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Maternal protein restriction with or without folic acid supplementation during pregnancy alters the hepatic transcriptome in adult male rats

  • Karen A. Lillycrop (a1), Joanne Rodford (a2), Emma S. Garratt (a2), Joanne L. Slater-Jefferies (a2), Keith M. Godfrey (a3), Peter D. Gluckman (a4), Mark A. Hanson (a2) and Graham C. Burdge (a2)...


Feeding pregnant rats a protein-restricted (PR) diet induces altered expression of candidate genes in the liver of the adult offspring, which can be prevented by supplementation of the PR diet with folic acid (PRF). We investigated the effect of maternal nutrition during pregnancy on the liver transcriptome in their adult male offspring. Pregnant rats were fed control, PR or PRF diets. Male offspring were killed on day 84. The liver transcriptome was analysed by microarray (six livers per maternal dietary group) followed by post hoc analysis of relative mRNA levels and gene ontology. These results were confirmed for selected genes by real-time RT-PCR. There were 311 genes that differed significantly ( ≥ 1·5-fold change; P < 0·05) between PR offspring (222 increased) and control offspring, while 191 genes differed significantly between PRF offspring (forty-five increased) compared with offspring of control dams. There were sixteen genes that were significantly altered in both PR and PRF offspring compared with controls. Ion transport, developmental process, and response to reactive oxygen species (RROS) and steroid hormone response (SHR) ontologies were altered in PR offspring. Folic acid supplementation prevented changes within RROS and SHR response pathways, but not in ion transport or developmental process. There was no effect of maternal PR on mRNA expression of imprinted genes. Insulin 1 and Pleckstrin homology-like domain family A member 2 were increased significantly in PRF compared with PR offspring. The present findings show that the pattern of induced changes in the adult liver transcriptome were dependent on maternal protein and folic acid intakes during pregnancy.

