Do the effects of orenatal famine exposure pass down generations? An epigenitic study.

Background: Poor nutrition during fetal development can permanently alter
growth, cardiovascular physiology and metabolic function. These alterations are
detrimental for cardiovascular health in later life. Animal studies
consistently find that prenatal undernutrition leads to hypertension,
dyslipidaemia and disturbed glucose tolerance as well as reduced lifespan.
Supported by 2 previous NHS grants, we have provided the first evidence in
humans that maternal undernutrition during gestation leads to a striking 2-fold
increase in cardiovascular disease in the offspring, in the Dutch famine birth
cohort.
Animal studies have recently started to unravel the underlying molecular
mechanisms. Poor intrauterine nutrition leads to persistent alterations to the
epigenetic regulation of specific genes, which give rise to altered expression
of a range of genes which may raise cardiovascular risk. Epigenetic alterations
have recently been identified to feature in cardiovascular disease, and are
thus likely to underlie many of the permanent effects of maternal
undernutrition on the offspring's health. Moreover, animal studies have
demonstrated that epigenetic alterations can be transmitted to subsequent
generations even when female offspring of the F1 generation were not exposed to
nutritional constraint during pregnancy and, importantly, that these
alterations are linked to a phenotype with increased cardiovascular risk.
The Dutch famine birth cohort presents a unique opportunity to resolve the
question of whether differences in the epigenetic regulation of genes are
induced by variations in maternal diet during pregnancy and whether these
epigenetic marks are associated with differential risk of cardiovascular
disease in future generations. Preliminary evidence from our study suggests
that the increase in cardiovascular disease may be conveyed to the offspring of
men and women who were exposed to famine in utero.

Objective: We aim to assess whether [1] epigenetic alterations are responsible
for the detrimental effects of maternal undernutrition during gestation on the
offspring*s (F1) cardiovascular health, and [2] these epigenetic alterations
pass down generations through epigenetic inheritance and are associated with
excess cardiovascular risk (F2).

Design and study population: To address aim 1, we will study the methylation
status of specific candidate genes in 793 members of the Dutch famine birth
cohort (F1). We will assess whether famine exposure in utero can induce
alterations in gene methylation status. Aim 2 will be addressed by carrying out
a study among 3 generations: women (F0) who were pregnant around the time of
the Dutch famine 1944-45 who delivered in the Wilhelmina Gasthuis Amsterdam,
their children (F1) and their grandchildren (F2). We will assess DNA
methylation as well as gene expression of the candidate genes in 80
grandmother-parent-child sets. Additionally, we will investigate the
cardiovascular risk profile in the F2 in order to study the intergenerational
effects of famine exposure on a functional level.
This study will test the hypothesis that epigenetic alterations, induced by
maternal undernutrition during gestation, are associated with a rise in
cardiovascular disease risk.

The burden for the participants consists of a buccal swab and completing a
questionnaire (estimated time 1 hour). Both procedures are safe and pain free.