Ancestral influences on health of grandchildren

Abstract: The late effects in adulthood of nutrition during adolescence, childhood, infancy, and the fetal and embryonic stages of development have attracted much attention in research, but less so the time of development of the genome. The issue of fetal origins of adult disease has particularly attracted interest. The effects are caused by nutritional constraints at critical phases of key fetal organ development. The general question pursued here is whether there are transgenerational effects. It is suggested that nutrients transiently influence the expression of specific subsets of genes during the slow growth period just before the prepubertal peak in growth velocity of children. Food availability during the slow growth period (SGP) just before the prepubertal peak in growth velocity of the paternal grandfather exerted an effect on longevity of their grandchildren (Paper I). Scarcity of food in the paternal grandfather's SGP was associated with extended survival of his grandchildren, whilst food abundance was associated with shortened life span of the grandchildren. One explanation was genomic imprinting, an intergenerational "feedforward" control loop linking grandparental nutrition with the grandchild's growth. Cardiovascular and diabetes related deaths were the outcomes. It was showed that cardiovascular mortality was reduced with poor availability of food in the father's SW, but also with good availability in the mother's SGP (Paper II). If the paternal grandfather was exposed to a surfeit of food during his SW, the proband had a fourfold excess mortality related to diabetes (OR 4.1, 95% c.i. 1.33-12.9 p=0.01) when age at death and the effects of parents and other grandparents exposure to food availability during their SGP were taken into account. A father's exposure to a surfeit of food during his SW, on the other hand, tended to protect the proband from diabetes. The effects were sex-specific; the paternal grandfather's food supply during the SGP was only linked to the mortality of grandsons, whilst paternal grandmother's food supply was only associated with the granddaughter's mortality (Paper Ill). Onset of paternal smoking during the SGP was associated with shorter mean gestational length of sons, but not of daughters. This indicates the existence of an inheritance with the sex-specific patterns of transmission suggesting a direct role for the Y chromosome and possible the X chromosome. Finally, the transgenerational sex-specific paternal grandpaternal/ grandchild effects and the effects of the proband's own early life circumstances were analysed (Paper IV). The transgenerational influence remained and the social circumstances were found important for the longevity of probands. In conclusion, the study explored the possible transgenerational effects from exposures occurring during the SGP prior to the prepubertal peak growth velocity. Such exposures seemed to influence gene expression in the next generation(s).