Prenatal stress and diet, and the fetal epigenome

Maternal stress and diet, and the fetal epigenome
Abstract
In children, a cluster of metabolic dysfunction including truncal obesity, hyperglycemia, and hyperlipidemia are
increasing in prevalence, disproportionately affect minority populations, and increase the risk for adverse long-
term outcomes. While genetic factors underlie some of this increase, these conditions also have a large
environmental component. Among suspected environmental contributors are prenatal stressors including
maternal depression and anxiety and chronic stress associated with adverse childhood experiences; the underlying
mechanisms remain poorly understood. One way in which genes and the in utero environment can interact to
trigger the initiation of disease is through epigenetic modifications. In fact, environmental exposures like social
stress can cause detectable long-term changes in pathways that contribute to appetite and satiety, nutrient
acquisition, metabolism, and fat deposition. However, the regions of the epigenome that are targeted by these
stressors remains unclear, primarily because available genome-scale array data are measured in DNA derived
from accessible tissues, such as blood—but epigenetic marks vary widely by cell type, and the measured cell
types may not be relevant to metabolic dysfunction. The exception is parent-of origin cytosine methylation marks
that control genomic imprinting, known as imprint control regions (ICRs). Methylation of these regions is
established early, before tissue specification, and therefore is similar across tissues. Aberrant methylation of ICRs
detectable in peripheral blood is implicated in numerous metabolic diseases, making ICRs promising targets for
investigations of metabolic diseases. Until recently, only 24 ICRs were known, limiting the scope of these
investigations. Our group recently identified the complete repertoire of DNA methylation marks that control
genomic imprinting; here, we seek to leverage these ICRs to identify methylation patterns associated with
metabolic dysfunction in children. We will test the hypothesis that prenatal stress substantially increases the risk
of cardiometabolic dysfunction among children, and that detectable epigenetic perturbations at ICRs mediate
these associations. We also will evaluate the extent to which anti-inflammatory diets such as the Mediterranean-
style diet modify these effects. We will leverage data and biological samples from our existing cohort resources
of the Newborn Epigenetics Study and Stress and Health In Pregnancy, where more than 750 women and their
children have been followed from 3 months gestation, and children now range in age from 2 to 15 years. We will
test the hypothesis that a Mediterranean-style diet prenatally, mitigates health effects of prenatal stress via
epigenetic mechanisms. This will provide much-needed data on the epigenetic fingerprint linking social stressors
to the cluster of metabolic outcomes in children, paving the way for clinical trials focused on dietary manipulation
to mitigate the effects of a wide variety of prenatal exposures.