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2000) and mice (Cole et al., 1995), most within a transcriptionally active ˜CpG
165 Prenatal glucocorticoids and the programming of adult disease


island™. All these mRNA species give rise to the same receptor protein, as only exons
2“9 encode the protein. The alternate untranslated ¬rst exons are spliced onto the
common translated sequence beginning at exon 2. In the rat, two of the alternate
exons are present in all tissues which have been studied; however, others are tissue
speci¬c (McCormick et al., 2000). This permits considerable complexity of tissue-
speci¬c variation in the control of GR expression and, potentially programming.
The tissue-speci¬c ¬rst exon usage appears to be altered by perinatal environ-
ment manipulations (McCormick et al., 2000). Indeed, handling permanently pro-
grammes increased expression of only one of the six alternate ¬rst exons (exon 17)
utilized in the hippocampus (McCormick et al., 2000). Exon 17 contains sites appro-
priate to bind the very third messenger/intermediate early gene transcription fac-
tors (AP-2, NGFI-A) induced by the neonatal manipulation (Meaney et al., 2000).
In contrast, prenatal dexamethasone exposure, which increases hepatic GR expres-
sion, decreased the proportion of hepatic GR mRNA containing the predominant
exon (exon 110), suggesting an increase in a minor exon 1 variant (McCormick et al.,
2000). Such tissue speci¬city of promoter usage may help explain why prenatal dex-
amethasone programmes increased adult GR expression in the periportal zone of
the liver and in the amygdala, but reduced GR expression in the hippocampus, and
unchanged expression in many other brain regions and tissues.
Intriguingly, the apparent congruence between the effects of prenatal and postna-
tal environmental manipulations upon the adult HPA axis appears to re¬‚ect distinct
underlying processes. Prenatal dexamethasone exposure permanently alters develop-
ing monoaminergic systems. Prenatal treatment decreases brain 5HT levels and
advances the expression of the neuronal 5HT transporter which functions as a
re-uptake site, removing 5HT from the synapse and thus attenuating its action,
including in the hippocampus (Slotkin et al., 1996a; Muneoka et al., 1997). In the
postnatal handling model, animals in the non-handled group have decreased hip-
pocampal 5HT turnover. It appears that distinct mechanisms operating at different
times of development can produce apparently similar permanent alterations in phe-
notype, in this case increased HPA axis activity.
The next crucial questions ask how discrete late prenatal/early postnatal events can
permanently alter gene expression. Intriguing recent data have explored this in terms
of chromatin. Some evidence is emerging for selective methylation/demethylation of
speci¬c promoters of the GR gene. Preliminary data suggest that the putative NGFI-
A site around exon 17 is subject to differential and permanent methylation/demethy-
lation in association with variations in maternal care (Weaver et al., 2002). Moreover,
GR itself appears under some circumstances to mediate differential demethylation of
target gene promoters, at least in liver-derived cells. The demethylation persists after
steroid withdrawal. During development, such target promoter demethylation
occurs before birth and may ¬ne-tune the promoter to ˜remember™ regulatory events
166 J. R. Seckl et al.


occurring during development (Thomassin et al., 2001). This provocative novel
mechanism of gene control by early life environmental events that persist throughout
the lifespan remains to be con¬rmed in other systems.

