Homocysteine: a role in fetal programming?

Developmental plasticity allows the generation of a number of phenotypes from a single genome (Gluckman & Hanson, 2004a). There is a substantial and growing body of evidence from epidemiological studies (Godfrey & Barker, 2001) and from animal models (Bertram & Hanson, 2001) that supports the hypothesis that constraints in the fetal environment, such as undernutrition, induce phenotypes with increased risk of cardiovascular and metabolic disease in later life; so-called fetal programming or phenotypic induction (Godfrey & Barker, 2001; Bateson et al. 2004; Gluckman & Hanson, 2004b). Gluckman & Hanson (2004b) suggest that the phenotype of the fetus reflects adaptations during development that predict the postnatal environment based upon signals from the mother. Phenotypes at increased risk of disease are due to a mis-match between the environment experienced in utero and the challenges of postnatal life (Gluckman & Hanson, 2004b). However, to some, this remains controversial (Huxley, 2006). There is an urgent need to identify the mechanism by which information about the maternal environment is transmitted to the fetus and how this is interpreted by the fetus to produce a particular phenotype in response to such developmental cues. Studies using the well-established model of a moderate reduction in dietary protein during pregnancy in the rat suggest that disruption of 1-carbon metabolism may contribute to one or both of these processes. Supply of methyl groups from donors such as glycine via 5-methyltetrahydrofolate (mTHF) is required for a number of critical pathways (for a review, see Muskiet, 2005). Supplementation of the maternal protein-restricted (PR) diet with glycine prevented hypertension in the adult offspring (Jackson et al. 2002; Brawley et al. 2004). This suggests that phenotypic induction in response to a maternal PR diet is closely associated with altered 1-carbon metabolism. Cellular differentiation during the development of the embryo involves stable suppression of transcriptionally silent genes by methylation of CpG dinucleotides in gene promoters (Bird, 2002). Such epigenetic regulation of gene expression requires the supply of methyl groups from mTHF via conversion of S-adenosylmethionine to S-adenosylhomocysteine (Muskiet, 2005). Lillycrop et al. (2005) showed that feeding a PR diet during pregnancy results in hypomethylation and increased expression of specific transcription factors, namely the glucocorticoid receptor (GR) and PPARa, which regulate energy homeostasis in the liver of the offspring. This suggests altered methylation of specific genes may be important in the induction in the offspring of a modified metabolic phenotype by maternal dietary constraint. Moreover, hypomethylation of GR and PPARa promoters was prevented by supplementation of the PR diet with folic acid. This suggests a causal link between 1-carbon metabolism, altered epigenetic regulation of gene expression and phenotypic induction. In this issue, Langley-Evans et al. (2006) point out that Bogdarina et al. (2004) did not find differences in the methylation of the glucokinase (GK) promoter in the liver of the offspring of dams fed a PR diet during pregnancy, although GK expression was increased, which questions the role of DNA methylation in phenotypic induction. One explanation of this apparent discrepancy may lie in the specificity of the control of gene expression by DNA methylation. Most genes are associated with CpG clusters known as islands, but in the majority of genes these CpG are always unmethylated and the level of expression is determined by the activities of various regulatory proteins such as transcription factors (Bird, 2002). Thus it may not be surprising that the expression of GK differed between offspring without a difference in methylation. Since GK is positively regulated by GR, increased GR activity in the liver of the offspring of rats fed a PR diet (Bertram et al. 2001; Lillycrop et al. 2005) alone may account for increased GK expression without a difference in the methylation status of the GK gene. If so, there would not be a discrepancy between the findings of Bogdarina et al. (2004) and Lillycrop et al. (2005). The important point is that in the liver of the offspring of the PR dams, transcription factors with numerous targets that are normally under stable suppression by DNA methylation are activated, presumably in a specific subset of cells as implied by Burns et al. (1997), thus changing the overall metabolic activity of the tissue. If disruption of 1-carbon metabolism is important for phenotypic induction by the PR diet, it might be hypothesised that this diet would be associated with increased homocysteine (Hcyst) concentration since folate is required for the remethylation of Hcyst to methionine (Muskiet, 2005). Exposure of the developing embryo to increased Hcyst concentration may contribute to induction of an altered phenotype by the PR diet as Hcyst directly modifies the activities of several important signal-transduction pathways and transcription factors (Malinow et al. 1993; Tsai et al. 1994; Dalton et al. 1997; Brown et al. 1998; Southern et al. 1998; Mujumdar et al. 2000; Woo et al. 2000; Nishimoto et al. 2003; Robert et al. 2005) and so may change the response of specific tissues to developmental cues. Two studies have reported measurements of maternal Hcyst concentration in pregnant rodents fed a PR diet. Petrie et al. (2002) found increased Hcyst concentration in serum from pregnant rats and mice fed a PR diet in early, but not British Journal of Nutrition (2006), 96, 415–417 DOI: 10.1079/BJN20061875 q The Author 2006