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Corresponding author

*Corresponding author: Dr K. A. Lillycrop, fax +44 2380 594459, email


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1 Bateson, P, Barker, D, Clutton-Brock, T, et al. (2004) Developmental plasticity and human health. Nature 430, 419421.
2 Godfrey, KM & Barker, DJ (2001) Fetal programming and adult health. Public Health Nutr 4, 611624.
3 Bertram, CE & Hanson, MA (2001) Animal models and programming of the metabolic syndrome. Br Med Bull 60, 103121.
4 Armitage, JA, Taylor, PD & Poston, L (2005) Experimental models of developmental programming: consequences of exposure to an energy rich diet during development. J Physiol 565, 38.
5 Burdge, GC, Hanson, MA, Slater-Jefferies, JL, et al. (2007) Epigenetic regulation of transcription: a mechanism for inducing variations in phenotype (fetal programming) by differences in nutrition during early life? Br J Nutr 97, 10361046.
6 Bertram, C, Trowern, AR, Copin, N, et al. (2001) The maternal diet during pregnancy programs altered expression of the glucocorticoid receptor and type 2 11β-hydroxysteroid dehydrogenase: potential molecular mechanisms underlying the programming of hypertension in utero. Endocrinology 142, 28412853.
7 Lillycrop, KA, Phillips, ES, Jackson, AA, et al. (2005) Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J Nutr 135, 13821386.
8 Lillycrop, KA, Slater-Jefferies, JL, Hanson, MA, et al. (2007) Induction of altered epigenetic regulation of the hepatic glucocorticoid receptor in the offspring of rats fed a protein-restricted diet during pregnancy suggests that reduced DNA methyltransferase-1 expression is involved in impaired DNA methylation and changes in histone modifications. Br J Nutr 97, 10641073.
9 Burdge, GC, Slater-Jefferies, J, Torrens, C, et al. (2007) Dietary protein restriction of pregnant rats in the F0 generation induces altered methylation of hepatic gene promoters in the adult male offspring in the F1 and F2 generations. Br J Nutr 97, 435439.
10 Burns, SP, Desai, M, Cohen, RD, et al. (1997) Gluconeogenesis, glucose handling, and structural changes in livers of the adult offspring of rats partially deprived of protein during pregnancy and lactation. J Clin Invest 100, 17681774.
11 Gluckman, PD, Lillycrop, KA, Vickers, MH, et al. (2007) Metabolic plasticity during mammalian development is directionally dependent on early nutritional status. Proc Natl Acad Sci U S A 104, 1279612800.
12 Gluckman, PD & Hanson, MA (2004) Living with the past: evolution, development, and patterns of disease. Science 305, 17331736.
13 Bogdarina, I, Murphy, HC, Burns, SP, et al. (2004) Investigation of the role of epigenetic modification of the rat glucokinase gene in fetal programming. Life Sci 74, 14071415.
14 Bogdarina, I, Welham, S, King, PJ, et al. (2007) Epigenetic modification of the renin–angiotensin system in the fetal programming of hypertension. Circ Res 100, 520526.
15 Maloney, CA, Gosby, AK, Phuyal, JL, et al. (2003) Site-specific changes in the expression of fat-partitioning genes in weanling rats exposed to a low-protein diet in utero. Obes Res 11, 461468.
16 Lillycrop, KA, Phillips, ES, Torrens, C, et al. (2008) Feeding pregnant rats a protein-restricted diet persistently alters the methylation of specific cytosines in the hepatic PPARα promoter of the offspring. Br J Nutr 100, 278282.
17 Burdge, GC, Lillycrop, KA, Jackson, AA, et al. (2008) The nature of the growth pattern and of the metabolic response to fasting in the rat are dependent upon the dietary protein and folic acid intakes of their pregnant dams and post-weaning fat consumption. Br J Nutr 99, 540549.
18 Ashburner, M, Ball, CA, Blake, JA, et al. (2000) Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 25, 2529.
19 Gheorghe, CP, Goyal, R, Holweger, JD, et al. (2009) Placental gene expression responses to maternal protein restriction in the mouse. Placenta 30, 411417.
20 Lucas, A, Baker, BA, Desai, M, et al. (1996) Nutrition in pregnant or lactating rats programs lipid metabolism in the offspring. Br J Nutr 76, 605612.
21 Bellinger, L, Lilley, C & Langley-Evans, SC (2004) Prenatal exposure to a maternal low-protein diet programmes a preference for high-fat foods in the young adult rat. Br J Nutr 92, 513520.
22 Bellinger, L, Sculley, DV & Langley-Evans, SC (2006) Exposure to undernutrition in fetal life determines fat distribution, locomotor activity and food intake in ageing rats. Int J Obes (Lond) 30, 729738.
23 Torrens, C, Brawley, L, Anthony, FW, et al. (2006) Folate supplementation during pregnancy improves offspring cardiovascular dysfunction induced by protein restriction. Hypertension 47, 982987.
24 Calder, PC & Yaqoob, P (2000) The level of protein and type of fat in the diet of pregnant rats both affect lymphocyte function in the offspring. Nutr Res 20, 9951005.
25 Langley-Evans, SC & Sculley, DV (2005) Programming of hepatic antioxidant capacity and oxidative injury in the ageing rat. Mech Ageing Dev 126, 804812.
26 Fernandez-Twinn, DS, Ekizoglou, S, Gusterson, BA, et al. (2007) Compensatory mammary growth following protein restriction during pregnancy and lactation increases early-onset mammary tumor incidence in rats. Carcinogenesis 28, 545552.
27 McGrath, M, Lepine, J, Lee, IM, et al. (2009) Genetic variations in UGT1A1 and UGT2B7 and endometrial cancer risk. Pharmacogenet Genomics 19, 239243.
28 Mitra, PS, Basu, NK & Owens, IS (2009) Src supports UDP-glucuronosyltransferase-2B7 detoxification of catechol estrogens associated with breast cancer. Biochem Biophys Res Commun 382, 651656.
29 Cecchin, E, Innocenti, F, D'Andrea, M, et al. (2009) Predictive role of the UGT1A1, UGT1A7, and UGT1A9 genetic variants and their haplotypes on the outcome of metastatic colorectal cancer patients treated with fluorouracil, leucovorin, and irinotecan. J Clin Oncol 27, 24572465.
30 Henry, SC, Daniell, XG, Burroughs, AR, et al. (2009) Balance of Irgm protein activities determines IFN-γ-induced host defense. J Leukoc Biol 85, 877885.
31 Calder, PC (2009) Early life programming of immune and lung function: can we now exclude a role of arachidonic acid exposure? Br J Nutr 102, 331333.
32 Zhao, H & Firestein, S (1999) Vertebrate odorant receptors. Cell Mol Life Sci 56, 647659.
33 Pluznick, JL, Zou, DJ, Zhang, X, et al. (2009) Functional expression of the olfactory signaling system in the kidney. Proc Natl Acad Sci U S A 106, 20592064.
34 Jackson, AA, Dunn, RL, Marchand, MC, et al. (2002) Increased systolic blood pressure in rats induced by a maternal low-protein diet is reversed by dietary supplementation with glycine. Clin Sci (Lond) 103, 633639.
35 Burdge, GC, Lillycrop, KA, Phillips, ES, et al. (2009) Folic acid supplementation during the juvenile-pubertal period in rats modifies the phenotype and epigenotype induced by prenatal nutrition. J Nutr 139, 10541060.
36 Jansson, T & Powell, TL (2000) Placental nutrient transfer and fetal growth. Nutrition 16, 500502.
37 Kwong, WY, Wild, AE, Roberts, P, et al. (2000) Maternal undernutrition during the preimplantation period of rat development causes blastocyst abnormalities and programming of postnatal hypertension. Development 127, 41954202.
38 Langley-Evans, SC, Phillips, GJ, Benediktsson, R, et al. (1996) Protein intake in pregnancy, placental glucocorticoid metabolism and the programming of hypertension in the rat. Placenta 17, 169172.
39 Temple, IK (2007) Imprinting in human disease with special reference to transient neonatal diabetes and Beckwith–Wiedemann syndrome. Endocr Dev 12, 113123.
40 Amor, DJ & Halliday, J (2008) A review of known imprinting syndromes and their association with assisted reproduction technologies. Hum Reprod 23, 28262834.
41 Guo, L, Choufani, S, Ferreira, J, et al. (2008) Altered gene expression and methylation of the human chromosome 11 imprinted region in small for gestational age (SGA) placentae. Dev Biol 320, 7991.
42 Sinclair, KD, Young, LE, Wilmut, I, et al. (2000) In-utero overgrowth in ruminants following embryo culture: lessons from mice and a warning to men. Hum Reprod 15, Suppl. 5, 6886.
43 Shao, WJ, Tao, LY, Gao, C, et al. (2008) Alterations in methylation and expression levels of imprinted genes H19 and Igf2 in the fetuses of diabetic mice. Comp Med 58, 341346.
44 Charalambous, M, da Rocha, ST & Ferguson-Smith, AC (2007) Genomic imprinting, growth control and the allocation of nutritional resources: consequences for postnatal life. Curr Opin Endocrinol Diabetes Obes 14, 312.
45 Gluckman, PD & Hanson, MA (2006) The consequences of being born small – an adaptive perspective. Horm Res 65, Suppl. 3, 514.
46 Ingrosso, D, Cimmino, A, Perna, AF, et al. (2003) Folate treatment and unbalanced methylation and changes of allelic expression induced by hyperhomocysteinaemia in patients with uraemia. Lancet 361, 16931699.


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