Glucocorticoid programming in humans?
From the above, it is clear that prenatal exposure to excess glucocorticoids reduces
birth weight in animal models and in humans. In animal models there are persist-
ing effects on blood pressure, glucose tolerance and the HPA axis. Here we assess
the possible relevance of such ¬ndings to human pathophysiology.
Glucocorticoid treatment during pregnancy reduces birth weight (French et al.,
1999; Bloom et al., 2001), but there is a worrying dearth of evidence addressing the
longer-term effects of prenatal glucocorticoid exposure. 11 -HSD-2 substrates such
as cortisol and prednisolone would be anticipated to have little effect; however, gluco-
corticoids such as dexamethasone are commonly exploited because of their effect on
the fetus. Substituted glucocorticoids such as dexamethasone and betamethasone,
which are poor substrates for 11 -HSD-2, are most commonly used to treat fetuses
at risk of preterm delivery, which may occur in up to 10% of pregnancies. There is no
doubt that such synthetic glucocorticoids enhance lung maturation and reduce mor-
tality in preterm infants (Crowley, 2000). Additionally, a single course of prenatal
corticosteroid is associated with a signi¬cant reduction in the incidence of intraven-
tricular haemorrhage and a trend towards less neurodevelopmental disability
(Crowley, 2000). However, a recent survey of British obstetric departments showed
that 98% were prescribing repeated courses of antenatal glucocorticoids
(Brocklehurst et al., 1999). Corticosteroid injections may be repeated four or more
times in threatened preterm labour between 24 and 34 weeks of gestation; however,
there is little evidence for the safety and ef¬cacy of such a regime (Whitelaw and
Thoresen, 2000). In addition, women at risk of bearing fetuses at risk of congenital
adrenal hyperplasia often receive low-dose dexamethasone from the ¬rst trimester to
suppress fetal adrenal androgen overproduction. Birth weight in such infants has
been reported as normal (Forest et al., 1993a; Mercado et al., 1995a); however, it must
be remembered that programming effects of antenatal glucocorticoids are seen in
animal models in the absence of any reduction in birth weight (Moss et al., 2001).
Recent overviews suggest that there is no evidence for additional bene¬t from
repeated courses of glucocorticoid therapy in pregnancy (Kay et al., 2000; Wal¬sch
et al., 2001), but that clear conclusions are prevented by the lack of prospective
randomized-controlled trials and by variations in protocols employed (type of
glucocorticoid, route and timing of administration, number of treatment courses).
There remains considerable concern that a view which approximates, ˜if some glu-
cocorticoid is good, then more is better™, is likely to be as erroneous for these steroids
in perinatal medicine as it is in other therapeutic arenas (Seckl and Miller, 1997).
167 Prenatal glucocorticoids and the programming of adult disease


Antenatal glucocorticoid administration has also been linked with higher blood
pressure in adolescence (Doyle et al., 2000), although this study is complicated by the
powerful effects of differential growth rates around puberty on blood pressure.A num-
ber of studies aimed at establishing the long-term neurological and developmental
effects of antenatal glucocorticoid exposure have been complicated by the fact that
most of the children studied were born before term and were therefore already at
risk of delayed neurological development. In a group of 6-year-old children, ante-
natal glucocorticoid exposure was associated with subtle effects on neurological
function, including reduced visual closure and visual memory (MacArthur et al.,
1982). Children exposed to dexamethasone, in early pregnancy because they were
at risk of congenital adrenal hyperplasia, and who were born at term, showed
increased emotionality, unsociability, avoidance and behavioural problems
(Trautman et al., 1995). These effects were seen in unaffected glucocorticoid-
exposed offspring. Furthermore, a recent study has shown that multiple doses of
antenatal glucocorticoids given to women at risk of preterm delivery were associ-
ated with reduced head circumference in the offspring (French et al., 1999). There
were also signi¬cant effects on behaviour; three or more courses of glucocorticoids
were associated with an increased risk of externalizing behaviour problems, dis-
tractibility and inattention (French et al., 1998).
As in other mammals, the human™s HPA axis appears to be programmed by the
early life environment. Higher plasma and urinary glucocorticoid levels are found
in children and adults who were of lower birth weight (Clark et al., 1996; Phillips
et al., 1998). This appears to occur in disparate populations (Phillips et al., 2000)
and may precede overt adult disease (Levitt et al., 2000), at least in a socially disad-
vantaged South African population. Additionally, adult HPA responses to ACTH
stimulation are exaggerated in those of low birth weight (Levitt et al., 2000; Reynolds
et al., 2001), re¬‚ecting the stress axis biology elucidated in animal models. The
HPA axis activation is associated with higher blood pressure, insulin resistance,
glucose intolerance and hyperlipidaemia (Reynolds et al., 2001). Finally, the
human GR gene promoter has multiple alternate untranslated ¬rst exons
(R. Reynolds and K. E. Chapman, unpublished observations), analogous to
those found in the rat and mouse. Whether these are the subjects of early life reg-
ulation and the molecular mechanisms by which this is achieved remain to be
determined.


Acknowledgements

Work in the authors™ laboratory is funded by grants from the Wellcome Trust, the
Scottish Hospitals Endowments Research Trust, the European Union and the British
Heart Foundation.
168 J. R. Seckl et al.


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