The developmental environment, epigenetic biomarkers and long-term health.

Evidence from both human and animal studies has shown that the prenatal and early postnatal environments influence susceptibility to chronic disease in later life and suggests that epigenetic processes are an important mechanism by which the environment alters long-term disease risk. Epigenetic processes, including DNA methylation, histone modification and non-coding RNAs, play a central role in regulating gene expression. The epigenome is highly sensitive to environmental factors in early life, such as nutrition, stress, endocrine disruption and pollution, and changes in the epigenome can induce long-term changes in gene expression and phenotype. In this review we focus on how the early life nutritional environment can alter the epigenome leading to an altered susceptibility to disease in later life.

Prenatal famine exposure, health in later life and promoter methylation of four candidate genes.

Poor nutrition during fetal development can permanently alter growth, cardiovascular physiology and metabolic function. Animal studies have shown that prenatal undernutrition followed by balanced postnatal nutrition alters deoxyribonucleic acid (DNA) methylation of gene promoter regions of candidate metabolic control genes in the liver. The aim of this study was to investigate whether methylation status of the proximal promoter regions of four candidate genes differed between individuals exposed to the Dutch famine in utero. In addition, we determined whether methylation status of these genes was associated with markers of metabolic and cardiovascular disease and adult lifestyle. Methylation status of the GR1-C (glucocorticoid receptor), PPARγ (peroxisome proliferator-activated receptor gamma), lipoprotein lipase and phosphatidylinositol 3 kinase p85 proximal promoters was investigated in DNA isolated from peripheral blood samples of 759 58-year-old subjects born around the time of the 1944-45 Dutch famine. We observed no differences in methylation levels of the promoters between exposed and unexposed men and women. Methylation status of PPARγ was associated with levels of high-density lipoprotein cholesterol and triglycerides as well as with exercise and smoking. Hypomethylation of the GR promoter was associated with adverse adult lifestyle factors, including higher body mass index, less exercise and more smoking. The previously reported increased risk of cardiovascular and metabolic disease after prenatal famine exposure was not associated with differences in methylation status across the promoter regions of these candidate genes measured in peripheral blood. The adult environment seems to affect GR and PPARγ promoter methylation.

No reduction in birth weight in phenylketonuria.

Birth weight in a total of 1886 British infants with phenylketonuria (PKU) born between 1964 and 1992 was examined in relation to sex, social class, gestational age, disease severity and birth year. Comparisons were made with two national surveys (British births 1970 and Office of Population Censuses and Surveys 1981). In contrast to a recent Dutch study, birth weight in British infants with PKU (mean 3307 g, median 3337 g) showed a similar distribution to population norms. Birth weight showed no temporal trends and no trends with disease severity. CONCLUSION. Birth weight is not reduced in British infants with PKU.

Intelligence in mild atypical phenylketonuria.

In 82 children with mild phenylketonuria (PKU) (blood phenylalanine (Phe) concentrations consistently below 900 mumol/l throughout follow up) the relationship between intelligence at age 4 (IQ by Stanford-Binet) and average blood Phe concentrations from birth to 4 years was examined. Of the 82 children 24 had received no treatment. In the group as a whole, and in the 24 untreated subjects alone, mean IQs were significantly below population norms, with deficits of approximately 4.5 points and 9 points respectively. After allowing for social class IQ fell progressively by approximately 6 points for each 100 mumol/l rise in mean Phe concentrations in both the treated and untreated subjects. This relationship resembled that previously reported in early treated children with more severe forms of PKU, except that the scale of the relationship was even greater. We conclude that all children whose blood Phe concentrations reach 400 mumol/l or above should receive a low Phe diet, at least during the preschool years, and that the aim should be to control blood Phe levels below 400 mumol/l throughout early childhood in all forms of PKU.

Outcome of treatment in young adults with phenylketonuria detected by routine neonatal screening between 1964 and 1971.

Intellectual status at 18 years is reported in 192 patients with phenylketonuria born in the UK between 1964 and 1971, together with their school progress. Mean IQs expressed as standard deviation scores (IQ-SDS) were significantly below estimated population norms, and showed a small decrease from 14 to 18 years of age (mean IQ-SDS -1.06 +/- 1.3 at 14 years and -1.28 +/- 1.07 at 18 years, t = 5.7, p < 0.0001). At 18 years, 27% of subjects had IQs over 2 SDs below the estimated population mean. IQ-SDS at 18 years, although significantly related to average phenylalanine control both between birth and 14 years, and between 14 and 18 years, was not independently related to either variable after allowing for IQ-SDS at 14 years. We conclude that general ability in young adults with early treated phenylketonuria, although reduced in comparison with their peers and closely related to phenylalanine control in early childhood, is not directly influenced by phenylalanine control in the four years preceding the 18th birthday. The apparent fall in IQ-SDS between 14 and 18 years may be due to methodological problems in the analysis of longitudinal IQ data without a control group, rather than providing evidence of intellectual decline.