Fat dads must not be blamed for their children's health problems

Good examples of epigenetic syndromes are the rare imprinted human growth disorders Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS), where IGF2 and H19 methylation are mechanistically implicated and are considered to be functionally important [7]. It now seems evident that disruption to epigenetic marks, such as DNA methylation or histone modifications, can affect the structure of chromatin and, therefore, the binding of transcription factors and other regulatory proteins [8]. DNA methylation is relatively easy to study from stored DNA samples and generally involves making comparative assessment of the methylation variation at CpG islands, promoters or differentially methylated regions (DMRs) between control and experimental groups of subjects. Importantly, there are both tissue- and age-specific methylation profiles and for many such marks, there is a high level of intra- and inter-individual variation that appears to have no phenotypic consequence. Caution must, therefore, be employed when analyzing these data. It is clear that more detailed and carefully controlled studies will be necessary to gain a complete understanding of key methylated marks and their variation relevance to development and disease [9].

There have been many studies investigating the effect of human placental expression of IGF2 and its receptors on fetal growth. Given the limitations of this type of study it is not surprising that they are usually confined to samples obtained at the time of birth. Unfortunately, many of these studies seem to report conflicting results. For example, in one study no correlation was reported between IGF2 expression and birth weight [10], whereas others have shown that in small for gestational age (SGA) babies' pregnancies, IGF2 expression is either increased [11], or decreased [12], including at the protein level [13]. Nevertheless, it seems likely that IGF2 should play an important role in dictating fetal growth, even though this effect may not be reliably detected in term placenta.

In the study by Soubry et al. [14], the authors assess the relationship between the physiological body mass index (BMI) or obesity status of the parents with the level of methylation seen for the IGF2 and H19 gene DMRs in the leucocytes from cord blood of their newborns (n = 79). They find an association between the father's obesity status and the loss of methylation at the DMR linked to IGF2 but not the H19 DMR . The main caveats of this study are the small numbers and the mixture of ethnicities. In addition, it has not been shown in this study whether a small change in methylation (in this case, 4 to 5%) at a DMR has any truly functional significance at the phenotype level. The authors point to their previous finding that a 5% loss of methylation could lead to a 10% increase in serum concentration of IGF2 [15]. While it seems feasible that this might have both short and longer term consequences for health, it has not as yet been associated with an actual change to fetal growth. The Soubry et al. [14] study, for example, found no correlation between methylation or parental obesity and birth weight. Nevertheless, this study provides the first evidence that hypo-methylation of the regulatory control region for IGF2 is influenced by increased paternal BMI and the study makes a compelling case for a larger analysis to be performed. It is surprising and counter intuitive to note that a similar effect of hypomethylation on the IGF2 DMR is seen both for paternal obesity and maternal preconceptual famine [16]. One might assume that the father's BMI was also affected by the famine.