Fetal Origins of Adult Disease Hypothesis
While epigenetic changes may occur throughout life, embryogenesis is thought to be the period with the highest vulnerability. Epigenetics is providing a missing link to understand the ability of adverse conditions, acting during intrauterine development, to shape the risk of adult-onset diseases that clinically start decades later.
This relationship, known as the fetal origins of adult disease hypothesis, or the Barker hypothesis, was first published in 1992 and subsequently confirmed epidemiologically for several health conditions. Studies on women prenatally exposed to famine during the Dutch Hunger Winter at the end of World War II revealed that nutritional deprivation, when occurring at critical intrauterine developmental stages, may cause epigenetic changes that shape the risk of specific adult-onset diseases in the fetus.
Timing appears to be crucial, because exposure during critical windows of development was associated with specific disorders later in life. Recent years revealed that other types of exposures during intrauterine development, including nutritional compounds, maternal cigarette smoking, environmental polycyclic aromatic hydrocarbons, and endocrine-disrupting chemicals, may cause epigenetic changes in the fetus.
These changes include aberrant DNA methylation, histone post-translational modifications, and microRNA dysregulation, and shape disease risk later in life.
The possibility to transmit epigenetic modifications across several generations, a phenomenon known as transgenerational epigenetic inheritance, is emerging from animal and human studies. Vinclozolin, a fungicide used in the wine industry, whose two major metabolites are anti-androgenic compounds, was shown, in an animal model, to act at the time of embryonic sex determination and cause epigenetic modifications in the male germ cell line.
These inherited modifications, occurring at multiple locations throughout the sperm epigenome, increased the risk of diseases for at least three generations after the initial exposure. Evidence is also accumulating for the ability of diethylstilbestrol, a nongenotoxic synthetic estrogen that decades ago was prescribed to prevent miscarriages, to cause transgenerational epigenetic effects.
Animal studies revealed that this compound alters DNA methylation, and the increased susceptibility for adverse health effects appears to be transmitted across several generations though the maternal and, as some studies reveal, paternal germ cell lineage, and human studies showing transgenerational inheritance are attracting considerable attention.