S60 Oral Submitted Presentations

Conclusions: We speculate that involvement of GSTM1 in

detoxification of paracetamol in pregnancy may result in depletion

of glutathione, leading to increased susceptibility of the fetal lung

to damage from other oxidants.

3B-4 Essential nutrient supplementation preventing adult

metabolic disease in a transgenerational model of

IUGR is accompanied by epigenetic regulation of

gene expression

K.M. Aagaard-Tillery1,2 *, Q. Fu2, R. McKnight2, W. Holland3,

R.H. Lane2. 1Division of Maternal-Fetal Medicine, Department of

Obstetrics & Gynecology, Baylor College of Medicine, Houston, TX,

and Departments of 2Pediatrics & 3Biochemistry and Molecular

Biology, University of Utah, Salt Lake City, UT, USA

Aims: We have shown that development of the adult metabolic

phenotype in response to a constrained in utero environment

is associated with altered fetal one-carbon metabolism, and

supplementation with essential nutrients along this pathway

(ENS) prevents adult obesity and hepatic insulin resistance in

our heritable transgenerational model of IUGR. We sought to

characterize the effect of ENS on the epigenetic regulation of

reprogrammed fetal gene expression.

Study design: Sprague-Dawley P1 dams underwent bilateral uterine

artery ligation (e19) or sham surgery; resultant F1 litters yielded

IUGR or sham lineages. Weaned F1 were allocated to ENS

(Teklad8640 + folic acid / choline / B12 / betaine / methionine /

arginine/zinc) or control diet (Teklad8640). F1 pairs were mated

by d80, and resultant F2 (n 512) were weaned to their parental

diet.

Subjects: Offspring of IUGR and sham lineages under control and

ENS diet allocation.

Outcome Measures: Expression, differential exon usage, and CpG

methylation of fetal gene(s) integral to the regulation of peripheral

Fig. 1. ENS Supplementation prevents heritable adult metabolic

disease.

metabolism and known to be reprogrammed under an altered

in utero environment.

Results: In our model, significant phenotypic differences in

F2 offspring of IUGR lineages (maternal and/or paternal) are

accompanied by significantly altered expression of Npas2, IGF-1

and DUSP5, an effect which is abrogated into adult life with ENS

(Figure 1). Abrogation of decreased IGF1 mRNA is accompanied

by ENS-mediated prevention of P2 hypermethylation (37.4±1.9%

meCpG vs 17.6±2%, p < 0.05).

Conclusions: Diet supplemented with essential nutrients, yet

unaltered in its caloric content, prevents adult obesity and insulin

resistance in a heritable transgenerational model of IUGR. This is

accompanied by significant alterations in the epigenetic regulation

and expression of reprogrammed metabolic genes.

3B-5 Statin treatment corrects endothelial dysfunction but not

markers of inflammation in offspring of protein restricted

dams

C. Torrens1 *, F.W. Anthony1, C.J. Kelsall1, N. Curzen2,

M.A. Hanson1. 1Centre for Developmental Origins of Health &

Disease and 2Wessex Cardiothoracic Unit, School of Medicine,

University of Southampton, Tremona Road, Southampton

SO16 6YD, UK

E-mail: c.torrens@soton.ac.uk

Aims: In the rat, dietary protein restriction during pregnancy

results in raised blood pressure and endothelial dysfunction in

the offspring (Torrens et al., 2006. Hypertension 47, 982 987).

Statins have actions beyond their lipid lowering effects (Davignon,

2004. Circulation 109: III39 43) so we tested the effect of statin

treatment in our model of endothelial dysfunction.

Study design and Subjects: Wistar rats were fed a control (C;

18% casein) or protein restricted (PR; 9% casein) diet throughout

pregnancy and returned to standard chow postpartum. At weaning a

subset of the PR group were given atorvastatin (PRS, 10 mg/kg/day)

in the drinking water. At 145 days of age male offspring were

sacrificed by CO2 inhalation.

Outcome measures: Blood was analysed for markers of inflam-

mation and responses to phenylephrine (PE), acetylcholine (ACh)

and sodium nitroprusside (SNP) were measured in small mesenteric

arteries mounted in a wire myograph. Differences were assessed

by one-way ANOVA. Significance was accepted at p < 0.05.

Results: Constriction to PE and endothelial-independent vasodi-

latation to SNP was similar in all groups. Responses to ACh

were blunted in the PR group compared to controls ( p < 0.05)

but were similar in the C and PRS groups. Analysis of plasma

showed similarly increased levels of the inflammatory markers b2-

microglobin and lipocalin-2 in both PR and PRS groups compared to

control ( p < 0.05).

Conclusions This data suggests that chronic atorvastatin therapy

may restore endothelial function in this model, independently of

an effect on cholesterol or inflammation.

This work was supported by the British Heart Foundation & Pfizer

3B-6 Statin therapy improves blood pressure and lipid

profiles in hypercholesterolemic mothers but not

C-reactive proteins levels or endothelial progenitor cell

expression

M. Elahi1 *, D. Mukhtar1, N. Kahraman2, F. Cagampang1, S. Ohri3,

M. Hanson1. 1Institute of Developmental Sciences, Developmental

Origins of Health & Disease Division, Mailpoint 887, Southampton,

SO16 6YD UK, 2Department of Pathology, BUPA Hospital,

Southampton, SO16 6UY, UK, 3Wessex Cardiac Centre, General

Hospital, Southampton, SO16 0YD, UK

E-mail: me1@soton.ac.uk

Aims: Cardiovascular (CV) disease is linked with inflammation

and inversely correlated with circulating endothelial progenitor

cells (EPCs). We have previously shown that statin therapy during

pregnancy and lactation in high fat (HF) fed mice alleviates the

risk of CV dysfunction in their offspring. Here, we examined the