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Epigenetic mechanisms of perinatal programming of hypothalamic-pituitary-adrenal function and health

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Environmental effects on the materno–foetal interaction determine birth outcomes that predict health over the lifespan. Thus, maternal undernutrition or stress associate with low birth weight, leading to an increased risk of metabolic and cardiovascular illness in the offspring. We argue that these effects are, in part, mediated by direct and indirect effects on the hypothalamic-pituitary-adrenal (HPA) axis such that (i) the effect of maternal adversity on foetal growth is mediated by adrenal glucocorticoids and (ii) environmental adversity alters maternal physiology and behaviour, which then programs HPA activity in the offspring.

Section snippets

The developmental origins of disease

Environmental influences during development produce sustained effects on cellular function and physiology; these effects in turn appear to form the basis for the developmental origins of vulnerability to chronic disease. Environmentally induced, stable phenotype modifications that are adaptive in earlier phases of the life cycle ultimately pose a risk of disease in the later stages of life. Although this may seem paradoxical, it is important to understand that success in the context of natural

Birth weight and foetal programming

Low birth weight is associated with an increased risk of hypertension, insulin resistance, type 2 diabetes and cardiovascular disease (e.g. 1, 2, 3). The association between birth weight and cardio-metabolic disease in later life is largely independent of classical lifestyle risk factors (e.g. smoking, excess alcohol intake, sedentary life), which are additive to the effect of birth weight. Importantly, the relationship between low birth weight and adult disease is broadly continuous across

Glucocorticoids and foetal growth

Glucocorticoid treatment during pregnancy reduces birth weight in animal models, including non-human primates, and humans 11, 12, 13, 14, 15. The effect is most notable in late pregnancy when foetal growth is accelerated. The catabolic glucocorticoids block growth mediators, such as insulin-like growth factor I [4]. Human foetal-blood cortisol levels are increased in intrauterine growth retardation, implicating endogenous cortisol in retarded foetal growth [16].

Glucocorticoid receptors (GRs),

Placental 11β-HSD-2 and birth weight

A deficiency of 11β-HSD-2 with reduced placental inactivation of maternal steroids can lead to overexposure of the foetus to glucocorticoids, retard foetal growth and program physiology 4, 5, 6, 7. Thus, lower placental 11β-HSD-2 activity in rats is associated with smaller foetuses [18]. Similar associations are reported in humans 16, 24, 25, 26, 27. Additionally, cord-blood levels of osteocalcin (a glucocorticoid-sensitive osteoblast product that does not cross the placenta) and other markers

Cardiovascular and metabolic programming

Dexamethasone treatment of pregnant rats reduces birth weight and elevates blood pressure in adult offspring [31]. Similarly, adult hypertension develops in sheep exposed to excess glucocorticoid in utero through either maternally administered dexamethasone or cortisol [32]. Inhibition of 11β-HSD by treatment of pregnant rats with carbenoxolone causes increased passage of maternal corticosterone to the foetal circulation and reduces birth weight 33, 34. Prenatal carbenoxolone-exposed rats

Programming of glucose–insulin homeostasis and metabolism

Prenatal overexposure to glucocorticoids during the final trimester of gestation programs hyperglycemia and hyperinsulinemia in adult rats 12, 34. Prenatal stress or inhibition of 11β-HSD have similar effects [41]. Maternal glucocorticoid administration alters cord glucose and insulin levels in the sheep foetus [42], and these effects persist into adulthood. In the sheep, antenatal glucocorticoid exposure alters adult glucose metabolism whether or not there is prior foetal growth restriction.

‘Thrifty phenotype’ hypothesis

The ‘thrifty phenotype’ hypothesis [60] suggests that the alterations in cardiovascular and metabolic activity associated with prenatal adversity (stress, undernutrition) and enhanced glucocorticoid exposure are adaptations that serve to ‘prepare’ the organism for conditions of reduced nutrient supply and/or increased metabolic demand. Such effects are viewed as anticipatory preparation for future demands [4]. Whether such alterations in phenotype occur uniquely as a function of adaptations on

Programming of stress responses

Activation of the HPA axis and the sympathetic catecholamines mobilizes energy substrates during a period of metabolic demand and increases blood flow to vital organs. Glucocorticoids also protect against sepsis. Glucocorticoids and catecholamines alter CNS function, enhancing the cognitive processing of and memory for stimuli associated with a stressor and thus increasing the animal's ability to acquire avoidance responses. These are obviously adaptive responses, and for individuals faced with

Postnatal programming

Prenatal programming effects derive from environmentally induced alterations of materno–foetal signalling, involving systems that determine foetal glucocorticoid exposure. Foetal glucocorticoid exposure, in turn, influences adult metabolism as well as HPA function. However, the impact of prenatal factors is determined by postnatal influences. The risk of adulthood obesity associated with foetal growth retardation depends upon the degree of postnatal catch-up growth. Similarly, the effects of

Molecular mechanisms for maternal effects on HPA responses to stress

Results of in vitro and in vivo studies 77, 78, 79 suggest that the effects of maternal LG on hippocampal GR expression are mediated by increases in serotonin (5-HT) turnover and hippocampal expression of the transcription factor nerve-growth-factor-inducible factor-A (NGFI-A). In vitro, 5-HT increases GR expression in cultured hippocampal neurons, and the effect of 5-HT is blocked by concurrent treatment with an antisense oligonucleotide directed at the NGFI-A mRNA [80]. The 5′ non-coding

Epigenetic programing of HPA stress responses

Recent studies address the possibility that environmental events might alter chromatin structure through effects on DNA methylation (see Box 3) and thus affect GR gene expression. Weaver et al. 69, 73, 80 examined the methylation status of individual CpGs in the exon 17 sequence; they focused on the NGFI-A consensus sequence that contains two CpG dinucleotides sites, which are potential targets for methylation. The results reveal significant differences in cytosine methylation within the 5′ CpG

Conclusion

Finally, it is important to note that parental effects on the expression of defensive responses, such as increased HPA activity, are a common theme in biology [85]. Such effects may represent examples where the environmental experience of the parent is translated through an epigenetic mechanism of inheritance into phenotypic variation in the offspring. Indeed, parental effects could result in the transmission of adaptive responses across more than a single generation. This same theme is clearly

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