Paternal grandparental exposure to crop failure or surfeit during a childhood slow growth period: Epigenetic marks on grandchildren’s growth, glucoregulatory and stress genes

Abstract

This latest in our series of papers describes transgenerational methylation related to midchildhood food availability in 19th century Överkalix, Sweden. Failed vs. bountiful crops differentially influenced methylation in grandchildren of paternal grandparents exposed to feast or famine during their Slow Growth Period (SGP), a sensitive period preceding the pre-pubertal growth spurt. In this case-study of 8 tracked 75-year old progeny with differential ancestral exposure, we found, in 40 posited gene ontology pathways, 39 differentially methylated CpG regions (DMRs) related to famine, excess food and food-insecurity stress, 9 of which with DMRs above 5%. Three gene ontology terms (GOs) “insulin processing”, “adipose development” and “hypothalamus development” were key, with DMRs >14%. An unbiased test of known pathways revealed four nuclear transcription factors upstream of promotors repressing the pathway following paternal grandparental famine experience, as well as 4 upregulated GOs with average DMRs >20%. We conclude that this is the first demonstration of human transgenerational inheritance of epigenetic marks following ancestral childhood exposure to variable food availability inducing early developmental origins of adult disease.

Intergenerational transmission of paternal trauma among US Civil War ex-POWs

“…Among 146 male probands in these studies, the estimated mortality hazard ratios on paternal over- and undernutrition, respectively, were a statistically significant 1.70 and a statistically insignificant 1.11 (a magnitude similar to ours) ( 20 ). A follow-up of eight descendants of the Överkalix study found that different geneontology pathways were implicated in paternal and maternal line transmission of nutritional stress ( 40 ). Although sexual dimorphism in developmental origins of health and disease is little understood, it is considered an outcome of both genetics and epigenetics ( 41 ).…”

The inheritance of cardiovascular disease risk

“…It also becomes apparent that epigenetic changes on the offspring can be mediated even in the early embryonic period, at a time when a couple does not know that they have conceived and are influenced by aspects of paternal behaviour, mediated by epigenetic effects on the sperm . The inheritance of cardiovascular and metabolic disease risk by epigenetic processes can be passed down to grand–offspring in both animal studies and human cohorts (see ), but the issue is controversial .…”