a salient mechanism perpetuating racial gaps in health. Emerging 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 AA mothers

and infants. Often an underexplored population, women during the preconception period are a critical group impacting this disparity, as exposures during pre-pregnancy period significantly impact the mother-infant dyad across the lifespan. In particular, studies document that the pervasive and lasting impact of chronic stressors

due to SRD, may affect AA women of childbearing age by creating a “weathering” effect, that is associated with inflammation and distinct epigenetic patterns, which can lead to deleterious outcomes postconception. There is a critical need to explore the etiologic pathways during the pre-pregnancy period that are influenced by SRD-

related trauma and contribute adverse outcomes in the mother-infant dyad. Trauma/stress exposure can impact the health of individuals from historically marginalized groups through modifications to the epigenome, which can induce changes in gene expression affecting the regulation of physiologic responses including endocrine, immune, cardiovascular systems, etc. Considering AA women

carry a disproportionate burden of incidence, morbidity, and mortality from chronic diseases, it is important to examine how preconception trauma from SRD alters the epigenome in women of childbearing potential. These stress-induced epigenetic modifications can be carried forward through the germline, to the potential detriment

of successive generations. Thus, we hypothesize that elevated SRD-related stress in AA women is associated with epigenetic signatures of inflammation and innate immune dysfunction during the preconception period, promoting a suboptimal environment for pregnancy. These distinct epigenetic alterations will be inherited in the

offspring via specific germline differentially methylated regions. This proposal will leverage an ongoing R01 to investigate the impact of SRD-related stress on women prior to conception and we will include a longitudinal cohort of mother-infant pairs from early gestation to 12-months following delivery to evaluate the transmission

of SRD-related epigenetic signatures from mother-to-child. Three specific aims are proposed: 1) To determine the burden of structural racism and discrimination on stress, systemic inflammation, and epigenetic signatures among preconception AA women and 2) To define the longitudinal impact of maternal SRD-related stress on

the inheritance of distinct epigenetic signatures in the offspring. This proposal offers an exceptional opportunity to understand the etiology of adverse pregnancy outcomes in AA women and identify the biomarkers and mechanisms that underlie the lasting biological effect of SRD, as these correlates impact not

only at an individual level but also generational.