The epigenetic effects of being conceived during the Dutch Famine
During his introduction, Torsten discussed the Dutch Hunger Winter 1944/1945 as a ‘natural’ experiment with which the effects of undernutrition can be studied. This Dutch Famine was a period of 4 months during which the average caloric intake of many adults in urban areas was only about 800-1000 kcal/day, and predominantly carbohydrate based (e.g. sugar beets, bread). The study done on volunteer offspring of the victims of this natural experiment has shown that malnutrition of a mother during pregnancy can negatively affect the epigenetic programming of the child, the severity of which is timing-dependent.
In a similar ‘natural experiment’, the incidence of coronary heart disease between 1968–1978 has been studied in Wales. The Barker study, as it was called, found that a lower birth weight increased the chance of mortality due to heart disease.
Epigenetic modifications (such as DNA methylation, histone modifications and non-coding RNAs) are responsible play an important role in organismal development. Think of, for example, the difference between a caterpillar and a butterfly.
Fur color in agouti mice is influenced by maternal diet (Jirtle and Skinner, Nature Reviews Genetics, 2007), such that genetically identical mice can have a different fur color. The promotor of a viral gene has ended up before the Agouti gene and supplants the less activity autochtone promotor. (20% of our DNA has (retro)viral origin.)
At least 4 metastable epialleles (MEs) have been identified in models with undernutrition in Gambia and with tissue-specific methylation in caucasion/vietnamese Californians. During a follow-up study with Gambian women, blood plasma concentration in maternal blood during and after conception was tested. To determine a baseline for the amount of biomarkers, an indicator group was used, with 2000+ non-pregnant females at the beginning of the study, and 80 females for the rest of the study. (Torsten mentioned a possible bias in the study design: that the willingness of women to join the study might depend on their health background; sickly women would have something to gain from increased access to health care. He also mentioned that collaegues in Amsterdam are doing similar research with Muslim women during Ramadam.)
6/8 biomarkers that were tested in the Gambian follow-up study show a significant difference between conception during rain and dry season. Torsten: “It’s not easy to decide what to investigate next given that almost all investigated biomarkers show a marked increase/decrease, although they are all implicated in the same methyle pathways.” 7/8 MEs studied were copied from earlier studies. Epigenetic state of any tissue can be inferred from peripheral blood lymphocytes (PBLs) [mesoderm] and hair follicles (HFs) [ectoderm]. PBL and HF methylation states not significantly different. Earlier research in vietnam (on corpses) was done with liver tissue (autopsies). Children conceived in meager times (rainy season) have a higher methylation of the 6 MEs in both PBL and HF. Phenotypical consequences of these differences in methylation are unknown, making it, for now, unnecessary and unwise to supplement pregnant Gambians. One thing which is supplemented to pregnant women all over the world is folic acids, because the advantages are so huge.
[See Slide 8b for an overview by Torsten, adapted from Jimenez et al., Biochimie 2012, whereas Slide 7a–8a summarize the mechanisms they propose.]