The developmental origins of health and disease (DOHaD) hypothesis predicts that environmental exposures experienced early in life have the potential to modify the risk associated with later-onset disease. The DOHaD hypothesis is supported by a large number of direct animal studies and a smaller number of compelling observational studies in humans, but the mechanism(s) underlying the ‘programming' effects of DOHaD remain largely unclear. Given the inherent property of environmental sensitivity, the demonstrated role in gene regulation, and the capacity for stable maintenance over time once established, epigenetic variation has rapidly emerged as a candidate mediator of such effects. However, little direct evidence exists in humans, primarily due to the inherent problems associated with unraveling the relative contributions of genetic and environmental influences to phenotypic outcomes. Robust evidence is required in several domains to establish epigenetic variation in the causal pathway to DoHAD-associated disease. Firstly, interindividual epigenetic variability in response to specific early-life environmental exposures needs to be demonstrated. Further, compelling data linking specific epigenetic variants to specific disease(s) is needed. Epigenetic variation should be apparent in a tissue relevant to the disease of interest prior to phenotypic onset in order to avoid confounding and the potential for reverse causation. Finally, the functional relevance of specific epigenetic change must be demonstrated. Compelling evidence is mounting in each of these domains but remains somewhat fragmented, providing small pieces of the overall complex puzzle. It is likely that only large longitudinal life course studies commencing prior to birth, with extensive environmental exposure data and biospecimens, can provide direct evidence in support of a role of epigenetic processes as drivers of the DOHaD in humans.

Keywords:
Developmental origins of health and disease, Fetal programming, Pregnancy, Complex disease, Epigenetics, DNA methylation, Diet, One-carbon metabolism, Epigenome-wide association studies
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