Outlier DNA methylation levels as an indicator of environmental exposure and risk of undesirable birth outcome

Abstract

We have identified a novel molecular phenotype that defines a subgroup of newborns who have highly disrupted epigenomes. We profiled DNA methylation in cord blood of 114 children selected from the lowest and highest quintiles of the birth weight distribution (irrespective of their mode of conception) at 96 CpG sites in genes we have found previously to be related to birth weight or growth and metabolism. We identified those individuals in each group who differed from the mean of the distribution by the greatest magnitude at each site and for the largest number of sites. Such 'outlier' individuals differ substantially from the rest of the group in having highly disrupted methylation levels at many CpG sites. We find that children from the lowest quintile of the birth weight distribution have a significantly greater number of disrupted CpGs than children from the highest quintile of the birth weight distribution. Among children from the lowest quintile of the birth weight distribution, 'outlier' individuals are significantly more common among children conceived in vitro than children conceived in vivo. These observations are novel and potentially important because they associate a molecular phenotype (multiple and large DNA methylation differences) in normal somatic tissues (cord blood) with both a prenatal exposure (conception in vitro) and a clinically important outcome (low birth weight). These observations suggest that some individuals are more susceptible to environmentally mediated epigenetic alterations than others.

Alteration in the expression of the renin-angiotensin system in the myocardium of mice conceived by in vitro fertilization†

“…Sustained changes in the expression of COL1 and COL3 in adulthood would further increase the risk of cardiovascular diseases, such as hypertension, arrhythmia, and cardiac hypertrophy, and enhance the process of cardiovascular fibrosis and remodeling [26]. The effects of ART on genome-wide changes in DNA methylation levels have been confirmed by several studies [64][65][66]. For instance, ART-conceived mice showed arterial tissue endothelial dysfunction and increased DNA methylation of the promoter of the eNOS gene [15].…”

RW‐2018—Research Workshop: The Effect of Nutrition on Epigenetic Status, Growth, and Health

“…However, the magnitude of these differences is small in comparison to population‐level variability. Careful analysis of such population‐level variability suggests that normal individuals differ strongly in their susceptibility to exposure‐mediated epigenetic “disruption.” This in turn suggests that true and measurable effects of environmental factors on epigenotype are most likely to be observed at the extremes of the intersection of environmental risk factors and human population variability . Careful analysis of such “outlier” populations is most likely to shed light on the molecular mechanisms by which suspected environmental risk factors are able to drive the epigenetic processes involved in disease risk.…”

“…By focusing on the outliers to understand the role of the epigenome in recording undesirable environmental exposures (and especially poor nutrition exposures), one may need tens of thousands of subjects to study because outliers constitute such a small fraction of the individuals in any disease phenotype of interest. However, focusing on the extremes of the exposures (ie, famine or extreme obesity if we are considering nutrition as an exposure) might allow insight into the mechanisms by which the exposures mediate less grievous effects in the general population …”

“…This in turn suggests that true and measurable effects of environmental factors on epigenotype are most likely to be observed at the extremes of the intersection of environmental risk factors and human population variability. 35 Careful analysis of such "outlier" populations is most likely to shed light on the molecular mechanisms by which suspected environmental risk factors are able to drive the epigenetic processes involved in disease risk. Consistent with the expectation that not all individuals are equally susceptible to individual environmental exposures or that all environmental exposures are not equally disruptive to the epigenome, 36,37 such normal tissue epigenetic "outliers" are found among colorectal cancer patients examined in The Cancer Genome Atlas (TCGA) population.…”

“…However, focusing on the extremes of the exposures (ie, famine or extreme obesity if we are considering nutrition as an exposure) might allow insight into the mechanisms by which the exposures mediate less grievous effects in the general population. 35…”